Consumer medicine information

Zyban SR

Bupropion hydrochloride

BRAND INFORMATION

Brand name

Zyban SR

Active ingredient

Bupropion hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zyban SR.

What is in this leaflet

This leaflet answers some common questions about Zyban SR tablets. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Zyban SR against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Zyban SR is used for

Zyban SR tablets contain bupropion hydrochloride as the active ingredient. (This active ingredient is also known as amfebutamone hydrochloride).

It is a medicine prescribed by your doctor as a short-term treatment to help you stop smoking, with appropriate counselling. For many patients, it reduces withdrawal symptoms and the urge to smoke. The exact mechanism of action is not fully understood, but it is believed that it interacts with chemicals in the brain to decrease cravings.

Ask your doctor if you have any questions about why Zyban SR tablets have been prescribed for you. Your doctor may have prescribed this medicine for another reason.

Zyban SR tablets are not addictive.

Use in children

This medicine is not recommended for use in children less than 18 years because it has not been adequately studied in these patients.

Before you take it

You should be fully committed to quitting smoking before you start to take Zyban SR tablets.

Tell your family, friends and work colleagues that you are trying to quit smoking so that they can offer you support and encouragement. You are more likely to quit smoking if you have suitable support.

Do not take Zyban SR tablets if:

  • you have ever had an allergic reaction to bupropion or any of the tablet ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following: wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash ("hives") or fainting.
  • you have or ever had a condition that causes fits or seizures, such as epilepsy
  • you are usually a heavy drinker and you have just stopped drinking alcohol or you plan to do so while taking Zyban SR
  • you have recently stopped taking tranquillizers (benzodiazepines) or you plan to do so while taking Zyban SR
  • you have a brain or spine tumour
  • you are taking any other medicines which contain bupropion
  • you have or have had an eating disorder (e.g. bulimia or anorexia nervosa)
  • you are taking medicines called monoamine oxidase inhibitors (MAOIs) or have taken them in the last 14 days
  • you are pregnant, trying to become pregnant or breastfeeding, unless your doctor says you should.
    Your doctor will discuss the risks and benefits of taking Zyban SR tablets if you are pregnant, planning a pregnancy or breastfeeding. Some studies have reported an increase in the risk of birth defects, particularly heart defects, in babies whose mothers were taking this medicine. It is not known if these are due to the use of Zyban SR.
  • the tablets have passed the expiry date (EXP) printed on the pack.
  • the packaging is torn or shows signs of tampering.

Talk to your doctor if you are not sure whether you should be taking Zyban SR tablets.

Before you start to take it

Your doctor needs to know certain information before you start taking this medicine. This is because some conditions make it more likely that you will have side effects. If any of these conditions applies to you, your doctor will monitor you more closely while you are taking Zyban SR tablets or recommend another treatment.

Tell your doctor if you have or have had any of these medical conditions.

  • Recent history of heart problems or unstable heart disease
  • Risk of seizures
    This medicine has been shown to cause fits (seizures) in some people. Fits are more likely, while taking Zyban SR, if you:
    - regularly drink a lot of alcohol
    - regularly take sedatives
    - have diabetes for which you use insulin or tablets
    - take stimulants or other medicines to control your appetite or weight
    - have a history of fits
    - have had a serious head injury
    - take medicines that are known to increase the chance of having a fit.
    If you have a fit during treatment, stop taking Zyban SR. See your doctor for advice.
  • Hypersensitivity reactions
    Stop taking this medicine and immediately contact your doctor if you experience an allergic reaction during treatment.
    Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following: wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash ("hives") or fainting.
    Some allergic reactions can last for quite a long time after exposure to an allergy-causing substance has finished.
  • Liver disorders, kidney disorders, elderly patients
    You may have more risk of side effects if you have kidney or liver problems, or are elderly.
    You may need to take a lower dosage and be checked more closely while you are taking Zyban SR tablets.
    Your doctor will advise you.
  • If you feel depressed or suicidal
    Some people become depressed when they try to stop smoking; very occasionally, they may think about committing suicide, or try to do so. These symptoms have also affected people taking Zyban SR for smoking cessation.
    If you feel depressed or think about suicide, get medical advice as soon as possible.
  • If you have had any mental health problems
    Some people taking Zyban SR have had hallucinations or delusions, disordered thoughts or extreme mood swings. These effects are more likely in people who have had mental health problems before, such as bipolar disorder.

Taking other medicines

Tell your doctor if you are allergic to foods, dyes, preservatives or any other medicines.

Tell your doctor if you are taking any other medicines including medicines you buy without a prescription from a pharmacy, supermarket or health food shop. It is important not to take medicines (e.g. antidepressants, antipsychotics, sedating antihistamines) that may increase the chance of you having a fit or seizure.

Speak with your doctor about other medicines you are taking.

Some medicines and substances that may interact with Zyban SR tablets include:

  • nicotine skin patches or nicotine gum.
    Using this medicine and nicotine replacement therapy (i.e. nicotine patches or nicotine gum) together may raise your blood pressure. Your doctor may want to check your blood pressure regularly to make sure that it stays within acceptable levels.
  • some medicines used to treat heart conditions and high blood pressure, depression or other mental health problems (such as desipramine or selective serotonin reuptake inhibitors (SSRIS)), cancer, epilepsy, Parkinson's disease, some muscle relaxants; medicines used to prevent stoke; some medicines to treat HIV infection (e.g. ritonavir, efavirenz)
  • alcohol.
    Some people find they are more sensitive to alcohol while taking this medicine. Your doctor may suggest that you don’t drink alcohol while you are taking Zyban SR tablets, or that you drink as little as possible.
  • a herbal preparation called St. John's Wort.

Tell your doctor or pharmacist if you are taking any of these.

How to take it

Your doctor will tell you how many Zyban SR tablets to take and how often to take them. You will also find this information on the label of your medicine.

If you find your sleep disturbed, try not to take this medicine too close to bedtime. If you take two tablets daily, take one early in the morning and one late in the afternoon.

Leave 8 hours between tablets.

How much to take

Do not take more tablets than your doctor has prescribed.

Do not take more than 1 tablet at a time and do not take more than 2 tablets in any one day. This is important so you do not increase your chance of having significant side effects.

Typically, the first prescription will be for 30 tablets which is slightly more than 2 weeks supply. Treatment will start while you are still smoking with a ‘target stop date’ set within the first two weeks. A larger pack size of 90 tablets is then usually prescribed for the rest of the treatment. This represents slightly more than 6 weeks supply.

The usual initial recommended dose is one 150 mg tablet each day for the first 3 days, increasing to one tablet twice daily. Doses should be taken at least 8 hours apart.

Take your medicine as recommended by your doctor.

If you have a liver disorder, your doctor will advise you on how many tablets to take as the dosage frequency will be reduced.

How long to take it

To be effective, it takes about one week for the medicine in Zyban SR tablets to reach the right levels in your body.

In order to maximise your chance of stopping, you should not stop smoking until you have been taking Zyban SR for 1 week. You should set a date to stop smoking during the second week.

The usual course of treatment is for at least 7 weeks.

Your doctor will advise you.

Zyban SR and nicotine replacement therapy (i.e. nicotine patches or nicotine gum) should only be used together under the supervision of your doctor.

How to take it

This medicine is intended for oral use only.

Do not chew, divide or crush Zyban SR tablets.

It is important to swallow it whole and not inhale any crushed tablets or inject any dissolved tablets.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Do not take a double dose to make up for the dose that you missed.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 131126) for advice, if you think you or anyone else may have taken too many Zyban SR tablets, even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking it

Things you must do

Tell your doctor or pharmacist that you are taking Zyban SR tablets if you are about to be started on any new medicines.

Tell your doctor if you become pregnant or are trying to become pregnant.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Minimise or avoid drinking alcohol when you are on Zyban SR treatment.

If you require a laboratory test, tell your doctor or hospital that you are taking Zyban SR. This medicine may interfere with some laboratory tests to detect certain drugs.

Things you must not do

Do not stop taking Zyban SR tablets or change the dose without first checking with your doctor.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use Zyban SR tablets to treat any other complaints unless your doctor says to.

Things to be careful of

Minimise or avoid drinking alcohol when you are on Zyban SR treatment. If you drink a lot of alcohol or suddenly stop, you may increase your chance of having a seizure. If you are taking sedatives (e.g. benzodiazepines) and stop these abruptly, this can also increase the chance of a seizure. Therefore, it is important to discuss your use of alcohol and medicines with your doctor before you begin taking Zyban SR.

Be careful driving or operating machinery until you know how Zyban SR tablets affect you. As with many other medicines, Zyban SR tablets may cause dizziness or drowsiness in some people.

Side effects

Check with your doctor as soon as possible if you have any problems while taking Zyban SR tablets, even if you do not think the problems are connected with the medicine or are not listed in this leaflet. Like other medicines, Zyban SR tablets can cause some side effects. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

The most commonly reported side effects are:

  • headache
  • difficulty sleeping
  • dry mouth
  • feeling sick (nausea), being sick (vomiting).

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • fever
  • weakness or lack of energy
  • dizziness
  • irritability, agitation
  • anxiety
  • tremor or shakiness
  • difficulty in concentrating
  • changes in mood
  • loss of appetite, anorexia
  • stomach pain, constipation
  • impaired vision
  • taste disorders
  • rash, itchy skin or lesions (particularly on sun-exposed areas)
  • sweating.

An increase in blood pressure may be recorded which in some cases can be severe. Your doctor will monitor this and advise you.

Tell your doctor immediately or go to the casualty department at your nearest hospital if you think you are having an allergic reaction to Zyban SR tablets.

Symptoms can include some or all of the following:

  • wheezing
  • swelling of the lips/mouth/eyelids
  • difficulty in breathing
  • hay fever
  • lumpy rash ("hives")
  • fainting.

Fits (seizures)
Symptoms of a fit include convulsions and usually loss of consciousness. Someone who has had a fit may be confused afterwards and may not remember what has happened.

Fits are more likely if you take too many Zyban SR tablets, if you take some other medicines as well as Zyban SR, or if you are at a higher than usual risk of fits (see the ‘Risk of seizures’ section of this leaflet).

You can reduce the chance of experiencing a seizure by giving your doctor the information they need and following carefully your doctor's directions on how to take Zyban SR.

If you have a fit, tell your doctor when you have recovered. Do not take any more Zyban SR tablets.

Effects of stopping smoking

People giving up smoking are often affected by nicotine withdrawal. Similar effects have also been reported in Zyban SR users undergoing a smoking cessation attempt. These may include:

  • difficulty sleeping, tremor or sweating
  • agitation or feelings of depression (sometimes with thoughts of suicide).

If you feel any worrisome changes of mood, talk to your doctor immediately.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed in this leaflet may also occur in some patients.

After taking it

Storage

Keep this medicine in a cool, dry place where it stays below 25°C.

Do not store it, or any other medicine, in a bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep this medicine where young children cannot reach it. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Zyban SR tablets or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets left over.

Product description

What it looks like

Zyban SR tablets are white, film-coated biconvex round tablets coded 'GX CH7' in black ink on one side.

Available in foil blisters in pack sizes of 30 and 90 tablets.

Ingredients

Active ingredient:
Zyban SR tablets contain 150 mg of the active ingredient bupropion hydrochloride.

Inactive ingredients:

  • microcrystalline cellulose
  • hypromellose
  • cysteine hydrochloride
  • magnesium stearate
  • carnauba wax
  • opadry aqueous film coating YS-1-18202-A white
  • opadry OY-7300 white
  • opacode WB monogramming ink NS-78-17821 black.

Zyban SR tablets do not contain glucose, lactose, tartrazine or any other azo dyes.

Sponsor

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Australia

Australian registration number:
AUST R 75233.

This leaflet was revised in July 2021.

Published by MIMS September 2021

BRAND INFORMATION

Brand name

Zyban SR

Active ingredient

Bupropion hydrochloride

Schedule

S4

 

1 Name of Medicine

Bupropion hydrochloride.

2 Qualitative and Quantitative Composition

Zyban SR sustained release tablets contain bupropion hydrochloride 150 mg as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Biconvex, round, white, film-coated sustained release tablets, one side printed GX CH7 with black ink and the other side plain.

4 Clinical Particulars

4.1 Therapeutic Indications

Zyban SR tablets are indicated as a short-term adjunctive therapy for the treatment of nicotine dependence in those who are committed to quitting smoking, when used in conjunction with counselling for smoking cessation/abstinence.

4.2 Dose and Method of Administration

Zyban SR tablets should be swallowed whole and not crushed or chewed as this may lead to an increased risk of adverse effects including seizures.

Use in 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 SR, preferably in the second week.
The initial dose is 150 mg to be taken daily for three days, increasing to 150 mg twice daily. There should be an interval of at least 8 hours between successive doses.
The maximum single dose must not exceed 150 mg and the maximum total daily dose must not exceed 300 mg.
Insomnia is a very common adverse event which is often transient. Insomnia may be reduced by avoiding bedtime doses (provided there is at least 8 hours between doses). If clinically indicated, dose reduction may be considered (see Section 5.1, Clinical trials).
Patients should be treated for at least 7 weeks.
Discontinuation should be considered if the patient has not made significant progress towards abstinence by the seventh week of therapy, since it is unlikely that they will stop smoking during that attempt.

Individualisation of therapy.

Patients are more likely to quit smoking and remain abstinent if they receive counselling. When prescribing Zyban SR, physicians should review the patient's overall smoking cessation program. It is important to provide brief but effective counselling to patients at each clinic visit, including asking patients about their smoking status at each visit, advising patients to stop smoking, and arranging a follow-up visit.
Patients should be encouraged to identify and avoid smoking trigger factors and advised to inform family, friends and coworkers of their decision to quit so that appropriate support can be provided.

Combination treatment with Zyban SR and a nicotine transdermal system.

The recommended posology does not require modification if Zyban SR is used in combination with nicotine transdermal systems for nicotine dependence (see Section 4.4 Special Warnings and Precautions for Use).

Use in children and adolescents.

The safety and efficacy of Zyban SR tablets in patients under 18 years of age have not been established.

Use in patients with liver impairment.

Zyban SR should be used with caution in patients with liver impairment.
Because of increased variability in the pharmacokinetics in patients with mild to moderate hepatic cirrhosis, a reduced frequency of dosing should be considered (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).
Zyban SR should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 150 mg on alternate days in these patients (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Zyban SR is contraindicated:
in patients with hypersensitivity to bupropion or any of the other components of the preparation;
in patients with a current seizure disorder or any history of seizures;
in patients with a known central nervous system (CNS) tumour;
in patients undergoing abrupt withdrawal from alcohol or benzodiazepines;
in patients currently being treated with any other preparation containing bupropion as the incidence of seizures is dose dependent;
in patients with a current or previous diagnosis of bulimia or anorexia nervosa;
with concomitant use of Zyban SR tablets and monoamine oxidase inhibitors (MAOIs). At least 14 days should elapse between discontinuation of MAOIs and initiation of treatment with Zyban SR tablets.

4.4 Special Warnings and Precautions for Use

Risk of seizures.

Bupropion is associated with a dose related risk of seizures, therefore the recommended dose of Zyban SR must not be exceeded. The incidence of seizure at doses of sustained release bupropion tablets up to 300 mg/day is approximately 0.1% (1/1,000).
There is an increased risk of seizures occurring with the use of Zyban SR in the presence of predisposing risk factors which lower the seizure threshold. Zyban SR 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.
All patients should be assessed for predisposing risk factors, which include:
concomitant administration of other medicinal products known to lower the seizure threshold, for example: antipsychotics, antidepressants (including SSRIs and tricyclic antidepressants), antimalarials, tramadol, theophylline, systemic steroids, quinolones, sedating antihistamines;
excessive use of alcohol or sedatives (see Section 4.3 Contraindications);
history of head trauma;
diabetes treated with hypoglycaemics or insulin;
use of stimulants or anorectic products.
Zyban SR should be discontinued and not recommenced in patients who experience a seizure while on treatment.

Hypersensitivity reactions.

Zyban SR should be discontinued promptly if patients experience hypersensitivity reactions during treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Clinicians should be aware that symptoms may persist beyond the discontinuation of bupropion, and clinical management should be provided accordingly.

Neuropsychiatric symptoms.

The pharmacology of bupropion resembles that of some antidepressants. Neuropsychiatric symptoms have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). In particular, psychotic and manic symptomatology has been observed, mainly in patients with a history of psychiatric illness. Additionally, Zyban SR may precipitate a manic episode in patients with bipolar disorder.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in patients undergoing a smoking cessation attempt. These symptoms have also been reported during Zyban SR treatment, and generally occurred during the early stages of treatment.
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 symptoms or suicidal ideation in patients being treated with bupropion, and should advise and monitor patients accordingly.

Cardiovascular disease.

In clinical practice, hypertension, which in some cases may be severe 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. Consideration should be given to discontinuation of Zyban SR 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 bupropion hydrochloride tablets 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.
There is limited clinical experience establishing the safety of bupropion hydrochloride in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups.

Inappropriate routes of administration.

Bupropion 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 intranasally or by parenteral injection.

Angle-closure glaucoma.

Zyban SR may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle closure glaucoma, especially in pre-disposed patients. Zyban SR should therefore be used with caution in patients with raised intraocular pressure and in those at risk of angle-closure glaucoma.

Serotonin syndrome.

Serotonin syndrome has been reported when bupropion is co-administered with drugs known to be associated with serotonin syndrome, including selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Serotonin syndrome has also been reported with overdosage (see Section 4.9 Overdose).

Use in 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 SR should be used with caution in patients with hepatic impairment and reduced frequency of dosing should be considered in patients with mild to moderate hepatic cirrhosis (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Zyban SR should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced frequency of dosing is required, as peak bupropion levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
All patients with hepatic impairment should be closely monitored for possible adverse effects (e.g. insomnia, dry mouth, seizures) that could indicate high drug or metabolite levels.

Use in renal impairment.

The active metabolites of bupropion are further metabolised and excreted by the kidneys. Therefore treatment of patients with renal impairment should be initiated at reduced frequency and/or dose, as bupropion and its metabolites may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible adverse effects (e.g. insomnia, dry mouth, seizures) that could indicate high drug or metabolite levels.

Use in the 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; hence a reduced frequency and/or dose may be required.

Paediatric use.

Please see Section 4.2 Dose and Method of Administration, Use in children and adolescents.

Effects on laboratory tests.

Bupropion has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false positive results, particularly for amphetamines. A more specific alternative chemical method should be considered to confirm a positive result.

4.5 Interactions with Other Medicines and Other Forms of Interactions

It is important to be aware of all medicines which patients are taking when considering their suitability for Zyban SR treatment. Zyban SR may interact with a number of medicines by lowering the seizure threshold (see Section 4.4 Special Warnings and Precautions for Use) or through other mechanisms.
In patients receiving medicinal products known to lower the seizure threshold, Zyban SR must only be used if there is a compelling clinical justification for which potential medical benefit of smoking cessation outweighs the potential increased risk of seizure (see Section 4.4 Special Warnings and Precautions for Use).
Physiological changes resulting from smoking cessation itself, with or without treatment with Zyban SR, may alter the pharmacokinetics of some medications taken concomitantly.
In vitro findings indicate that bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 IIB6 (CYP2B6) (see Section 5.2 Pharmacokinetic Properties). Care should therefore be exercised when Zyban SR is coadministered with drugs known to affect the CYP2B6 isoenzyme (e.g. orphenadrine, cyclophosphamide, ifosfamide, ticlopidine, clopidogrel).
Although bupropion is not metabolised by the CYP2D6 isoenzyme, in vitro human P450 studies have shown that bupropion and hydroxybupropion are inhibitors of the CYP2D6 pathway. In a human pharmacokinetic study, administration of bupropion hydrochloride increased plasma levels of desipramine. This effect was present for at least 7 days after the last dose of bupropion hydrochloride. Concomitant use of Zyban SR with other drugs metabolised by the CYP2D6 isoenzyme has not been formally studied. Therefore, concomitant therapy with drugs predominantly metabolised by this isoenzyme (such as certain beta-blockers (e.g. metoprolol), antiarrhythmics (e.g. flecainide), SSRIs, TCAs, antipsychotics) should be initiated at the lower end of the dose range of the concomitant medication. If Zyban SR is added to the treatment regimen of a patient already receiving a medication metabolised by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index (see Section 5.2 Pharmacokinetic Properties).
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 is not primarily metabolised by CYP2D6, in one study, bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion.
Since bupropion is extensively metabolised, the coadministration of drugs known to induce metabolism (e.g. carbamazepine, phenobarbital, phenytoin, ritonavir, efavirenz) or inhibit metabolism (e.g. valproate) may affect its clinical activity.
In two studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20-80%. In another healthy volunteer study, ritonavir 100 mg plus lopinavir 400 mg (Kaletra) twice daily decreased bupropion exposure by at least as much as 600 mg twice daily ritonavir alone. Similarly, efavirenz 600 mg once daily for two weeks reduced the exposure of bupropion by approximately 55%. This effect of ritonavir/Kaletra and efavirenz is thought to be due to the induction of metabolism of bupropion and its metabolites. 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.
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 hydrochloride treatment. The consumption of alcohol during bupropion hydrochloride treatment should be minimised or avoided.
Post-marketing data show a possible pharmacodynamics interaction between bupropion and SSRIs and SNRIs resulting in an increased risk of serotonin syndrome (see Section 4.4 Special Warnings and Precautions for Use, Serotonin syndrome).
Limited clinical data suggest a higher incidence of neuropsychiatric adverse events in patients receiving bupropion concurrently with either levodopa or amantadine. Administration of Zyban SR to patients receiving either levodopa or amantadine concurrently should be undertaken with caution.
Although there is no clear evidence, it is possible that an interaction may occur between bupropion and the herbal remedy St. John's wort (Hypericum perforatum), which may result in an increase in undesirable effects.
Coadministration of digoxin with bupropion may decrease digoxin levels.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effect of bupropion on human fertility. A reproductive study in rats at oral doses up to 300 mg/kg/day revealed no evidence of impaired fertility.
(Category B2)
Pregnant women should be encouraged to quit smoking without the use of pharmacotherapy.
Some 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. These findings are not consistent across studies. The prescribing physician will need to weigh the option of alternative treatments in women who are pregnant or are planning to become pregnant, and should only prescribe bupropion if the expected benefits are greater than the potential risks.
The prospectively observed proportion of cardiac birth defects in pregnancies with prenatal exposure to bupropion in the first trimester in the international Pregnancy Register was 9/675 (1.3%).
In a retrospective, managed care database study (n = 7005 infants), there was no greater proportion of congenital malformations (2.3%) or cardiovascular malformations (1.1%) associated with first trimester exposure to bupropion (n = 1213 infants) compared with the use of other antidepressants in the first trimester (n = 4743 infants; 2.3% and 1.1% for congenital and cardiovascular malformations, respectively) or bupropion use outside the first trimester (n = 1049 infants; 2.2% and 1.0%, respectively).
In a retrospective case control analysis using data from the National Birth Defects Prevention Study, there were 12,383 case infants and 5869 control infants. A statistically significant association was observed between the occurrence of a left outflow tract heart defect in the infant and self reported maternal bupropion use in early pregnancy (n = 10; adjusted OR = 2.6; 95% CI 1.2, 5.7). No association was observed between maternal bupropion use and any other type of cardiac defect or with all categories of heart defects combined.
A further case control analysis of data from the Slone Epidemiology Center Birth Defects Study included 7913 infant cases of cardiac defects and 8611 controls. This found no statistically significant increase of left outflow tract heart defects with maternal bupropion use (n = 2; adjusted OR = 0.4; 95% CI 0.1, 1.6). However, a statistically significant association was observed for ventricular septal defects (n = 17; adjusted OR = 2.5; 95% CI 1.3, 5.0) following the use of bupropion alone during the first trimester.
Studies in pregnant mice, rats and rabbits showed no evidence of adverse effects on embryofetal development at oral doses up to 100, 450 and 150 mg/kg/day, respectively. In mice and rats, administration of bupropion in late gestation had no effects on parturition. In mice and rabbits, systemic exposure (based on AUC) to bupropion and its metabolites at these dose levels in repeat dose studies was less than in humans at the maximum recommended therapeutic dose. In rats, exposure to bupropion in reproduction studies was up to approximately twice, and to its metabolites was less than human exposure.
In an additional study in pregnant rats, no adverse effects on perinatal development were observed at oral doses up to 150 mg/kg/day.
As animal studies are not always predictive of the human response and some clinical data suggest a potential risk of congenital cardiovascular malformations, administration of bupropion hydrochloride tablets should only be considered during pregnancy if the expected benefits are greater than the potential risks.
 In rats, no adverse effects on postnatal development were observed at oral doses up to 150 mg/kg/day. Plasma concentrations of bupropion were greater than, and of its metabolites were less than, human plasma concentrations at the maximum recommended therapeutic dose.
As bupropion and its metabolites are excreted in human breast milk, mothers should be advised not to breastfeed while taking bupropion hydrochloride tablets.

4.7 Effects on Ability to Drive and Use Machines

As with other CNS acting drugs, Zyban SR may affect the ability to perform tasks that require judgement or motor and cognitive skills. Patients should therefore exercise caution before driving or use of machinery until they are reasonably certain Zyban SR tablets do not adversely affect their performance.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

Clinical trial information.

Bupropion hydrochloride tablets were generally well tolerated when used to treat nicotine dependence as an aid to smoking cessation. In Table 1, the frequency of AEs reported in the treatment phase of the pivotal comparative trial (study 405) is presented. AEs are shown if they occurred at an incidence of 1% or more and if the AE was reported more frequently in patients treated with bupropion hydrochloride tablets, nicotine transdermal system (NTS) or bupropion hydrochloride tablets plus NTS when compared to patients treated with placebo.

Postmarketing data.

Table 2 provides information on the undesirable effects of bupropion identified from clinical trials and postmarketing clinical experience for which a possible causal relationship with bupropion has been established. It is important to note that smoking cessation is often associated with nicotine withdrawal symptoms, some of which are also recognised as adverse events associated with Zyban SR.
Adverse reactions are categorised by body system and listed according to frequency using the following convention; very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000) and very rare (< 1/10,000).

4.9 Overdose

Acute ingestion of doses in excess of 10 times the maximum therapeutic dose have been reported. In addition to those events reported under Adverse Effects (Undesirable Effects), overdose has resulted in symptoms including drowsiness, hallucinations and loss of consciousness and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias; cases of fatal outcome have been reported. Serotonin syndrome has also been reported.
Seizures have been reported in approximately one-third of all reported overdoses with bupropion (in patients treated for depression and smoking cessation). Although most patients recovered without sequelae, deaths associated with overdoses of bupropion have been reported rarely in patients ingesting massive doses of the drug. Where fatalities have occurred, there are no data on time to death following overdose.

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 also recommended. No specific antidote for bupropion is known.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bupropion is a selective inhibitor of the neuronal reuptake of catecholamines (noradrenaline and dopamine) with minimal effect on the reuptake of indolamines (serotonin) and no inhibitory effect on monoamine oxidase. The mechanism by which bupropion enhances the ability of patients to abstain from smoking is unknown. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.
In clinical trials, treatment with bupropion hydrochloride tablets reduced withdrawal symptoms compared to placebo and there was evidence of reduction in craving for cigarettes or urge to smoke compared to placebo.

Clinical trials.

The clinical efficacy of bupropion hydrochloride tablets was demonstrated in three pivotal efficacy studies (403, 405 and 406) in chronic cigarette smokers (> 15 cigarettes per day). Participants were ≥ 18 years of age, motivated to quit smoking, and had a history of not quitting for more than 3 months of the year. Patients received individual smoking cessation counselling in conjunction with treatment.
The primary endpoint in all studies was total abstinence during a specified 4 week time interval, and patients who had just a single inhalation during the observation period were classified as treatment failures. Abstinence was confirmed biologically by measuring exhaled carbon monoxide levels. Secondary endpoints included 1 week point prevalence measures of abstinence (smoking status for a 7 day period prior to each clinic visit), duration of continuous abstinence and reported cigarette craving or nicotine withdrawal symptoms.
Studies 403 and 405 were multicentre, double blind, placebo controlled, parallel, randomised trials, in which the primary efficacy measure was abstinence for a 4 week period during therapy (weeks 4 to 7). Study 403 was a dose response trial in which 613 patients were randomised to 7 weeks treatment with placebo, bupropion hydrochloride 100 mg/day (50 mg bd), bupropion hydrochloride 150 mg once daily or bupropion hydrochloride 300 mg/day (150 mg bd). There was a dose dependent increase in the percentage of patients able to achieve 4 week abstinence rates (weeks 4 to 7) across the bupropion hydrochloride groups. Treatment with bupropion hydrochloride 150 mg/day and 300 mg/day was significantly more effective compared with placebo, with 27% and 36% of patients abstaining respectively (p ≤ 0.05, placebo 17%). In addition, treatment with bupropion hydrochloride 300 mg/day was more effective than placebo in helping patients maintain continuous abstinence through to week 26 (6 months) of the study (19%, p ≤ 0.05). At week 52, there was no significant difference in continuous abstinence rates between bupropion hydrochloride 300 mg/day and placebo, however weekly point prevalence abstinence demonstrated statistical significance in favour of bupropion hydrochloride tablets (p < 0.05).
Study 405 was a comparative trial, consisting of a 1-2 week baseline period, a 7 week treatment period (weeks 1-7), a 2 week tapering of therapy (weeks 8-9), and a 1 year follow-up (weeks 10-52). 893 patients were randomised to placebo, bupropion hydrochloride tablets 150 mg bd (300 mg/day), nicotine transdermal system (NTS, 21 mg/day) or bupropion hydrochloride/NTS combination. The 4 week abstinence rates for all active therapies were significantly higher (p ≤ 0.01) than placebo: 36%, 49% and 58% for NTS, bupropion hydrochloride 150 mg bd, and combination treatment respectively versus 23% for placebo. The effect of bupropion hydrochloride was significantly higher (p ≤ 0.01) than the effect of NTS. The comparison of the effect of bupropion hydrochloride/NTS v.s. bupropion hydrochloride alone did not reach statistical significance (p = 0.06).
During the follow-up phase, continuous abstinence rates following cessation of treatment were significantly superior compared to placebo at weeks 10 and 12 for the NTS group, and from week 3 to week 52 for the bupropion hydrochloride alone and bupropion hydrochloride/NTS groups (p ≤ 0.05). Though the bupropion hydrochloride/NTS treatment group consistently displayed the highest continuous abstinence rate throughout the study, no statistically significant differences were observed between bupropion hydrochloride alone and bupropion hydrochloride/NTS. Statistical significance in favour of the bupropion hydrochloride alone and bupropion hydrochloride/NTS groups versus NTS alone was demonstrated from weeks 10 through 52. Bupropion hydrochloride tablets demonstrated a positive effect on subjective symptoms (i.e. a reduction in cigarette craving and nicotine withdrawal symptoms).
Study 406 was a multicentre, randomised, double blind, placebo controlled comparison of bupropion hydrochloride for the treatment of relapse in patients who achieved abstinence from smoking while on bupropion hydrochloride tablets. The study consisted of a baseline phase, a 7 week open label phase in which 784 patients were treated with bupropion hydrochloride tablets 150 mg bd (300 mg/day), and a 45 week double blind phase in which patients who achieved abstinence in the open label phase were randomised to placebo or bupropion hydrochloride tablets 150 mg bd under double blind conditions for a further 45 weeks. Additional primary endpoints in this study were time to relapse and continuous abstinence at weeks 12, 24, 36 and 52. Secondary endpoints included one week point prevalence abstinence.
Four week abstinence from smoking was achieved in 48.5% of patients. Median time to relapse was 20 weeks for placebo and 32 weeks for the bupropion hydrochloride treatment group (p = 0.03). Continuous abstinence rates showed no significant difference between bupropion hydrochloride and placebo at weeks 36 and 52. Significant point prevalence abstinence (p < 0.05) was consistently seen at all time points except week 40 (p = 0.07).
In all three pivotal efficacy studies (403, 405 and 406), changes in pulse rate and blood pressure were minor and there were no clinically significant differences between treatment groups. No consistent differences in bodyweight changes between treatment groups were observed for studies 403 and 405. In study 406, weight gain was statistically greater for placebo treated patients than for bupropion hydrochloride treated patients at every time point examined. Cessation of smoking was associated with an increase in bodyweight after both placebo and active treatment. All three studies suggested this effect was attenuated while taking bupropion hydrochloride tablets.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of bupropion hydrochloride tablets to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 150 to 300 mg/day.
The absorption of bupropion is not significantly affected when taken with food.

Distribution.

Bupropion is widely distributed with an apparent volume of distribution of approximately 2000 L. Bupropion and its major active metabolite, hydroxybupropion, are moderately bound to plasma proteins (84% and 77%, respectively).
The extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.

Metabolism.

Bupropion is extensively metabolised in humans. Three pharmacologically active metabolites have been identified in plasma: hydroxybupropion and the amino alcohol isomers, threohydrobupropion and erythrohydrobupropion. These may have clinical importance, as their plasma concentrations are as high or higher than those of bupropion. Erythrohydrobupropion cannot be measured in the plasma after a single dose of bupropion hydrochloride tablets. The active metabolites are further metabolised to inactive metabolites and excreted in the urine.
Peak plasma concentrations of hydroxybupropion and threohydrobupropion are achieved approximately 6 hours following administration of a single dose of Zyban SR.
In vitro studies indicate that bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 IIB6 (CYP2B6), while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Following oral administration of a single 150 mg dose of bupropion, there was no difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its major metabolites between smokers and nonsmokers.
Bupropion has been shown to induce its own metabolism in animals following subchronic administration. In humans, there is no evidence of enzyme induction of bupropion or hydroxybupropion in volunteers or patients receiving recommended doses of bupropion hydrochloride for 10 to 45 days.

Excretion.

Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and faeces, respectively. The fraction of the dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. Less than 10% of this 14C dose was accounted for in the urine as active metabolites.
The mean apparent clearance following oral administration of bupropion hydrochloride is approximately 200 L/hr and the mean elimination half-life of bupropion is approximately 20 hours.
The elimination half-life of hydroxybupropion is approximately 20 hours and its area under the plasma drug concentration versus time curve (AUC) at steady state is approximately 14 to 17 times that of bupropion. The elimination half-lives for threohydrobupropion and erythrohydrobupropion are longer (37 and 33 hours, respectively) and steady-state AUC values are 8 and 1.6 times higher than that of bupropion, respectively. Steady state for bupropion and its metabolites is reached within 8 days.

Patients with renal impairment.

The effect of renal disease on the pharmacokinetics of bupropion has not been studied. The elimination of the major metabolites of bupropion may be affected by reduced renal function (see Section 4.4 Special Warnings and Precautions for Use).

Patients with hepatic impairment.

The pharmacokinetics of bupropion and its active metabolites were not statistically significantly different in patients with mild to moderate cirrhosis when compared to healthy volunteers, although more variability was observed between individual patients. For patients with severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference approximately 70% and 3-fold, respectively) and more variable when compared to the values in healthy volunteers; the mean half-life was also longer (by approximately 40%). For the metabolites, the mean Cmax was lower (by approximately 30 to 70%), the mean AUC tended to be higher (by approximately 30 to 50%), the median Tmax was later (by approximately 20 hours) and the mean half-lives were longer (by approximately 2 to 4-fold) than in healthy volunteers (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Elderly.

Pharmacokinetics studies in the elderly have shown variable results. A single dose study showed that the pharmacokinetics of bupropion and its metabolites in the elderly do not differ from those in the younger adults. Another pharmacokinetic study, single and multiple doses, has suggested that accumulation of bupropion and its metabolites may occur to a greater extent in the elderly. Clinical experience has not identified differences in tolerability between elderly and younger patients, but greater sensitivity in older patients cannot be ruled out.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity tests showed that bupropion did not cause gene mutations in bacterial or mammalian cells in vitro, chromosomal damage in vitro or DNA damage in vivo. An increase in chromosomal aberrations was observed in one of three in vivo rat bone marrow cytogenetic studies.

Carcinogenicity.

Lifetime carcinogenicity studies were performed in rats and mice at oral doses up to 300 and 150 mg/kg/day, respectively. In male rats and male and female mice, systemic exposure (based on AUC) to bupropion and its metabolites at these dose levels in repeat dose studies was less than in humans at the maximum recommended therapeutic dose. In female rats, exposure to bupropion was up to approximately 4-fold, and to its metabolites was less than human exposure. In the rat study, there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day and this may be secondary to hepatic enzyme induction. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumours of the liver and other organs was seen in either study.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, hypromellose, cysteine hydrochloride, magnesium stearate, carnauba wax, Opacode WB monogramming ink NS-78-17821 black (PI), Opadry aqueous film coating YS-1-18202-A white (PI) and Opadry OY-7300 white (PI).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

PA/Al/PVC/Al blister packs of 3, 10, 30, 60, 90, 100 and 120 tablets.

Note.

Not all pack sizes are marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

The chemical name of bupropion is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. Molecular weight: 276.2.

Chemical structure.


CAS number.

31677-93-7.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes