Drug Interaction Report

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.

MONITOR CLOSELY: The use of bupropion is associated with a dose-related risk of seizures. The risk may be further increased when coadministered with other agents that can reduce the seizure threshold, including selective serotonin reuptake inhibitors (SSRIs) such as citalopram and escitalopram. 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.

Pharmacokinetically, bupropion may increase the plasma concentrations of citalopram. The mechanism of interaction has not been described. Unlike other SSRIs, citalopram is not known to be significantly metabolized by CYP450 2D6, which is inhibited by bupropion and its metabolite, hydroxybupropion. In one study, bupropion increased citalopram peak plasma concentration (Cmax) and systemic exposure (AUC) by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion and its three active metabolites. The interaction has not been studied with escitalopram.

MANAGEMENT: Extreme caution is advised if bupropion is administered with any substance that can reduce the seizure threshold, 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. Clinical and laboratory monitoring may be appropriate for citalopram or escitalopram whenever bupropion is added to or withdrawn from therapy. Bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.

MONITOR CLOSELY: Escitalopram can cause dose-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias such as torsade de pointes and sudden death. In a double-blind, placebo-controlled ECG study consisting of 113 healthy subjects, the change from baseline in QTc (Fridericia-corrected) was 4.3 msec for escitalopram 10 mg/day and 10.7 msec for the supratherapeutic dosage of 30 mg/day. Based on the established exposure-response relationship, the predicted QTc change from placebo under the Cmax for 20 mg/day is 6.6 msec. Cases of QT interval prolongation and torsade de pointes have been reported during postmarketing use. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). Also, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MONITOR CLOSELY: Concomitant use of escitalopram with agents that possess or enhance serotonergic activity may potentiate the risk of a potentially life-threatening condition called serotonin syndrome. The exact mechanism by which serotonin syndrome occurs may differ based on the agent(s) involved. It is thought to result from the hyperstimulation of postsynaptic 5-HT receptors and while postsynaptic 5-HT1A and 5-HT2A receptors are usually implicated, it is more likely that no single receptor is solely responsible. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, the risk of experiencing central nervous system (CNS) and/or respiratory depressant effects may be increased when escitalopram is combined with another agent that also has these adverse reactions, particularly in patients who are already at an increased risk, such as debilitated or elderly patients.

MANAGEMENT: If coadministration of escitalopram with other agents that both prolong the QT interval and possess or enhance serotonergic activity is required, caution and close clinical monitoring are advised. Some authorities consider the use of escitalopram with other agents that prolong the QT interval or in patients with known QT interval prolongation to be contraindicated. Patients should be monitored closely for and counseled to seek immediate medical attention should they experience any signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor) or prolonged QT interval (e.g., irregular heartbeat, dizziness, lightheadedness, fainting). Additional monitoring for CNS and/or respiratory depression may be advisable if the concurrent medication could also cause these side effects. In this situation, ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities. The product labeling of the concomitant medication should be consulted for further guidance, such as specific dosage adjustment and/or management recommendations should serious adverse reactions occur.

GENERALLY AVOID: Excessive use or abrupt discontinuation of alcohol after chronic ingestion may precipitate seizures in patients receiving bupropion. Additionally, there have been rare postmarketing reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who drank alcohol during treatment with bupropion. According to one forensic report, a patient died after taking large doses of both bupropion and alcohol. It is uncertain whether a drug interaction was involved. Single-dose studies in healthy volunteers given bupropion and alcohol failed to demonstrate either a significant pharmacokinetic or pharmacodynamic interaction.

MANAGEMENT: The manufacturer recommends that alcohol consumption be minimized or avoided during bupropion treatment. The use of bupropion is contraindicated in patients undergoing abrupt discontinuation of alcohol.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: Additive or synergistic effects on blood pressure may occur when bupropion is combined with sympathomimetic agents such as nasal decongestants, adrenergic bronchodilators, ophthalmic vasoconstrictors, and systemic vasopressors. Treatment with bupropion can result in elevated blood pressure and hypertension. In clinical practice, hypertension, in some cases severe and requiring acute treatment, has been observed in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have occurred in both patients with and without evidence of preexisting hypertension. Furthermore, postmarketing cases of hypertensive crisis have been reported during the initial titration phase with bupropion-naltrexone treatment.

MANAGEMENT: Caution is advised when bupropion is used with other drugs that increase dopaminergic or noradrenergic activity due to an increased risk of hypertension. Blood pressure and heart rate should be measured prior to initiating bupropion therapy and monitored at regular intervals consistent with usual clinical practice, particularly in patients with preexisting hypertension. Dose reduction or discontinuation of bupropion should be considered in patients who experience clinically significant and sustained increases in blood pressure or heart rate.

MONITOR: The concomitant use of bupropion and nicotine replacement for smoking cessation may increase the risk of hypertension. In a clinical study (n=250), 6.1% of patients who used sustained-release bupropion with nicotine transdermal system developed treatment-emergent hypertension, compared to 2.5% of patients treated with bupropion alone, 1.6% treated with nicotine alone, and 3.1% treated with placebo. Three patients in the bupropion plus nicotine group and one patient in the nicotine-only group discontinued treatment due to hypertension. The majority had evidence of preexisting hypertension.

MANAGEMENT: Blood pressure monitoring is recommended for patients concomitantly using bupropion and nicotine replacement for smoking cessation.