Drug Interactions between Cymbalta and Wellbutrin

ADJUST DOSE: Coadministration of bupropion may elevate the plasma concentrations of drugs metabolized by CYP450 2D6. The proposed mechanism is decreased clearance due to bupropion's inhibition of CYP450 2D6 activity. In a study of 15 male volunteers who were extensive metabolizers of CYP450 2D6, administration of a single 50 mg dose of desipramine following treatment with bupropion 150 mg twice daily increased the desipramine peak plasma concentration (Cmax), systemic exposure (AUC) and half-life by an average of 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. In addition, when combined with serotonergic drugs, such as certain selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) that are CYP450 2D6 substrates, elevated plasma levels may potentiate the risk of a potentially life-threatening condition called serotonin syndrome. In a case report of a 62-year-old woman with depression, serotonin syndrome developed after three weeks of bupropion and sertraline therapy, initially misdiagnosed as worsening depression and treated with venlafaxine, leading to further symptom progression. The patient recovered after discontinuing the offending medications and treating for serotonin syndrome, with authors highlighting bupropion's role in increasing SSRI levels through CYP450 2D6 inhibition. Symptoms of serotonin syndrome include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.

MONITOR CLOSELY: The use of bupropion is associated with a dose-related risk of seizures. The risk may be further increased when coadministered with serotonergic agents that can reduce the seizure threshold such as certain selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs). These agents are often individually epileptogenic and may have additive effects when combined. The estimated incidence of seizures is approximately 0.4% for immediate-release bupropion hydrochloride at dosages between 300 to 450 mg/day (equivalent to 348 to 522 mg/day of bupropion hydrobromide) but increases almost tenfold between 450 mg and 600 mg/day (equivalent to 522 and 696 mg/day of bupropion hydrobromide). Data for sustained-release (SR) bupropion hydrochloride revealed a seizure incidence of approximately 0.1% at dosages up to 300 mg/day and 0.4% at 400 mg/day. Likewise, in clinical trials, an overall seizure incidence of approximately 0.1% has been reported with extended-release (XL) bupropion hydrochloride at dosages up to 450 mg/day and approximately 0.39% at 450 mg/day. The 0.4% seizure incidence may exceed that of other marketed antidepressants by as much as 4-fold.

MANAGEMENT: According to bupropion product labeling, if coadministration of bupropion with CYP450 2D6 substrates is required, concomitant medications should be initiated at the lower end of the dose range. If the concomitant agents possess serotonergic activity (e.g., SSRIs, SNRIs, and/or TCAs) patients should be monitored more closely for and counseled about the signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor). Additionally, if the coadministered agent is known to lower the seizure threshold, extreme caution is advised particularly in the elderly and in patients with a history of seizures or other risk factors for seizures (e.g., head trauma; brain tumor; severe hepatic cirrhosis; metabolic disorders; CNS infections; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; diabetes treated with oral hypoglycemic agents or insulin). Bupropion as well as concomitant medications should be initiated at the lower end of the dosage range and titrated gradually as needed and as tolerated. The maximum recommended dosage for the specific bupropion formulation should not be exceeded. Bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.