Drug Interaction Report

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 antidepressants, CNS stimulants, acetylcholinesterase inhibitors, phenothiazines, and dopaminergic blocking agents such as neuroleptics and metoclopramide. 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.

ADJUST DOSE: Coadministration with bupropion may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6, including many antidepressants, neuroleptics, CNS stimulants (e.g., amphetamines), metoclopramide, and some acetylcholinesterase inhibitors (e.g., donepezil, galantamine). The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by bupropion and its metabolite, hydroxybupropion. Approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent are extensive metabolizers of CYP450 2D6 and may be affected by this interaction. 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. A case report describes a 4-fold increase in plasma levels of imipramine and its metabolite, desipramine, in a 64-year-old woman following the addition of bupropion 225 mg/day. Plasma levels of desipramine were increased twofold more than the imipramine levels, which is consistent with the fact that desipramine is primarily metabolized by CYP450 2D6 while imipramine is also metabolized by other CYP450 isoenzymes. In another report, an 83-year-old woman became unsteady, confused, and lethargic following the addition of bupropion SR 300 mg/day. Her nortriptyline level was found to have increased by 185%. A later rechallenge prompted recurrence of the interaction. Likewise, a 62-year-old woman with no history of seizures developed a generalized tonic-clonic seizure in association with toxic trimipramine plasma levels following the addition of bupropion 300 mg/day. No further seizures occurred following dosage reductions of both drugs.

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 concomitant medications that are substrates of CYP450 2D6 whenever bupropion is added to or withdrawn from therapy. Bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.

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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 antidepressants, CNS stimulants, acetylcholinesterase inhibitors, phenothiazines, and dopaminergic blocking agents such as neuroleptics and metoclopramide. 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.

ADJUST DOSE: Coadministration with bupropion may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6, including many antidepressants, neuroleptics, CNS stimulants (e.g., amphetamines), metoclopramide, and some acetylcholinesterase inhibitors (e.g., donepezil, galantamine). The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by bupropion and its metabolite, hydroxybupropion. Approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent are extensive metabolizers of CYP450 2D6 and may be affected by this interaction. 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. A case report describes a 4-fold increase in plasma levels of imipramine and its metabolite, desipramine, in a 64-year-old woman following the addition of bupropion 225 mg/day. Plasma levels of desipramine were increased twofold more than the imipramine levels, which is consistent with the fact that desipramine is primarily metabolized by CYP450 2D6 while imipramine is also metabolized by other CYP450 isoenzymes. In another report, an 83-year-old woman became unsteady, confused, and lethargic following the addition of bupropion SR 300 mg/day. Her nortriptyline level was found to have increased by 185%. A later rechallenge prompted recurrence of the interaction. Likewise, a 62-year-old woman with no history of seizures developed a generalized tonic-clonic seizure in association with toxic trimipramine plasma levels following the addition of bupropion 300 mg/day. No further seizures occurred following dosage reductions of both drugs.

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 concomitant medications that are substrates of CYP450 2D6 whenever bupropion is added to or withdrawn from therapy. Bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.

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MONITOR CLOSELY: The use of bupropion is associated with a dose-related risk of seizures. The risk may be further increased when coadministered with selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), monoamine oxidase inhibitors, neuroleptic agents, central nervous system stimulants, opioids, tricyclic antidepressants, other tricyclic compounds (e.g., cyclobenzaprine, phenothiazines), systemic steroids, or any substance that can reduce the seizure threshold (e.g., carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, lindane, theophylline). 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: 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. Bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.

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MONITOR CLOSELY: Concomitant use of agents with serotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, cyclobenzaprine, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: In general, the concomitant use of multiple serotonergic agents should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life. For example, some experts suggest a 5-week washout period following use of fluoxetine and 3 weeks following the use of vortioxetine before administering another serotonergic agent. Individual product labeling for washout periods should be consulted for current recommendations. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.

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GENERALLY AVOID: Several case reports suggest that serotonin reuptake inhibitors may potentiate the pharmacologic response to sympathomimetic agents. The exact mechanism of interaction is unclear. In one case report, a patient experienced jitteriness, racing thoughts, stomach cramps, dry eyes, palpitations, tremors, and restlessness following a single dose of phentermine ingested approximately a week after she had discontinued fluoxetine. Because of the long half-life of fluoxetine and its metabolite, an interaction with fluoxetine is possible. Similar toxic reactions have been reported when fluoxetine was used concomitantly with amphetamine or phenylpropanolamine. Additionally, some sympathomimetic agents such as amphetamines may possess serotonergic activity and should generally not be administered with serotonin reuptake inhibitors because of the additive risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. The interaction was suspected in a patient treated with dexamphetamine who developed symptoms consistent with the serotonin syndrome approximately 2 weeks after the addition of venlafaxine. The medications were discontinued and the patient was given cyproheptadine for suspected serotonin syndrome, whereupon symptoms promptly resolved. A second episode occurred when dexamphetamine was subsequently resumed and citalopram added. The patient improved following cessation of citalopram on his own, and residual symptoms were successfully treated with cyproheptadine.

MANAGEMENT: In general, amphetamines and other sympathomimetic appetite suppressants should not be combined with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Close monitoring for enhanced sympathomimetic effects and possible serotonin syndrome is recommended if these agents must be used together. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

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GENERALLY AVOID: Several case reports suggest that serotonin reuptake inhibitors may potentiate the pharmacologic response to sympathomimetic agents. The exact mechanism of interaction is unclear. In one case report, a patient experienced jitteriness, racing thoughts, stomach cramps, dry eyes, palpitations, tremors, and restlessness following a single dose of phentermine ingested approximately a week after she had discontinued fluoxetine. Because of the long half-life of fluoxetine and its metabolite, an interaction with fluoxetine is possible. Similar toxic reactions have been reported when fluoxetine was used concomitantly with amphetamine or phenylpropanolamine. Additionally, some sympathomimetic agents such as amphetamines may possess serotonergic activity and should generally not be administered with serotonin reuptake inhibitors because of the additive risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. The interaction was suspected in a patient treated with dexamphetamine who developed symptoms consistent with the serotonin syndrome approximately 2 weeks after the addition of venlafaxine. The medications were discontinued and the patient was given cyproheptadine for suspected serotonin syndrome, whereupon symptoms promptly resolved. A second episode occurred when dexamphetamine was subsequently resumed and citalopram added. The patient improved following cessation of citalopram on his own, and residual symptoms were successfully treated with cyproheptadine.

MANAGEMENT: In general, amphetamines and other sympathomimetic appetite suppressants should not be combined with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Close monitoring for enhanced sympathomimetic effects and possible serotonin syndrome is recommended if these agents must be used together. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

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MONITOR: Coadministration of amphetamines and amphetamine-like drugs with other agents that also increase serotonin levels or effects, may increase the risk of serotonin syndrome. The exact mechanism by which serotonin levels are increased differs depending on the specific medication(s) involved. Serotonin syndrome is believed 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. Clinical data are limited. Serotonin syndrome involving amphetamines has most frequently been reported with the use of MDMA, or ecstasy, an amphetamine derivative with enhanced serotonergic activity over classical amphetamines, which tend to be more dopaminergic. However, case reports of serotonin syndrome involving amphetamines and amphetamine-like drugs have been documented with concomitant use of other serotonergic substances (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors). Abuse and/or overdose may increase the risk of experiencing this adverse effect.

MANAGEMENT: Caution is recommended when amphetamines and amphetamine-like drugs are used with other agents that also increase serotonin levels or effects. Initiating patients with lower doses and ensuring close clinical monitoring for signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, tremor) is advised. Particular caution is recommended when increasing the dosages of these agents. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately, and treatment rendered as indicated.

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MONITOR: Coadministration of amphetamines and amphetamine-like drugs with other agents that also increase serotonin levels or effects, may increase the risk of serotonin syndrome. The exact mechanism by which serotonin levels are increased differs depending on the specific medication(s) involved. Serotonin syndrome is believed 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. Clinical data are limited. Serotonin syndrome involving amphetamines has most frequently been reported with the use of MDMA, or ecstasy, an amphetamine derivative with enhanced serotonergic activity over classical amphetamines, which tend to be more dopaminergic. However, case reports of serotonin syndrome involving amphetamines and amphetamine-like drugs have been documented with concomitant use of other serotonergic substances (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors). Abuse and/or overdose may increase the risk of experiencing this adverse effect.

MANAGEMENT: Caution is recommended when amphetamines and amphetamine-like drugs are used with other agents that also increase serotonin levels or effects. Initiating patients with lower doses and ensuring close clinical monitoring for signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, tremor) is advised. Particular caution is recommended when increasing the dosages of these agents. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately, and treatment rendered as indicated.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. 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 physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. 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 physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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