The manufacturers issue warnings about concurrent use ofbupropion with alcohol, amantadine, levodopa, drugs that canlower convulsive threshold, drugs metabolised by cytochrome P450 isoenzyme CYP2D6, drugs which affect CYP2B6,and also use of nicotine.
Clinical evidence,mechanism, importance and management
The manufacturers report rare adverse neuropsychiatric events or reduced alcohol tolerance in patients drinking alcohol during bupropion treatment. They recommend that consumption of alcohol should be minimised or avoided (See reference number 1,2). For comment on increased risk of seizures with alcohol see (d), below.
The manufacturers say that concurrent use of bupropion and levodopa or amantadine should be undertaken with caution because limited clinical data suggest a higher incidence of undesirable effects (nausea, vomiting, excitement, restlessness, postural tremor) in patients given bupropion with either drug. Good monitoring is therefore appropriate and patients should be given small initial bupropion doses,which are increased gradually (See reference number 1,2).
The manufacturers advise caution if bupropion is used with drugs such as clopidogrel,cyclophosphamide, ifosfamide, orphenadrine, and ticlopidine as bupropion is metabolised to its major metabolite hydroxybupropion by CYP2B6 and these drugs are also metabolised by this isoenzyme (See reference number 1,2). However,there is no evidence to suggest that this is a problem in practice.
The manufacturers of bupropion predict that it may inhibit metabolism of drugs by cytochrome P450 isoenzyme CYP2D6, which might result in a rise in their plasma levels. They name haloperidol,risperidone, thioridazine, flecainide, propafenone. The recommendation is that if any of these drugs is added to treatment with bupropion, doses at lower end of range should be used. If bupropion is added to existing treatment,decreased dosages should be considered (See reference number 1,2). This seems a prudent precaution as bupropion raises levels of desipramine, , dextromethorphan, , metoprolol, , all of which are metabolised by this isoenzyme.
(e) Drugs and circumstances that can lower convulsive threshold
There is a small dose-related risk of seizures with bupropion. At a daily dose of 300mg of sustained-release formulation risk is 0.1%,which increases to 0.4 % at a dose of 450mg of immediate-release formulation, and increases tenfold between doses of 450 and 600mg daily (See reference number 2). The manufacturers caution use of other drugs that lower convulsive threshold, concern being that these drugs might further increase risk of seizures. The UK(See reference number 1) and US(See reference number 2) manufacturers list antipsychotics,antidepressants (see SSRIs, and tricyclics,), systemic steroids, , and theophylline. The UK manufacturers additionally list antimalarials,tramadol, quinolones and sedating antihistamines. A maximum dose of 150mg of bupropion should be considered for patients prescribed such drugs (See reference number 1). Caution is also urged with regard to circumstances that may lower convulsive threshold, including use of anorectics or stimulants, , excessive use of alcohol or sedatives, addiction to cocaine or opiates. Bupropion is contraindicated during abrupt withdrawal from alcohol or any drug known to be associated with seizures on withdrawal (See reference number 1,2).
Nicotine transdermal patches are reported not to affect pharmacokinetics of bupropion or its metabolites (See reference number 1). The manufacturers of bupropion say that limited data suggest that giving up smoking is more easily achieved if bupropion is taken while using a nicotine transdermal system, but a higher rate of treatment-emergent hypertension has been noted with combined treatment (See reference number 1,2). They recommend weekly monitoring to check for any evidence of a blood pressure increase (See reference number 1). The same warning would also seem to be applicable to use of nicotine in any other form (oral or nasal).
For a report of acute myocardial ischaemia attributed to combined use of bupropion,nicotine (from smoking) and pseudoephedrine, see ‘Bupropion
Zyban (Bupropion hydrochloride). GlaxoSmithKline UK. UK Summary of product characteristics,October 2006.
Zyban (Bupropion hydrochloride). GlaxoSmithKline. US Prescribing information,August 2007.