Bupropion

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 bupropion 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 bupropion 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.

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.

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 bupropion 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 bupropion 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.

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 bupropion 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.

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. The patient should be closely monitored for possible undesirable effects that could indicate high drug or metabolite levels.

Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 CYP2B6. 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%. 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.

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 treatment. The consumption of alcohol during bupropion treatment should be minimised or avoided.

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

Co-administration of digoxin with bupropion may decrease digoxin levels. Digoxin AUC_0–24h 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.

Administration of bupropion 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) in patients receiving bupropion concurrently with either levodopa or amantadine.

There is an increased risk of seizures occurring with the use of bupropion in the presence of predisposing risk factors which lower the seizure threshold. Bupropion 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:

• 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 bupropion, a maximum dose of 150mg daily for the remainder of their treatment should be considered.
• alcohol abuse.
• history of head trauma.
• diabetes treated with hypoglycaemics or insulin.
• use of stimulants or anorectic products.

Bupropion should be discontinued and not recommenced in patients who experience a seizure while on treatment.

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.

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. Bupropion should not be used in pregnancy. Pregnant women should be encouraged to quit smoking without the use of pharmacotherapy.

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 bupropion should be made taking into account the benefit of breast-feeding to the newborn/infant and the benefit of bupropion 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.

As with other CNS acting drugs bupropion may affect ability to perform tasks that require judgement or motor and cognitive skills. Bupropion 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 bupropion does not adversely affect their performance.

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 bupropion.

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).

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

Common: Depression, 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

Nervous system disorders

Common: Tremor, concentration disturbance, headache, dizziness, taste disorders

Rare: Seizures**, dystonia, ataxia, Parkinsonism, incoordination, memory impairment, paraesthesia, syncope

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

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.
*** Cases of suicidal ideation and suicidal behaviour have been reported during bupropion therapy.