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 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: Lithium may enhance the pharmacologic effects of selective serotonin reuptake inhibitors (SSRIs) and 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. The exact mechanism by which lithium increases serotonergic activity is unknown. The interaction has been reported with fluoxetine and fluvoxamine and the serotonin-norepinephrine reuptake inhibitor venlafaxine. 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. Conversely, SSRIs may elevate the plasma concentrations of lithium and increase the risk of lithium toxicity. The interaction has been associated with fluoxetine, while citalopram and paroxetine reportedly do not cause the interaction. Excessive somnolence has been reported with lithium and fluvoxamine.

MANAGEMENT: Caution is advised if lithium is prescribed in combination with SSRIs. Lithium levels should be assessed regularly and the dosage adjusted accordingly. 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, a 5-week washout period is generally recommended following use of fluoxetine before administering another serotonergic agent. 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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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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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 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 including 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). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In addition, central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking escitalopram with certain other drugs that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: Caution is recommended if escitalopram is used in combination with other drugs that can prolong the QT interval. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. When escitalopram is used in combination with other drugs that cause CNS and/or respiratory depression, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. 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.

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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 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.

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MONITOR CLOSELY: Concomitant use of agents with serotonergic activity including selective serotonin reuptake inhibitors, tricyclic antidepressants, and other antidepressants 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.

MONITOR CLOSELY: Escitalopram can cause dose-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval including tricyclic antidepressants and other antidepressants (e.g., trazodone) 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).

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. 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. Due to the potential for additive effects on the QT interval, ECG monitoring may also be appropriate when escitalopram is used with tricyclic antidepressants or other antidepressants like trazodone. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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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: 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: Excessive use or abrupt discontinuation of benzodiazepines and other sedatives after chronic ingestion may precipitate seizures in patients receiving bupropion. Conversely, bupropion may antagonize the central pharmacologic effects of sedatives. Bupropion can cause agitation, anxiety, and insomnia and has been shown to decrease the sedative effect of diazepam in healthy volunteers given single doses of the drugs.

MANAGEMENT: Although sedatives may be prescribed to treat agitation, anxiety, and insomnia associated with bupropion use, patients should be alerted to the possibility of an increased risk of seizures during excessive exposure to these drugs. Patients should not attempt to alter the dosages or discontinue the medications on their own without consulting with their physician. The use of bupropion is contraindicated in patients undergoing abrupt discontinuation of sedatives.

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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: 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: The concomitant use of thyroid hormones, especially large doses, with sympathomimetic drugs may potentiate sympathomimetic effects and increase the risk of cardiac insufficiency in patients who have coronary artery disease.

MANAGEMENT: Monitoring for increased sympathomimetic effects and cardiac function may be advisable.

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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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Case reports suggest that thyroid hormone supplementation may enhance the therapeutic effects of fluoxetine in the treatment of major depression. The mechanism is unknown.

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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.

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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.

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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.

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ADJUST DOSING INTERVAL: Consumption of certain foods as well as the timing of meals relative to dosing may affect the oral absorption of T4 thyroid hormone (i.e., levothyroxine). T4 oral absorption is increased by fasting and decreased by foods such as soybean flour (e.g., infant formula), cotton seed meal, walnuts, dietary fiber, calcium, and calcium fortified juices. Grapefruit or grapefruit products may delay the absorption of T4 thyroid hormone and reduce its bioavailability. The mechanism of this interaction is not fully understood.

MANAGEMENT: Some manufacturers recommend administering oral T4 as a single daily dose, on an empty stomach, one-half to one hour before breakfast. In general, oral preparations containing T4 thyroid hormone should be administered on a consistent schedule with regard to time of day and relation to meals to avoid large fluctuations in serum levels. Foods that may affect T4 absorption should be avoided within several hours of dosing if possible. Consult local guidelines for the administration of T4 in patients receiving enteral feeding.

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GENERALLY AVOID: Alcohol may potentiate the cardiovascular effects of amphetamines. The exact mechanism of interaction is unknown. In one study, concurrent administration of methamphetamine (30 mg intravenously) and ethanol (1 gm/kg orally over 30 minutes) increased heart rate by 24 beats/minute compared to methamphetamine alone. This increases cardiac work and myocardial oxygen consumption, which may lead to more adverse cardiovascular effects than either agent alone. Subjective effects of ethanol were diminished in the eight study subjects, but those of methamphetamine were not affected. The pharmacokinetics of methamphetamine were also unaffected except for a decrease in the apparent volume of distribution at steady state. The interaction was suspected in a case report of a 20-year-old male who experienced retrosternal chest pain shortly after drinking alcohol and taking a double dose of his amphetamine/dextroamphetamine medication (Adderall 15 mg X 2) to stay alert. The patient had no family history of cardiovascular diseases, and his past medical history was remarkable only for ADHD. Prior to the episode, the patient had not taken his medication for weeks and had been drinking whiskey the previous three nights before going to bed. The patient was diagnosed with myocardial infarction likely secondary to amphetamine-induced coronary vasospasm.

MANAGEMENT: Concomitant use of amphetamines and alcohol should be avoided if possible, especially in patients with a history of heart disease.

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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.

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GENERALLY AVOID: Acute ethanol ingestion may potentiate the CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: Patients should be advised to avoid alcohol during benzodiazepine therapy.

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ADJUST DOSING INTERVAL: Concurrent administration of calcium-containing products may decrease the oral bioavailability of levothyroxine by one-third in some patients. Pharmacologic effects of levothyroxine may be reduced. The exact mechanism of interaction is unknown but may involve nonspecific adsorption of levothyroxine to calcium at acidic pH levels, resulting in an insoluble complex that is poorly absorbed from the gastrointestinal tract. In one study, 20 patients with hypothyroidism who were taking a stable long-term regimen of levothyroxine demonstrated modest but significant decreases in mean free and total thyroxine (T4) levels as well as a corresponding increase in mean thyrotropin (thyroid-stimulating hormone, or TSH) level following the addition of calcium carbonate (1200 mg/day of elemental calcium) for 3 months. Four patients had serum TSH levels that were higher than the normal range. Both T4 and TSH levels returned to near-baseline 2 months after discontinuation of calcium, which further supported the likelihood of an interaction. In addition, there have been case reports suggesting decreased efficacy of levothyroxine during calcium coadministration. It is not known whether this interaction occurs with other thyroid hormone preparations.

MANAGEMENT: Some experts recommend separating the times of administration of levothyroxine and calcium-containing preparations by at least 4 hours. Monitoring of serum TSH levels is recommended. Patients with gastrointestinal or malabsorption disorders may be at a greater risk of developing clinical or subclinical hypothyroidism due to this interaction.

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MONITOR: One study has suggested that caffeine withdrawal may significantly increase blood lithium levels. The mechanism may be involve reversal of a caffeine-induced increase in renal lithium excretion.

MANAGEMENT: When caffeine is eliminated from the diet of lithium-treated patients, caution should be exercised. When caffeine consumption is decreased, close observation for evidence of lithium toxicity and worsening of the psychiatric disorder is recommended. Patients should be advised to notify their physician if they experience symptoms of possible lithium toxicity such as drowsiness, dizziness, weakness, ataxia, tremor, vomiting, diarrhea, thirst, blurry vision, tinnitus, or increased urination.

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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.

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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.

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The recommended maximum number of medicines in the 'Central Nervous System (CNS) Drugs' category to be taken concurrently is usually three. Your list includes five medicines belonging to the 'Central Nervous System (CNS) Drugs' category:

• bupropion
• clonazepam
• dextroamphetamine
• escitalopram
• fluoxetine

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'psychotropic agents' category to be taken concurrently is usually three. Your list includes four medicines belonging to the 'psychotropic agents' category:

• bupropion
• clonazepam
• escitalopram
• fluoxetine

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'antidepressants' category to be taken concurrently is usually one. Your list includes three medicines belonging to the 'antidepressants' category:

• bupropion
• escitalopram
• fluoxetine

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.