Monoamine oxidase inhibitors (MAOI): Since monoamine oxidase A and B inhibitors also enhance the catecholaminergic pathways, by a different mechanism from bupropion, naltrexone/bupropion must not be used with MAOI (see Contraindications).
Opioid analgesics: Naltrexone/bupropion is contraindicated in patients currently dependent on chronic opioid or opiate agonist therapy (e.g., methadone), or patients in acute opiate withdrawal (see Contraindications). Due to the antagonistic effect of naltrexone at the opioid receptor, patients taking naltrexone/bupropion may not fully benefit from treatment with opioid-containing medicinal products, such as cough and cold remedies, antidiarrhoeal preparations and opioid analgesics. In patients requiring intermittent opiate treatment, naltrexone/bupropion therapy should be temporarily discontinued and opiate dose should not be increased above the standard dose (see Precautions). If chronic opiate therapy is required, naltrexone/bupropion treatment must be stopped. Naltrexone/bupropion may be used with caution after chronic opioid use has been stopped for 7 to 10 days in order to prevent precipitation of withdrawal.
Drugs metabolised by cytochrome P450 (CYP) enzymes: Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 CYP2B6; thus, the potential exists for interaction when administered with medicinal products that induce or inhibit CYP2B6. Although not metabolised by the CYP2D6 isoenzyme, bupropion and its main metabolite, hydroxybupropion, inhibit the CYP2D6 pathway and the potential exists to affect medicinal products metabolised by CYP2D6.
CYP2D6 substrates: In a clinical study, naltrexone/bupropion (32 mg naltrexone hydrochloride/360 mg bupropion hydrochloride daily) was co-administered with a 50 mg dose of metoprolol (a CYP2D6 substrate). Naltrexone/bupropion increased metoprolol AUC and Cmax by approximately 4- and 2-fold, respectively, relative to metoprolol alone. Similar clinical drug interactions resulting in increased pharmacokinetic exposure of CYP2D6 substrates have also been observed with bupropion as a single medicinal product with desipramine and venlafaxine.
Co-administration of bupropion with drugs that are metabolised by CYP2D6 isozyme including certain antidepressants (SSRIs and many tricyclic antidepressants, e.g. desipramine, imipramine, paroxetine), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medicinal product. Although citalopram is not primarily metabolised by CYP2D6, in one study, bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. 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. If naltrexone/bupropion is added to the treatment regimen of a patient already receiving a drug metabolised by CYP2D6, the need to decrease the dose of the original medicinal product should be considered, particularly for those concomitant medicinal products with a narrow therapeutic index. When feasible, the option of therapeutic drug monitoring should be considered for medicinal products with a narrow therapeutic index, such as tricyclic antidepressants.
CYP2B6 inducers, inhibitors and substrates: Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the CYP2B6 isozyme. The potential exists for a drug interaction between naltrexone/bupropion and drugs that induce or are substrates of the CYP2B6 isozyme.
Since bupropion is extensively metabolised, caution is advised when naltrexone/bupropion is co-administered with medicinal products known to induce CYP2B6 (e.g., carbamazepine, phenytoin, ritonavir, efavirenz) as these may affect the clinical efficacy of naltrexone/bupropion. 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 20 to 80%. Similarly, efavirenz 600 mg once daily for two weeks reduced the exposure of bupropion by approximately 55% in healthy volunteers.
Co-administration of medicinal products that may inhibit 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 hydroxybupropion. 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, but could potentially lead to reduced efficacy of naltrexone/bupropion.
OCT2 substrates: Bupropion and its metabolites competitively inhibit the OCT2 in the basolateral membrane of the renal tubule responsible for creatinine secretion, in a manner similar to the OCT2 substrate cimetidine. Therefore, mild increases in creatinine observed after long-term treatment with naltrexone/bupropion are likely due to inhibition of OCT2 and not indicative of changes in creatinine clearance. Use of naltrexone/bupropion with other OCT2 substrates (e.g., metformin) in clinical trials did not indicate the need for dose adjustment or other precautions.
Other interactions: 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. There are no known pharmacokinetic interactions between naltrexone and alcohol. The consumption of alcohol during naltrexone/bupropion treatment should be minimised or avoided.
Caution should be used when prescribing naltrexone/bupropion to patients with predisposing factors that may increase the risk of seizure including: as treatment with naltrexone/bupropion may result in lowered glucose in patients with diabetes, the dose of insulin and/or oral diabetic medicinal products should be assessed to minimise the risk of hypoglycaemia, which could predispose patients to seizure; concomitant administration of medicinal products that may lower the seizure threshold, including antipsychotics, antidepressants, antimalarials, tramadol, theophylline, systemic steroids, quinolones and sedating antihistamines.
Naltrexone/bupropion is contraindicated in patients receiving concomitant treatment with monoamine oxidase inhibitors, bupropion or naltrexone, patients undergoing acute alcohol or benzodiazepine withdrawal, patients currently dependent on chronic opioids, or opiate agonists (see Contraindications).
Administration of naltrexone/bupropion to patients receiving either levodopa or amantadine concurrently should be undertaken with caution. Limited clinical data suggest a higher incidence of adverse reactions (e.g., nausea, vomiting, and neuropsychiatric adverse reactions - see Adverse Reactions) in patients receiving bupropion concurrently with either levodopa or amantadine.
Administration of naltrexone/bupropion with inhibitors or inducers of UGT 1A2 and 2B7 should be undertaken with caution as these may alter the exposure of naltrexone.
Naltrexone/bupropion has not been studied in conjunction with alpha-adrenergic blockers or clonidine.
Since bupropion is extensively metabolised, caution is advised when naltrexone/bupropion is co-administered with medicinal products known to inhibit metabolism (e.g. valproate), as these may affect its clinical efficacy and safety.
Naltrexone/bupropion should preferably be taken with food, as it is known that both naltrexone and bupropion plasma concentrations are increased with food and the safety and efficacy data from clinical trials is based on dosing with food.