Auvelity (dextromethorphan HBr/bupropion HCl)

Commercially available as bilayer extended-release tablets (Auvelity(R)) containing 45 mg of immediate-release dextromethorphan hydrobromide and 105 mg of extended-release bupropion hydrochloride. Dosage of both drugs is expressed in terms of the salt.

For the treatment of major depressive disorder in adults, the recommended initial dosage of the fixed combination of dextromethorphan/bupropion is dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg once daily in the morning for the first 3 days of therapy. On the fourth day of therapy and thereafter, dosage of the fixed combination should be increased to the maximum recommended dosage of dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg twice daily given at least 8 hours apart. Do not exceed 2 doses within the same day.

The commercially available fixed combination of dextromethorphan hydrobromide and bupropion hydrochloride (dextromethorphan/bupropion; Auvelity(R)) is administered orally as extended-release tablets without regard to food. The extended-release tablets should be swallowed whole and should not be crushed, divided, or chewed.

Dextromethorphan/bupropion is intended for oral use only. Seizures and/or deaths have been reported when bupropion has been administered intranasally or by parenteral injection.

No dosing information is available for this tab.

When dextromethorphan/bupropion is used, interactions associated with each drug in the fixed combination should be considered.

Bupropion is metabolized to hydroxybupropion, principally by cytochrome P-450 (CYP) 2B6; CYP isoenzymes are not involved in the formation of other bupropion metabolites. Dextromethorphan is metabolized primarily by CYP2D6 to dextrorphan.

Bupropion and its metabolites inhibit CYP2D6. At therapeutically relevant concentrations, dextromethorphan does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Dextromethorphan does not induce CYP1A2, CYP3A4, or CYP2B6.

Dextromethorphan is a substrate of the P-glycoprotein (P-gp) transporter. Dextromethorphan does not inhibit transporters at therapeutically relevant concentrations.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antidepressants/Sibutramine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sibutramine has demonstrated antidepressant effects. (1)

CLINICAL EFFECTS: Concurrent use of sibutramine and an antidepressant may result in additive or synergistic central nervous system (CNS) effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The Australian,(2) Canadian,(1) and UK(3) manufacturers of sibutramine formerly stated that concurrent use with antidepressants is contraindicated. The Canadian manufacturer also states that concurrent use of St. John's wort is contraindicated.(1)

DISCUSSION: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The use of sibutramine with other CNS-active agents has not been evaluated.(1-3)

Bupropion/Pimozide; Thioridazine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Bupropion may inhibit the metabolism of pimozide and thioridazine at CYP2D6.(1,2) These agents are also known to lower the seizure threshold.(1,3,4,6)

CLINICAL EFFECTS: Concurrent use may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(1) Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(1,6) As well, concurrent use may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,3,4,6)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(3,4) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(7)

PATIENT MANAGEMENT: The concurrent use of pimozide or thioridazine with strong CYP2D6 inhibitors such as bupropion is contraindicated.(1,6) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Concurrent use should be initiated with low initial bupropion dosing and small gradual dosage increases of bupropion.(3,4) Single doses of bupropion should not exceed 150 mg.(3,4) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(3) or 450 mg for depression.(4)

DISCUSSION: The interactions of pimozide and thioridazine with bupropion have not been studied. In a controlled study in healthy subjects, steady-state paroxetine (60 mg daily, another strong inhibitor of CYP2D6) increased the area-under curve (AUC) and maximum concentration (Cmax) of a single dose of pimozide (2 mg) by 151% and 62%, respectively.(1)

Bupropion; Solriamfetol/Mao Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Bupropion and solriamfetol increase dopamine and norepinephrine concentrations via blockade of the dopamine and norepinephrine reuptake transporters.(1-4) Monoamine oxidase inhibitors (MAOIs) block the metabolism of norepinephrine and dopamine, also leading to increased neuronal concentrations of norepinephrine and dopamine.(5)

CLINICAL EFFECTS: The concurrent administration of bupropion or solriamfetol and MAOIs may increase the risk for hypertensive crisis, severe hypertension, or other adverse reactions,(3-4) including mania, psychosis or agitation with bupropion,(3) and headache, nausea, anorexia, or anxiety with solriamfetol.(4)

PREDISPOSING FACTORS: Patients with pre-existing hypertension may be more likely to experience treatment-emergent hypertension.(3) Patients with moderate to severe renal impairment may be at higher risk for increases in blood pressure and heart rate from solriamfetol due to prolonged drug exposure.(4)

PATIENT MANAGEMENT: The US manufacturers of bupropion and solriamfetol state that concurrent use of bupropion or solriamfetol with a MAOI is contraindicated due to the risk for hypertensive reactions.(3,4) The US manufacturer of phenelzine states that concurrent use of bupropion is contraindicated.(5) At least 14 days should elapse between the discontinuation of a MAOI and the initiation of bupropion or solriamfetol,(3-5) except in the case of methylene blue.(6) Do not initiate bupropion or solriamfetol therapy in patients receiving methylene blue until 24 hours after the last dose of these agents.(3,6) In emergency situations in patients maintained on bupropion or solriamfetol, weigh the availability and safety of alternatives to methylene blue against the risk of acute hypertension. If methylene blue therapy is required, the patient's bupropion or solriamfetol should be immediately discontinued. Patients' blood pressure should be closely monitored for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first.(3,6) In non-emergency situations in patients maintained on bupropion or solriamfetol when methylene blue therapy is planned, discontinue the patient's bupropion or solriamfetol at least 2 weeks in advance of methylene blue therapy. The patient's bupropion or solriamfetol therapy may be resumed 24 hours after the last dose of linezolid or methylene blue.(3,6) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of hypertensive crisis.

DISCUSSION: The US manufacturers of bupropion and solriamfetol state that concurrent use of bupropion or solriamfetol with a MAOI is contraindicated.(3,4) The US manufacturer of phenelzine states that concurrent use of bupropion is contraindicated.(5) At least 14 days should elapse between the discontinuation of a MAOI and the initiation of bupropion or solriamfetol.(1-5) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(6,7) Metaxalone is a weak inhibitor of MAO.(8,9) FDA alerts in July 2011(6) described the risk for serotonin syndrome when bupropion is used concurrently with methylene blue or other MAOIs. In October 2011 FDA updated these alerts, describing the risk for serotonin syndrome when MAOIs are combined with bupropion (and selected other psychiatric agents not associated with case reports of serotonin syndrome) as unclear.(7) Subsequent bupropion and solriamfetol prescribing information describes an increased risk for hypertensive reactions when co-prescribed with MAOIs.(3,4)

Dextromethorphan/Metaxalone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dextromethorphan inhibits neural reuptake of serotonin. Metaxalone, a weak inhibitor of MAO, may increase neuronal serotonin concentrations.(1)

CLINICAL EFFECTS: The concurrent use of dextromethorphan with MAOIs may result in hypotension, hyperpyrexia, sedation, somnolence, and death. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

PREDISPOSING FACTORS: Higher opioid concentrations as may occur due to inhibition of opioid clearance, patient specific genomic factors (e.g. poor metabolizer status for a P450 enzyme), or high opioid dosage may increase the risk for a severe interaction.

PATIENT MANAGEMENT: Dextromethorphan should not be used in patients taking MAOIs such as metaxalone. Use alternative agents for cough. The US manufacturer of Nuedexta (dextromethorphan-quinidine) states Nuedexta is contraindicated within 14 days of MAOI administration.(1) Quinidine increases systemic dextromethorphan concentrations 10 to 20-fold.

DISCUSSION: Metaxalone is a weak inhibitor of MAO.(2,3) There are at least two reports of potential interactions between MAOIs and dextromethorphan. Concomitant use of quinidine, a strong CYP2D6 inhibitor, increases systemic dextromethorphan concentrations 10 to 20-fold. Other strong CYP2D6 inhibitors such as bupropion, fluoxetine and paroxetine could similarly increase dextromethorphan levels and risk for serotonin toxicity in patients also receiving MAOIs.(4,5)

Select Opioids/Sibutramine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent administration may result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: Concurrent use of sibutramine and certain opioids may result in serotonin syndrome, a serious and potentially fatal reaction. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The UK manufacturer of sibutramine formerly stated that sibutramine should not be administered with other drugs that raise serotonin levels in the brain, including certain opioids such as dextromethorphan, meperidine, pentazocine, and fentanyl.(2) The US manufacturer of sibutramine stated that in general, sibutramine should not be administered with other serotonergic agents such as dextromethorphan, meperidine, pentazocine, and fentanyl. However, if concurrent administration is clinically indicated, the patient should be appropriately observed.(1) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. Patients in whom serotonin syndrome is suspected should receive immediate medical attention.

DISCUSSION: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. Because sibutramine inhibits serotonin reuptake and serotonin syndrome has been reported during concomitant use of selective serotonin reuptake inhibitors and certain opioids such as dextromethorphan, meperidine, pentazocine, and fentanyl, the UK manufacturer of sibutramine states that sibutramine should not be administered with these agents.(2)

Selected Antidepressants/Iomeprol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both iomeprol and selected antidepressants may lower the seizure threshold.(1)

CLINICAL EFFECTS: Use of iomeprol in a patient receiving selected antidepressants may increase the risk of seizure.(1) Antidepressants included in this monograph are tricyclic antidepressants (except formulations which also include benzodiazepines), bupropion, and oral monoamine oxidase(MAO) inhibitors used to treat depression.

PREDISPOSING FACTORS: Iomeprol associated seizures are more likely in patients with intracranial tumors or epilepsy.(1)

PATIENT MANAGEMENT: The manufacturer of iomeprol states that tricyclic antidepressants and MAO inhibitors should be discontinued 48 hours before iomeprol use. Treatment with an antidepressant should not be resumed until 24 hours post-procedure.(1) The UK manufacturer of bupropion states that it must not be used in the presence of predisposing risk factors such as medicinals which are known to lower the seizure threshold unless there is a compelling clinical justification that concurrent use outweighs the potential increased risk of seizure.(2)

DISCUSSION: Because selected antidepressants may lower seizure threshold, antidepressants should be discontinued 48 hours before iomeprol use. Treatment with an antidepressant should not be resumed until 24 hours post-procedure.(1)

Selected Cyp2d6 Substrates/Mavorixafor

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mavorixafor is a strong inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)

CLINICAL EFFECTS: Concurrent use of mavorixafor may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The US manufacturer of mavorixafor states concurrent use with CYP2D6 substrate that are highly dependent on CYP2D6 metabolism is contraindicated.(1) The US manufacturer of doxepin states if concurrent use of doxepin and strong CYP2D6 inhibitors such as mavorixafor is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on doxepin plasma concentrations.(5)

DISCUSSION: Mavorixafor (400 mg) increased dextromethorphan (CYP2D6 substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold and 9-fold, respectively.(1) Selected CYP2D6 substrates linked to this monograph include: aripiprazole, atomoxetine, brexpiprazole, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, fenfluramine, metoclopramide, methoxyphenamine, metoprolol, mexiletine, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.

Selected Opioids; Dextromethorphan/Selected Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Selected opioids inhibit neural reuptake of serotonin. MAOIs may increase neuronal serotonin concentrations via inhibition of MAO-A.(26)

CLINICAL EFFECTS: The concurrent use of selected opioids with MAOIs has resulted in hypotension, hyperpyrexia, sedation, somnolence, and death. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(26)

PREDISPOSING FACTORS: Higher opioid concentrations as may occur due to inhibition of opioid clearance, patient specific genomic factors (e.g. poor metabolizer status for a P450 enzyme), or high opioid dosage may increase the risk for a severe interaction.

PATIENT MANAGEMENT: Dextromethorphan, diamorphine, meperidine, and tapentadol should not be used in patients taking MAOIs. Use alternative agents for cough or pain. The US manufacturer of Nuedexta(dextromethorphan-quinidine) states Nuedexta is contraindicated within 14 days of MAOI administration.(28) Quinidine increases systemic dextromethorphan concentrations 10 to 20-fold. Other strong CYP2D6 inhibitors such as bupropion, fluoxetine and paroxetine could similarly increase dextromethorphan levels. The US manufacturer of selegiline states that concurrent use with dextromethorphan or meperidine is contraindicated. The US manufacturers of meperidine and tapentadol and the UK manufacturer of diamorphine state that they should not be used concurrently with or within 14 days of taking an MAOI.

DISCUSSION: The interaction between meperidine and MAOIs has been well documented. There are at least two reports of potential interactions between MAOIs and dextromethorphan. Concomitant use of quinidine, a strong CYP2D6 inhibitor, increases systemic dextromethorphan concentrations 10 to 20-fold. Other strong CYP2D6 inhibitors such as bupropion, fluoxetine and paroxetine could similarly increase dextromethorphan levels and risk for serotonin toxicity in patients also receiving MAOIs. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Serotonergic Agents/Dapoxetine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent administration of dapoxetine with other serotonergic agents may result in additive effects on serotonin, resulting in serotonin syndrome.(1,2)

CLINICAL EFFECTS: Concurrent use of dapoxetine with other serotonergic agents may result in serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: Use of multiple drugs which increase serotonin levels is associated with an increased risk for this toxidrome.

PATIENT MANAGEMENT: Dapoxetine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort.(1,2) Dapoxetine should not be initiated within 14 days of receiving other serotonergic agents. Other serotonergics should not be initiated within 7 days of receiving dapoxetine.(2)

DISCUSSION: This interaction is based on class labeling for these agents. Although there is no clinical documentation for an interaction between dapoxetine and either the elective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents, including sumatriptan and dihydroergotamine.

Strong Cyp2d6 Inhibitors/Sofpironium

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of sofpironium.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels and adverse effects of sofpironium, including increased risk of anticholinergic side effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of sofpironium and strong CYP2D6 inhibitors should be avoided.(1) If concurrent therapy is warranted with a strong CYP2D6 inhibitor, monitor patients closely for anticholinergic side effects.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of paroxetine (a strong CYP2D6 inhibitor) with sofpironium increased the maximum concentration (Cmax) and area-under-the-curve (AUC) by approximately 2-fold compared to sofpironium administration alone.(1) Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.(2,3)

Strong Cyp2d6 Inhibitors/Valbenazine (> 40 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Valbenazine's active metabolite (alpha-HTBZ) is metabolized by CYP2D6 and CYP3A4.(1) Bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine are strong inhibitors of CYP2D6.(2,3)

CLINICAL EFFECTS: Concurrent use of bupropion, dacomitinib, fluoxetine, paroxetine, quinidine or terbinafine may result in elevated levels and adverse effects of valbenazine such as somnolence and QT prolongation.

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its own metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction.(2) Concurrent use of strong CYP3A4 inhibitors may further increase levels of valbenazine.(1)

PATIENT MANAGEMENT: Reduce the valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP2D6 inhibitor.(1) During concomitant therapy with a strong CYP2D6 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine did not affect valbenazine maximum concentration (Cmax) or area-under-the-curve (AUC). However, Cmax and AUC for the active metabolite of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold, respectively. Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Bupropion Combinations/Strong Cyp2b6 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP2B6 inducers may induce the metabolism of bupropion.(1,2) For the dextromethorphan/bupropion combination, the metabolism of dextromethorphan may also be increased.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP2B6 inducers may decrease the effectiveness of bupropion.(1,2) For the dextromethorphan/bupropion combination, the levels and effectiveness of dextromethorphan may also be decreased.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturers of dextromethorphan/bupropion and naltrexone/bupropion state concurrent use with strong CYP2B6 inducers should be avoided.(1,2)

DISCUSSION: In a clinical study, carbamazepine 200 mg decreased the maximum concentration (Cmax) and area-under-curve (AUC) of bupropion by 74% and 76%, respectively, and decreased the Cmax and AUC of dextromethorphan by 59% and 64%, respectively.(1) In a study with 34 subjects, the effects of 150 mg of bupropion alone and 150 mg of bupropion with carbamazepine (a strong CYP2B6 inducer) were compared. Carbamazepine decreased bupropion AUC by 90% and peak Cmax by 87%. In addition, hydroxybupropion peak concentration Cmax by 71% and AUC by 50%.(3) In a study in 16 healthy subjects, rifampin (600 mg/day, a moderate CYP2B6 inducer) increased bupropion (150 mg single dose) apparent clearance 2-fold and decreased the bupropion half-life by 48%. In addition, concurrent rifampin increased the Cmax of hydroxybupropion by 43% and decreased the hydroxybupropion AUC by 38%.(4) Strong CYP2B6 inducers linked include: carbamazepine.(5,6)

Bupropion/Aripiprazole Lauroxil Submicronized

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors such as bupropion may inhibit the metabolism of aripiprazole.(1-4) Both agents are also known to lower the seizure threshold.(1,3,4)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1-4) Concurrent use may also result in additive effects on the seizure threshold, increasing the risk of seizures.(3,4)

PREDISPOSING FACTORS: The pharmacokinetic interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(3,4)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics such as aripiprazole should be undertaken only with extreme caution and with low initial bupropion dosing, small gradual dosage increases of bupropion,(3,4) and reduced dosages of aripiprazole.(5-7) Because Aristada Initio is only available in a single strength as a single-dose pre-filled syringe, the US manufacturer of the extended release aripiprazole lauroxil, submicronized (Aristada Initio) recommends avoiding use of strong CYP2D6 inhibitors such as bupropion with Aristada Initio.(1) Single doses of bupropion should not exceed 150 mg when used with aripiprazole.(3,4) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(4) or 450 mg for depression.(3)

DISCUSSION: Drug interaction studies have not been conducted with Aristada Initio. Aristada Initio has a long half-life (15-18 days).(1) The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole.(1)

Bupropion; Solriamfetol/Linezolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bupropion and solriamfetol increase dopamine and norepinephrine concentrations via blockade of the dopamine and norepinephrine reuptake transporters.(1-4) Linezolid is a weak, nonselective monoamine oxidase inhibitor (MAOI) that blocks the metabolism of norepinephrine and dopamine, also leading to increased neuronal concentrations of norepinephrine and dopamine.(5)

CLINICAL EFFECTS: The concurrent administration of bupropion or solriamfetol and linezolid may increase the risk for serotonin syndrome and/or severe hypertensive, or other adverse reactions, including mania, psychosis or agitation with bupropion, and headache, nausea, anorexia, or anxiety with solriamfetol.(1-2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: Patients with pre-existing hypertension may be more likely to experience treatment-emergent hypertension.(1) Patients with moderate to severe renal impairment may be at higher risk for increases in blood pressure and heart rate from solriamfetol due to prolonged drug exposure.(2)

PATIENT MANAGEMENT: The US manufacturers of bupropion and solriamfetol state that concurrent use of bupropion or solriamfetol with a MAOI is contraindicated due to the risk for hypertensive reactions.(1,2) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(5) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(6,7) In non-emergency situations in patients maintained on bupropion or solriamfetol when linezolid therapy is planned, discontinue the patient's bupropion or solriamfetol at least 2 weeks in advance of linezolid therapy.(1,6) In emergency situations in patients maintained on bupropion or solriamfetol, weigh the availability and safety of alternatives to linezolid against the risk of acute hypertension. If linezolid therapy is required, the patient's bupropion or solriamfetol should be immediately discontinued. Patients' blood pressure should be closely monitored for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first.(1,6) The patient's bupropion or solriamfetol therapy may be resumed 24 hours after the last dose of linezolid.(1,6) Clinical studies have found a low incidence of serotonin syndrome in patients on concomitant linezolid and serotonergic agents, ranging from 0.24% to 4%, depending on the quality and size of the study. While linezolid-associated serotonin syndrome is potentially serious and fatal, if treated early, it is quickly reversible with discontinuation of offending agents and supportive care. Therefore, some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use of linezolid without a washout is warranted, the patient should be closely monitored.(8-13) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: The US manufacturers of bupropion and solriamfetol state that concurrent use of bupropion or solriamfetol with a MAOI is contraindicated.(1,2) An FDA alert in July 2011(6) described the risk for serotonin syndrome when bupropion is used concurrently with linezolid. In October 2011 FDA updated these alerts, describing the risk for serotonin syndrome when MAOIs are combined with bupropion (and selected other psychiatric agents not associated with case reports of serotonin syndrome) as unclear.(7) Subsequent bupropion and solriamfetol prescribing information describes an increased risk for hypertensive reactions when co-prescribed with MAOIs.(1,2)

Dopamine Transporter Binders/Ioflupane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ioflupane binds to the dopamine transporter. Agents that also bind to this transporter may affect the results of single photon emission computed tomography (SPECT) brain imaging using ioflupane.(1)

CLINICAL EFFECTS: SPECT imaging using ioflupane may not be accurate in patients taking other drugs that bind to the dopamine transporter binders.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: It is unknown if discontinuing other agents that bind to the dopamine transporter prior to a scan with ioflupane will decrease interference with the scan.(1) If use of these drugs can be safely suspended, consider discontinuing for at least 5 biological half-lives before administration of ioflupane.(1) Make sure the radiologist interpreting the scan knows the patient is taking another agent that binds to the dopamine transporter. Alternative diagnostic tools may need to be considered.

DISCUSSION: Ioflupane binds to the dopamine transporter. Agents that also bind to this transporter may affect the results of the scan. These agents include amoxapine, amphetamine, armodafinil, benztropine, bupropion, buspirone, citalopram, cocaine, dexmethylphenidate, escitalopram, fluoxetine, fluvoxamine, mazindol, methamphetamine, methylphenidate, modafinil, norephedrine, paroxetine, phentermine, phenylpropanolamine, selegiline, and sertraline.(1) In patients taking venlafaxine or desvenlafaxine, there have been cases of altered ioflupane uptake that impacted image interpretation. The mechanism of interference of these drugs with ioflupane is not known.(1)

Selected Cyp1a2 Or Cyp2d6 Substrates/Givosiran

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Givosiran interferes with the first and rate-limiting step in hepatic heme biosynthesis, which may lower hepatic heme levels and decrease production and/or activity of cytochrome P450 enzymes.(1,2)

CLINICAL EFFECTS: Concurrent use of givosiran may result in elevated levels of and toxicity from agents metabolized by CYP1A2 or CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: Avoid the concurrent use of givosiran with agents that are sensitive substrates of CYP1A2 or CYP2D6, or CYP1A2 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is unavoidable, decrease the dose of the CYP1A2 or CYP2D6 substrate and monitor patients for toxicity.

DISCUSSION: A study of 9 patients with acute intermittent porphyria found that givosiran decreased the maximum concentration (Cmax) and area-under-curve (AUC) of caffeine (a CYP1A2 substrate) by 1.3- and 3.1-fold, respectively, compared to caffeine alone. Givosiran also decreased the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) by 2- and 2.4-fold, respectively, compared to dextromethorphan alone.(1,2) Selected CYP2D6 substrates linked to this monograph include: atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, nefazodone, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, and venlafaxine. Selected CYP1A2 substrates linked to this monograph include: agomelatine, aminophylline, rasagiline, tacrine, theophylline, tizanidine, and yohimbine.

Selected Cyp2d6 Substrates/Desvenlafaxine (>100 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Desvenlafaxine is considered a weak inhibitor of CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of desvenlafaxine may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP2D6 pathway.(1) Agents linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

PREDISPOSING FACTORS: With perphenazine and tolterodine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: Reduce the dose of CYP2D6 substrates by up to one-half when coadministered with desvenlafaxine 400 mg.(1) Studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. CYP2D6 substrates should be dosed at the original level when coadministered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued.(1) The manufacturer of desvenlafaxine does not provide recommendations for use of desvenlafaxine at dosages between 100-400 mg concurrently with CYP2D6 substrates. Monitor for toxicity of the CYP2D6 substrate and consider reducing its dosage.

DISCUSSION: In a study, coadministration of desvenlafaxine 100 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 25% and 17%.(1) In a study, coadministration of desvenlafaxine 400 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 50% and 90%.(1) Selected CYP2D6 substrates linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

Selected Cyp2d6 Substrates/Panobinostat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Panobinostat is a moderate inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)

CLINICAL EFFECTS: Concurrent use of panobinostat may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: Avoid the concurrent use of panobinostat with agents that are sensitive CYP2D6 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is warranted, monitor patients for toxicity.(1)

DISCUSSION: In a study in 14 subjects with advanced cancer, panobinostat (20 mg daily on Days 3, 5, and 8) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dextromethorphan (60 mg) by 20-200% and 20-130%, respectively. Dextromethorphan exposures were extremely variable.(1) Selected CYP2D6 substrates linked to this monograph include: atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.

Selected Strong Cyp2d6 Inhibitors/Nasal Metoclopramide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of metoclopramide.

CLINICAL EFFECTS: Concurrent use may result in elevated levels of metoclopramide, which may increase the risk of extrapyramidal symptoms such as tardive dyskinesia, which may be permanent. Tardive dyskinesia typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs. Concurrent use may also result in serotonin syndrome. Symptoms of serotonin syndrome include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death.

PREDISPOSING FACTORS: Patients with renal and/or hepatic impairment may have an increased risk from this combination.

PATIENT MANAGEMENT: The manufacturer of metoclopramide nasal spray states concurrent use with strong CYP2D6 inhibitors is not recommended. If concurrent therapy is warranted, patients should be monitored for extrapyramidal symptoms and signs and symptoms of serotonin syndrome. Instruct patients to report any abnormal/uncontrollable muscle movements, muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study in 20 healthy male subjects, concurrent fluoxetine (60 mg daily, another strong CYP2D6 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg single dose) by 42% and 89%, respectively.(1,2) There have been case reports of serotonin syndrome in patients receiving concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(3) sertraline,(5-7) and venlafaxine.(7) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)

Selected Strong Cyp2d6 Inhibitors/Tamoxifen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.

PREDISPOSING FACTORS: Concurrent use of strong CYP2D6 inhibitors in patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The Canadian and UK manufacturers of fluoxetine state that whenever possible co-administration with tamoxifen should be avoided.(14-15) The National Comprehensive Cancer Network's (NCCN) breast cancer guidelines advise caution when coadministering strong CYP2D6 inhibitors with tamoxifen. NCCN states when prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid SSRIs that are strong and moderate CYP2D6 inhibitors, particularly fluoxetine and paroxetine, if an appropriate alternative exists.(16) Cancer Care Ontario breast cancer guidelines state concurrent use of strong CYP2D6 inhibitors should be avoided.(17) The European Society of Medical Oncology (ESMO) clinical practice guidelines for early breast cancer states patients on tamoxifen should be advised to avoid concurrent use of strong and moderate CYP2D6 inhibitors. Consider alternatives to tamoxifen if CYP2D6 inhibitors cannot be replaced with alternative agents.(18) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient.

DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(19) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(20-21) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(22-24) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(25-29) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Strong inhibitors of CYP2D6 include bupropion, dacomitinib, fluoxetine, paroxetine, peruvian bark extract, and terbinafine.(30-31)

Strong & Moderate Cyp2d6 Inhibitors/Eliglustat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP3A4, eliglustat metabolism can be further inhibited.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a strong or moderate inhibitor of CYP2D6 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)

PREDISPOSING FACTORS: If the patient has hepatic impairment, is also taking an inhibitor of CYP3A4 and/or is an extensive or intermediate metabolizer of CYP2D6, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in both extensive and intermediate CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be continued at 84 mg once daily.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in poor metabolizers of CYP2D6 should be avoided and is contraindicated in extensive and intermediate metabolizers of CYP2D6.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(5)

DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Strong inhibitors of CYP2D6 include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(1,3,4) Moderate inhibitors of CYP2D6 include: abiraterone, asunaprevir, capivasertib, cinacalcet, duloxetine, escitalopram, levomepromazine, levomethadone, mirabegron, moclobemide, and rolapitant.(1,3,4)

Strong 2D6 Inhibitors/Atomoxetine; Vortioxetine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: FDA designates atomoxetine as a 'sensitive substrate' at CYP2D6. Sensitive substrates are drugs whose area-under-curve (AUC) increases 5-fold or higher when given a strong inhibitor of a particular enzyme.(1) Although metabolized via several CYP P-450 pathways, vortioxetine appears primarily metabolized via CYP2D6.(2-3) Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine are strong inhibitors of CYP2D6. Terbinafine is a moderate to strong inhibitors of CYP2D6.(1,4)

CLINICAL EFFECTS: Concurrent use of bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, or terbinafine may result in elevated levels and adverse effects of atomoxetine or vortioxetine. Atomoxetine adverse effects may include elevated blood pressure, tachycardia, insomnia, irritability, nausea/vomiting, or appetite suppression.(5,7) Vortioxetine adverse effects may include headache, nausea, vomiting, dizziness, or abnormal dreams.(2,3)

PREDISPOSING FACTORS: Patients who are CYP2D6 ultrarapid metabolizers may be affected to a greater extent by CYP2D6 inhibitors. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: When a strong CYP2D6 inhibitor is added to existing atomoxetine therapy, exposure to atomoxetine may increase greater than 5-fold, depending upon the dosage and specific CYP2D6 inhibitor involved. The manufacturer of atomoxetine recommends downward dosage adjustments when patients receive concomitant treatment with strong CYP2D6 inhibitors.(5) When initiating atomoxetine in children and adolescents weighing up to 70 Kg who are already receiving strong CYP2D6 inhibitors, the atomoxetine dose should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.(5) When initiating atomoxetine in children and adolescents weighing over 70 Kg and adults who are receiving strong CYP2D6 inhibitors, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.(5) The manufacturer of vortioxetine recommends reducing vortioxetine dose by half when a strong CYP2D6 inhibitor is coadministered.(2)

DISCUSSION: In a single-blind study in 22 healthy subjects, the concurrent administration of paroxetine (20 mg twice daily in one arm, 20 mg one daily in another arm) with atomoxetine (20 mg twice daily) resulted in increases in the maximum concentration (Cmax), area-under-curve (AUC), and half-life of atomoxetine by 3.5-fold, 6.5-fold, and 2.5-fold, respectively. There were no changes in paroxetine pharmacokinetics.(4) In extensive metabolizers administered paroxetine(2,3) or fluoxetine(2) with atomoxetine, the AUC of atomoxetine is approximately 6-fold to 8-fold and the Cmax is about 3-fold to 4-fold greater than with atomoxetine alone. In vitro studies suggest that administration of CYP P-450 inhibitors to poor metabolizers would not increase plasma atomoxetine concentrations.(2) A drug interaction study conducted over 28 days evaluated the effect of bupropion 150 mg twice daily on the tolerance and steady-state kinetics of vortioxetine 10 mg daily in 28 healthy subjects. Vortioxetine AUC and Cmax increased by 2.3 and 2.1 fold respectively.(3) Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine are strong inhibitors of CYP2D6. Terbinafine is a moderate to strong inhibitors of CYP2D6.(1,4)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Bupropion Combinations/Moderate Cyp2b6 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate CYP2B6 inducers may induce the metabolism of bupropion.(1,2) For the dextromethorphan/bupropion combination, the metabolism of dextromethorphan may also be increased.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP2B6 inducers may decrease the effectiveness of bupropion.(1,2) For the dextromethorphan/bupropion combination, the levels and effectiveness of dextromethorphan may also be decreased.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Consider the use of alternative agents in patients maintained on bupropion for psychiatric indications and inform patients that bupropion may not be effective for smoking cessation during concurrent moderate CYP2B6 inducers. If concurrent use is warranted, monitor patients for decreased levels and effectiveness if moderate CYP2B6 inducers are initiated. The dosage of bupropion may need to be increased; however, the maximum recommended dose of bupropion should not be exceed.(2)

DISCUSSION: In a clinical study, carbamazepine 200 mg decreased the maximum concentration (Cmax) and area-under-curve (AUC) of bupropion by 74% and 76%, respectively, and decreased the Cmax and AUC of dextromethorphan by 59% and 64%, respectively.(1) In a study with 34 subjects, the effects of 150 mg of bupropion alone and 150 mg of bupropion with carbamazepine (a strong CYP2B6 inducer) were compared. Carbamazepine decreased bupropion AUC by 90% and peak Cmax by 87%. In addition, carbamazepine increased hydroxybupropion Cmax by 71% and AUC by 50%.(3) In a study in 16 healthy subjects, rifampin (600 mg/day, a moderate CYP2B6 inducer) increased bupropion (150 mg single dose) apparent clearance 2-fold and decreased the bupropion half-life by 48%. In addition, concurrent rifampin increased the Cmax of hydroxybupropion by 43% and decreased the hydroxybupropion AUC by 38%.(4) Moderate CYP2B6 inducers linked include: dipyrone, efavirenz, rifampin, and ritonavir.(4,5)

Bupropion/Amantadine; Foslevodopa; Levodopa

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Amantadine, levodopa, and bupropion have dopamine agonist effects. Toxicity may result from cumulative dopamine agonist effects.(1) Foslevodopa is a prodrug of levodopa.(2)

CLINICAL EFFECTS: Concurrent administration of amantadine/levodopa and bupropion may result in CNS toxicity, such as, restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use caution when amantadine/levodopa and bupropion are used concurrently. Monitor for signs of CNS toxicity, which may include restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.(1)

DISCUSSION: CNS toxicity has been reported with concurrent administration of amantadine and bupropion. Three out of six nursing home residents administered concurrent bupropion and amantadine developed confusion, restlessness, agitation, gross motor tremors, ataxia, gait disturbance, dizziness, and vertigo. Two patients had severe symptoms and were hospitalized.(3) In a case report, bupropion (75 mg twice daily) was added to amantadine, haloperidol, and benztropine. The patient became disoriented and agitated, developed visual and auditory hallucinations, impaired attention and memory, a fluctuating level of awareness, and unsteady gait.(4)

Bupropion/Antipsychotics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both bupropion and the antipsychotics are known to lower the seizure threshold.(1,2) Bupropion is also a strong inhibitor of CYP2D6.(3)

CLINICAL EFFECTS: Concurrent use of bupropion and an antipsychotic may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1,2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1)

Bupropion/Aripiprazole Im Every 2 Months

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors such as bupropion may inhibit the metabolism of aripiprazole. Both agents are also known to lower the seizure threshold.(1-3)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole. Concurrent use may also result in additive effects on the seizure threshold, increasing the risk of seizures.(1-3)

PREDISPOSING FACTORS: The pharmacokinetic interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(2-3)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics such as aripiprazole should be undertaken only with extreme caution and with low initial bupropion dosing, small gradual dosage increases of bupropion,(2-3) and reduced dosages of aripiprazole.(1) Single doses of bupropion should not exceed 150 mg.(2-3) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(3) or 450 mg for depression.(2) The US manufacturer of aripiprazole IM every 2 months injection (Abilify Asimtufii) makes the following recommendations for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 960 mg every 2 months and a strong CYP2D6 inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2 months. - if the patient is taking both a strong CYP2D6 inhibitor AND a strong CYP3A4 inhibitor, avoid use of Abilify Asimtufii.

DISCUSSION: There have been no specific drug-drug interaction studies with aripiprazole long-acting injections. The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold.(1)

Bupropion/Aripiprazole Im Monthly

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors such as bupropion may inhibit the metabolism of aripiprazole.(1-2) Both agents are also known to lower the seizure threshold.(1,3-4)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1) Concurrent use may also result in additive effects on the seizure threshold, increasing the risk of seizures.(1,3-4)

PREDISPOSING FACTORS: The pharmacokinetic interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(3-4)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics such as aripiprazole should be undertaken only with extreme caution and with low initial bupropion dosing, small gradual dosage increases of bupropion,(3-4) and reduced dosages of aripiprazole.(1) Single doses of bupropion should not exceed 150 mg.(3-4) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(4) or 450 mg for depression.(3) The US manufacturer of aripiprazole IM monthly injection (Abilify Maintena) recommends the following dose adjustments for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 400 mg per month and a strong CYP2D6 inhibitor is started, then decrease aripiprazole dose to 300 mg per month. - if the aripiprazole dose is 400 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 200 mg per month. - if the aripiprazole dose is 300 mg per month and a strong CYP2D6 inhibitor is started, then decrease aripiprazole dose to 200 mg per month. - if the aripiprazole dose is 300 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 160 mg per month.(1)

DISCUSSION: There have been no drug-drug interaction studies with aripiprazole long-acting injections. The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of oral aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole.(1)

Bupropion/Aripiprazole Immediate Release

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors such as bupropion may inhibit the metabolism of aripiprazole.(1-2) Both agents are also known to lower the seizure threshold.(1,3-4)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1) Concurrent use may also result in additive effects on the seizure threshold, increasing the risk of seizures.(3-4)

PREDISPOSING FACTORS: The pharmacokinetic interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(3-4)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics such as aripiprazole should be undertaken only with extreme caution and with low initial bupropion dosing, small gradual dosage increases of bupropion,(3-4) and reduced dosages of aripiprazole.(1) Single doses of bupropion should not exceed 150 mg.(3-4) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(5) or 450 mg for depression.(3) The US manufacturer of oral aripiprazole states that the dose of aripiprazole should be reduced to one-half of its normal dose when strong CYP2D6 inhibitors, such as bupropion, are coadministered, unless aripiprazole is being used as adjunctive therapy for Major Depressive Disorder. If the patient is also receiving a strong CYP3A4 inhibitor, the dose of aripiprazole should be reduced to one-fourth its normal dose. When the inhibitor is discontinued, the dose of aripiprazole should be increased.(1)

DISCUSSION: The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole.(1)

Bupropion/Aripiprazole Lauroxil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors such as bupropion may inhibit the metabolism of aripiprazole. Both agents are also known to lower the seizure threshold.(1-3)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole. Concurrent use may also result in additive effects on the seizure threshold, increasing the risk of seizures.(1-3)

PREDISPOSING FACTORS: The pharmacokinetic interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor. Poor metabolizers of CYP2D6 are not expected to experience increased aripiprazole exposure.(1) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(2-3)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics such as aripiprazole should be undertaken only with extreme caution and with low initial bupropion dosing, small gradual dosage increases of bupropion,(2-3) and reduced dosages of aripiprazole.(1) Single doses of bupropion should not exceed 150 mg.(2-3) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(3) or 450 mg for depression.(2) The US manufacturer of aripiprazole lauroxil extended-release injection (Aristada) recommends the following dose adjustments for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - Reduce the dose of aripiprazole lauroxil to the next lower strength. No dosage adjustment is necessary in patient taking the 441 mg dose, if tolerated. - For patients taking both a strong CYP2D6 and CYP3A4 inhibitor, avoid 662 mg, 882 mg, and 1,064 mg doses. No dose adjustment is necessary in patients taking the 441 mg dose, if it is tolerated. If the patient is a poor metabolizer of CYP2D6, no dose adjustment is required.(1)

DISCUSSION: The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold.(1)

Bupropion/Hypoglycemics; Insulin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bupropion can lower the seizure threshold and when given concurrently with other medications that also lower the threshold there is an increased risk of seizure. Concurrent use of hypoglycemics or insulin increases the risk of hypoglycemia which can result in seizures.(1,2)

CLINICAL EFFECTS: Concurrent use of bupropion and hypoglycemics or insulin may increase the risk of seizure.(1,2)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; or with concomitant medications known to lower seizure threshold (antidepressants, antipsychotics, systemic steroids, theophylline).(1,2)

PATIENT MANAGEMENT: The use of bupropion in patients treated with oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2)

Bupropion/Iloperidone; Milsaperidone; Zuclopenthixol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors such as bupropion may inhibit the metabolism of iloperidone, milsaperidone, and zuclopenthixol.(1-7) These agents are also known to lower the seizure threshold.(1-7)

CLINICAL EFFECTS: Concurrent administration of bupropion may result in elevated iloperidone, milsaperidone, or zuclopenthixol levels and toxicities, including the risk for QTc prolongation.(1-7) Concurrent use may also result in additive effects on the seizure threshold, increasing the risk of seizures.

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(8) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(8) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(2,3)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics such as iloperidone should be undertaken only with extreme caution and with low initial bupropion dosing, small gradual dosage increases of bupropion, and reduced dosages of iloperidone. Single doses of bupropion should not exceed 150 mg. The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation or 450 mg for depression.(2,3) The US manufacturer of iloperidone and milsaperidone states that the dose should be reduced to one-half of its normal dose when strong CYP2D6 inhibitors such as bupropion are coadministered.(4,5) If bupropion is discontinued iloperidone and milsaperidone exposure will wane, and the dose should be increased.(4,5) Concurrent administration of iloperidone or milsaperidone with both a CYP2D6 inhibitor and CYP3A4 inhibitor does not have additive inhibitory effects compared to either inhibitor alone. The dose of iloperidone or milsaperidone should be reduced to one-half of its normal dose, and further dose reduction is not required.(4,5) The UK manufacturer of zuclopenthixol states that zuclopenthixol is partly metabolized by CYP2D6. Concurrent use with CYP2D6 inhibitors may increase the risk of adverse effects and cardiotoxicity.(6) The Swedish manufacturer of zuclopenthixol states that dose adjustment of zuclopenthixol may be required when used concurrently with CYP2D6 inhibitors.(7) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The interactions of iloperidone and zuclopenthixol with bupropion have not been studied. Other CYP2D6 inhibitors have been reported to interact with iloperidone and zuclopenthixol. In a study in 23 healthy subjects, fluoxetine (a strong CYP2D6 inhibitor, 20 mg twice daily for 21 days) increased the area-under-curve (AUC) of iloperidone (3 mg single dose) and its P88 metabolite by 2- to 3-fold. The AUC of iloperidone's P95 metabolite decreased by 50%.(4) In a study in patients with schizophrenia, paroxetine (a strong CYP2D6 inhibitor, 20 mg daily for 5-8 days) increased the maximum concentration (Cmax) of iloperidone and its P88 metabolite by about 1.6-fold. The Cmax of iloperidone's P95 metabolite decreased by 50%.(4) Coadministration of paroxetine (20 mg daily) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(4) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(4) A retrospective review of psychiatry patients found that fluoxetine and paroxetine increased the dose-adjusted zuclopenthixol concentration by 93% and 78%, respectively.(9)

Bupropion/Risperidone Intramuscular Every 2 Weeks

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bupropion is a strong CYP2D6 inhibitor and may inhibit the metabolism of risperidone.(1-4) Both bupropion and risperidone are known to lower the seizure threshold.(1-3)

CLINICAL EFFECTS: Concurrent use may result in elevated levels and increased side effects from risperidone. Concurrent use of bupropion and risperidone may result in additive effects on the seizure threshold, increasing the risk of seizures.(1-3)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1,2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The US manufacturer of extended release risperidone microspheres for injection (Risperdal Consta) recommends that patients maintained on the 25 mg dose of this product continue to receive the 25 mg dose when either fluoxetine or paroxetine (strong CYP2D6 inhibitors) is initiated, unless clinical judgment necessitates lowering the dose or interrupting therapy. If a decision is made to lower the dose, the dose may be lowered 2 to 4 weeks before the initiation of fluoxetine or paroxetine.(3)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1) In a study in 7 patients maintained on risperidone (doses ranged from 2 mg daily to 4 mg daily), the addition of duloxetine (60 mg daily) increased risperidone levels by 25%. The mean plasma risperidone/9-hydroxyrisperidone ratio increased 1.95-fold. One patient developed mild extrapyramidal symptoms. His risperidone level at the time was 72 ng/ml.(7) In contrast, a retrospective chart review compared 7 patients receiving concurrent risperidone and duloxetine to control patients receiving only risperidone and found no significant effect on risperidone levels.(8) A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(9) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(9) A study in 3 poor metabolizer and 8 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(10) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(11) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(11)

Bupropion/Risperidone Intramuscular Monthly

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors such as bupropion may inhibit the metabolism of risperidone. Both agents are also known to lower the seizure threshold.(1-3)

CLINICAL EFFECTS: Concurrent administration of bupropion with risperidone may result in elevated levels of and toxicity from risperidone. Concurrent use may also result in additive effects on the seizure threshold, increasing the risk of seizures.(1-3)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1-2)

PATIENT MANAGEMENT: The concurrent use of bupropion and risperidone should be undertaken only with extreme caution and with low initial bupropion dosing, small gradual dosage increases of bupropion,(1-2) and reduced dosages of risperidone.(3) Single doses of bupropion should not exceed 150 mg.(1-2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) The US manufacturer of risperidone for monthly intramuscular injection (Risvan) makes the following recommendations for patients who receive a strong CYP2D6 inhibitor, such as bupropion: - Initiation of a CYP2D6 inhibitor: the recommended dose of risperidone is 75 mg started at least 2 to 4 weeks prior to starting a strong CYP2D6 inhibitor to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors are initiated in patients receiving risperidone 75 mg, it is recommended to continue treatment with 75 mg unless clinical judgment necessitates interruption of risperidone treatment. - Discontinuation of a CYP2D6 inhibitor: the effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone (active metabolite) have not been studied.(3)

DISCUSSION: No specific drug interaction studies have been performed with intramuscular risperidone extended-release formulation (Risvan) and bupropion. The drug interaction data summarized is based on studies with oral risperidone and other strong CYP2D6 inhibitors: A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(4) A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(5) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(6)

Bupropion/Risperidone Subcutaneous Every 1-2 Months

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bupropion is a strong CYP2D6 inhibitor and may inhibit the metabolism of risperidone.(1-4) Both bupropion and risperidone are known to lower the seizure threshold.(1-3)

CLINICAL EFFECTS: Concurrent use may result in elevated levels and increased side effects from risperidone. Concurrent use of bupropion and risperidone may result in additive effects on the seizure threshold, increasing the risk of seizures.(1-3)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1,2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The manufacturer of extended release risperidone injectable suspension (Uzedy) recommends patients be placed on the lowest dose (50 mg monthly or 100 mg once every 2 months) of Uzedy before the planned start of strong CYP2D6 inhibitor therapy to adjust for the expected increase in risperidone plasma concentrations. When strong CYP2D6 inhibitors are initiated in patients receiving Uzedy 50 mg monthly or 100 mg once every 2 months, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of risperidone treatment.(3)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1) In a study in 7 patients maintained on risperidone (doses ranged from 2 mg daily to 4 mg daily), the addition of duloxetine (60 mg daily) increased risperidone levels by 25%. The mean plasma risperidone/9-hydroxyrisperidone ratio increased 1.95-fold. One patient developed mild extrapyramidal symptoms. His risperidone level at the time was 72 ng/ml.(7) In contrast, a retrospective chart review compared 7 patients receiving concurrent risperidone and duloxetine to control patients receiving only risperidone and found no significant effect on risperidone levels.(8) A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(9) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(9) A study in 3 poor metabolizer and 8 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(10) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(11) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(11)

Bupropion/Risperidone Subcutaneous Monthly

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bupropion is a strong CYP2D6 inhibitor and may inhibit the metabolism of risperidone.(1-4) Both bupropion and risperidone are known to lower the seizure threshold.(1-3)

CLINICAL EFFECTS: Concurrent use may result in elevated levels and increased side effects from risperidone. Concurrent use of bupropion and risperidone may result in additive effects on the seizure threshold, increasing the risk of seizures.(1-3)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1,2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)

PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The manufacturer of extended release risperidone injectable suspension (Perseris) recommends patients be placed on the lowest dose (90 mg) of Perseris two to four weeks before the planned start of a strong CYP2D6 inhibitor to adjust for the expected increase in risperidone plasma concentrations. When a strong CYP2D6 inhibitor is initiated in patients receiving Perseris 90 mg, it is recommended to continue treatment with 90 mg unless clinical judgment necessitates interruption of risperidone treatment.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1) A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(7) A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(8) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(9)

Bupropion/Selected Antidepressants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Depending upon the antidepressant, one or two mechanisms may be involved. Both bupropion and antidepressants are known to lower the seizure threshold.(1,2) Bupropion, a strong inhibitor of CYP2D6 may increase systemic exposure (AUC, area-under-curve) to antidepressants metabolized by this pathway. The tricyclic antidepressants, the SSRIs, and the SNRIs are the most sensitive to CYP2D6 inhibition and are addressed in separate monographs. Antidepressants which are metabolized by CYP2D6 but less susceptible to CYP2D6 inhibition are: mianserin, mirtazapine, nefazodone active metabolite (mCPP), and trazodone active metabolite (mCPP).(3)

CLINICAL EFFECTS: Concurrent use of bupropion and an antidepressant may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2) Concurrent use may also increase levels of and side effects from antidepressants metabolized by CYP2D6, such as mianserin, mirtazepine, nefazodone, and trazodone.(3)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids).(1,2)

PATIENT MANAGEMENT: The concurrent use of bupropion and antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) In a study in 15 male subjects who were extensive metabolizers of CYP2D6, bupropion (150 mg twice daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine (50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2)

Bupropion/Snris; Ssris

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both bupropion and the SSRIs and SNRIs are known to lower the seizure threshold.(1,2) In addition, bupropion, a strong inhibitor of CYP2D6, may inhibit the metabolism of SSRIs and SNRIs metabolized by CYP2D6. The potential for bupropion to inhibit the metabolism of the antidepressant differs. Antidepressants that are very sensitive to CYP2D6 inhibition have a greater potential for increased effects. Antidepressants which are very sensitive to CYP2D6 inhibition and have the greatest potential for increased effects are: fluoxetine,(3) paroxetine,(4) and venlafaxine.(5) Antidepressants which are moderately sensitive to CYP2D6 inhibition are: fluvoxamine.(6) Antidepressants which are metabolized by CYP2D6 but less susceptible to CYP2D6 inhibition and therefore have a lower potential for increased effects are: citalopram(7) and duloxetine.(8)

CLINICAL EFFECTS: Concurrent use of bupropion and a SSRI or SNRI may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2) Concurrent use may also increase levels of and side effects from antidepressants metabolized by CYP2D6, such as citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine, and venlafaxine.(3-10)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids).(1,2) With paroxetine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(11)

PATIENT MANAGEMENT: The concurrent use of bupropion and SSRIs or SNRIs should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) In a study in 15 male subjects who were extensive metabolizers of CYP2D6, bupropion (150 mg twice daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine (50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2) In a clinical study, citalopram steady state levels were not significantly different in poor metabolizers and extensive metabolizers of CYP2D6. Coadministration of a drug that inhibits CYP2D6 with citalopram is unlikely to have clinically significant effects on citalopram metabolism, based on the study results in CYP2D6 poor metabolizers.(7) Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the AUC of duloxetine by about 60%.(8) An in vivo study of single-dose fluvoxamine evaluated pharmacokinetic changes in 13 poor metabolizers (PM) compared to 16 extensive metabolizers (EM). The mean Cmax, AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group.(6) Fluoxetine, paroxetine, and venlafaxine are classified as sensitive CYP2D6 substrates with an increase in AUC >= 5-fold.(9) The FDA defines sensitive substrates as drugs that have an increase in AUC >= 5-fold and moderate sensitive substrates have an increase in AUC >= 2-fold to <5-fold when administered with strong inhibitors.(10)

Bupropion/Steroids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both bupropion and systemic steroids are known to lower the seizure threshold.(1,2)

CLINICAL EFFECTS: Concurrent use of bupropion and systemic steroids may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, antipsychotics, theophylline).(1,2)

PATIENT MANAGEMENT: The concurrent use of bupropion and systemic steroids should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and systemic steroids should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2)

Bupropion/Theophylline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both bupropion and theophylline are known to lower the seizure threshold.(1,2)

CLINICAL EFFECTS: Concurrent use of bupropion and theophylline may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, antipsychotics, systemic steroids).(1,2)

PATIENT MANAGEMENT: The concurrent use of bupropion and theophylline should be undertaken only with extreme caution and with low initial dosing of bupropion and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and theophylline should be undertaken only with extreme caution and with low initial bupropion dosing and small, gradual dosage increases.(1,2)

Bupropion/Tricyclic Antidepressants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Depending upon the antidepressant, one or two mechanisms may be involved. Both bupropion and tricyclic antidepressants are known to lower the seizure threshold.(1,2) Bupropion, a strong inhibitor of CYP2D6, may increase systemic exposure (AUC, area-under-curve) to tricyclic antidepressants that are metabolized by this pathway. Antidepressants which are very sensitive to CYP2D6 inhibition are: desipramine, doxepin, and trimipramine. Antidepressants which are moderately sensitive to CYP2D6 inhibition are: amitriptyline, imipramine, maprotiline, and nortriptyline. Antidepressants which are metabolized by CYP2D6 but less susceptible to CYP2D6 inhibition includes clomipramine.(3)

CLINICAL EFFECTS: Concurrent use of bupropion and a tricyclic antidepressant may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2) Concurrent use may also increase levels of and side effects from antidepressants metabolized by CYP2D6, such as amitriptyline, clomipramine, imipramine, maprotiline, and nortriptyline.(3)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids).(1,2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The concurrent use of bupropion and tricyclic antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) If concurrent use of doxepin and bupropion is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on doxepin plasma concentrations.(5)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) In a study in 15 male subjects who were extensive metabolizers of CYP2D6, bupropion (150 mg twice daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine (50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2)

Dextromethorphan-Bupropion/Selected Strong Cyp2d6 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of dextromethorphan.(1-5)

CLINICAL EFFECTS: Patients may experience increased adverse effects of dextromethorphan due to elevated systemic concentrations. Elevated levels of dextromethorphan or concomitant use of two or more serotonergic agents increases the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(6) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(6) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(6) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(6)

PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(6)

PATIENT MANAGEMENT: The manufacturer of dextromethorphan-bupropion recommends a dose reduction when coadministered with strong CYP2D6 inhibitors as follows: - For major depressive disorder, the maximum dosage is 45 mg/105 mg daily. - For agitation associated with Alzheimer's dementia, start with 30 mg/105 mg daily then increase to a maximum dosage of 45 mg/105 mg daily on day 8.(1) Monitor patients for elevated dextromethorphan levels or symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a clinical trial, paroxetine 20 mg (a strong CYP2D6 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of dextromethorphan by 2.69- and 2.38-fold, respectively.(1) An open label parallel group trial evaluated the interaction between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with a mean age of 33.6 years. Subjects were randomly divided into 2 groups: - Group 1 received paroxetine 20 mg once daily for 12 days, followed by the addition of dextromethorphan-quinidine twice daily for 8 days. - Group 2 received dextromethorphan-quinidine twice daily for 8 days, followed by paroxetine 20 mg daily for 12 days. Overall, adverse effects were reported in 19 of 26 subjects who received combination therapy (73%) and 15 of 27 subjects who received monotherapy (56%). Adverse effects from the combination differed somewhat between groups and were more closely associated with the second drug product administered. Group 1 reported dizziness, headache, somnolence, euphoria, nausea, and vomiting after the addition of dextromethorphan-quinidine to paroxetine. Group 2 adverse events were dizziness, headache, nausea, vomiting, insomnia, anxiety, and hyperhidrosis after the addition of paroxetine to dextromethorphan.(2) Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of dextromethorphan by 27-fold.(5) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(7,8) and paroxetine.(9) Selected strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, quinidine, and terbinafine.(10)

Dextromethorphan-Bupropion/Slt Ssris That Inhibit Cyp2d6

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fluoxetine and paroxetine, strong inhibitors of CYP2D6, may inhibit the metabolism of dextromethorphan.(1-5)

CLINICAL EFFECTS: Patients may experience increased adverse effects of dextromethorphan due to elevated systemic concentrations. Concomitant use of two or more serotonergic agents increases the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(6) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(6) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(6) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(6)

PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(5)

PATIENT MANAGEMENT: The manufacturer of dextromethorphan-bupropion recommends a dose reduction when coadministered with strong CYP2D6 inhibitors as follows: - For major depressive disorder, the maximum dosage is 45 mg/105 mg daily. - For agitation associated with Alzheimer's dementia, start with 30 mg/105 mg daily then increase to a maximum dosage of 45 mg/105 mg daily on day 8.(1) Monitor patients for elevated dextromethorphan levels or symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a clinical trial, paroxetine 20 mg (a strong CYP2D6 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of dextromethorphan by 2.69- and 2.38-fold, respectively.(1) An open label parallel group trial evaluated the interaction between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with a mean age of 33.6 years. Subjects were randomly divided into 2 groups: - Group 1 received paroxetine 20 mg once daily for 12 days, followed by the addition of dextromethorphan-quinidine twice daily for 8 days. - Group 2 received dextromethorphan-quinidine twice daily for 8 days, followed by paroxetine 20 mg daily for 12 days. Overall, adverse effects were reported in 19 of 26 subjects who received combination therapy (73%) and 15 of 27 subjects who received monotherapy (56%). Adverse effects from the combination differed somewhat between groups and were more closely associated with the second drug product administered. Group 1 reported dizziness, headache, somnolence, euphoria, nausea, and vomiting after the addition of dextromethorphan-quinidine to paroxetine. Group 2 adverse events were dizziness, headache, nausea, vomiting, insomnia, anxiety, and hyperhidrosis after the addition of paroxetine to dextromethorphan.(2) Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of dextromethorphan by 27-fold.(5) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(7,8) and paroxetine.(9)

Dextromethorphan/Selected Serotonergic Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Dextromethorphan inhibits neuronal reuptake of serotonin. Concurrent administration with one or more serotonergic agents may increase serotonin effects, leading to serotonin toxicity.(1-11)

CLINICAL EFFECTS: The concurrent use of dextromethorphan with serotonergic agents may increase the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(3) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(3) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(3) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(3)

PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(1-11)

PATIENT MANAGEMENT: Monitor patients on multiple serotonergic agents for symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Dextromethorphan inhibits neuronal reuptake of serotonin and may potentially precipitate dose-dependant serotonin toxicity in conjunction with other serotonergic agents.(4,5) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to duloxetine,(6) escitalopram,(7) fluoxetine,(8,9) paroxetine,(10) and sertraline.(11) Selected serotonergic agents linked to this monograph include: centanafadine, citalopram, clomipramine, duloxetine, escitalopram, fluvoxamine, imipramine, levomilnacipran, milnacipran, sertraline, venlafaxine, vilazodone and vortioxetine.

Selected Cyp2d6 Inhibitors/Metoprolol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of metoprolol.(1,2)

CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from metoprolol.(1,2)

PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6,(1,2) elderly,(3) and on higher doses of beta-blockers.(3)

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metoprolol and inhibitors of CYP2D6. The dosage of metoprolol may need to be adjusted.(1,2) The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(4)

DISCUSSION: In a case report, a patient maintained on metoprolol developed bradycardia following the addition of bupropion.(5) In a study in 20 healthy females, diphenhydramine increased the AUC of metoprolol by 21%. Heart rate reduction increased 29%.(6) In a randomized study in 16 healthy subjects, diphenhydramine decreased metoprolol oral and nonrenal clearance by 2-fold in extensive 2D6 metabolizers. In extensive 2D6 metabolizers, metoprolol-induced effects on heart rate, systolic blood pressure, and aortic blood flow peak velocity were all increased. There were no effects of diphenhydramine in poor metabolizers.(7) Fluoxetine has been shown to inhibit metoprolol metabolism in vitro.(8) There is a case report of severe bradycardia following the addition of fluoxetine to metoprolol.(9) In a 3-way, randomized, cross-over study in healthy subjects, paroxetine (20 mg daily) increased the area-under-curve (AUC) of both S- and R-metoprolol by 3-fold, and 4-fold, respectively, regardless of whether the formulation of metoprolol was immediate release or extended release. Concurrent paroxetine also significantly decreased heart rate and blood pressure when compared to metoprolol alone.(10) In an open-label, randomized, cross-over study in 10 healthy subjects, paroxetine increased the AUC of S-metoprolol and R-metoprolol from an immediate release formulation (50 mg)by 4-fold and 5-fold, respectively. Paroxetine increased the AUC of S-metoprolol and R-metoprolol from an extended release formulation (100 mg) by 3-fold and 4-fold, respectively.(11) In a study in patients with acute myocardial infarction and depression, paroxetine (20 mg daily) increased the AUC of metoprolol 3-fold. Mean heart rate was significantly lower following the addition of paroxetine to metoprolol. Two patients experienced bradycardia and severe orthostatic hypotension.(12) In an open trial in 8 healthy males, paroxetine (20 mg daily) increased the AUC of S-metoprolol and R-metoprolol by 4-fold and 7-fold, respectively.(13) There are case reports of complete atrioventricular block(14) and bradycardia(15) with concurrent metoprolol and paroxetine. A systematic review and meta-analysis of CYP2D6 interactions between metoprolol and either paroxetine or fluoxetine reviewed 9 articles including 4 primary and 2 observational studies as well as 3 case reports. Experimental studies noted paroxetine increased the AUC of metoprolol 3-fold to 5-fold and significantly decreased blood pressure and heart rate. Paroxetine and fluoxetine have shown equipotent inhibitor capacity on CYP2D6. The metabolite, norfluoxetine, is also an inhibitor of CYP2D6.(16) A retrospective cohort study evaluated morbidity in patients on a beta-blocker primarily metabolized by CYP2D6 (e.g., nebivolol, metoprolol, carvedilol, propranolol, labetalol) and started on a strong or moderate CYP2D6-inhibiting antidepressant (e.g., fluoxetine, paroxetine, bupropion, duloxetine). Use of such an antidepressant with a beta-blocker was associated with an increased risk of hospitalization or ED visit due to an adverse hemodynamic event (HR 1.53, 95% CI 1.03-2.81, p=0.04).(3) CYP2D6 inhibitors include: abiraterone, bupropion, celecoxib, cinacalcet, citalopram, dacomitinib, dimenhydrinate, diphenhydramine, duloxetine, escitalopram, fedratinib, fluoxetine, hydroxychloroquine, imatinib, lorcaserin, osilodrostat, paroxetine, ranitidine, ranolazine, rolapitant, and sertraline. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Cyp2d6 Inhibitors/Perhexiline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the metabolism of perhexiline by CYP2D6.

CLINICAL EFFECTS: Concurrent use of perhexiline and a CYP2D6 inhibitor may result in elevated levels of perhexiline and toxicity, including risk of QT prolongation or torsade de pointes.

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Patients maintained on perhexiline should be carefully monitored if a CYP2D6 inhibitor is initiated or discontinued. The dosage of perhexiline may need to be adjusted. If concurrent therapy is warranted, monitor ECG more frequently and consider obtaining serum calcium, magnesium, and potassium levels at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The Adverse Drug Reactions Advisory Committee has received five reports of an interaction between perhexiline and SSRIs.(1) In one report, an 82 year-old male developed symptoms of perhexiline toxicity ten days after the addition of citalopram to his regimen. Citalopram was discontinued on Day 10. The patient's perhexiline level, previously stable between 0.29 mg/L and 0.34 mg/l, was found to be 0.82 mg/L on day 15. Perhexiline dosage was reduced.(1) In another report, a 62 year-old male developed perhexiline toxicity following the addition of paroxetine to his regimen. After paroxetine was discontinued, perhexiline levels returned to baseline.(3) In another report, an 84 year-old female developed perhexiline toxicity following the addition of fluoxetine to her regimen. Despite the discontinuation of fluoxetine, perhexiline levels were slow to return to baseline.(3) Selected CYP2D6 inhibitors linked to this monograph include: bupropion, citalopram, dacomitinib, escitalopram, fluoxetine, hydroquinidine, levomepromazine, paroxetine, quinidine, and terbinafine.(4)

Selected Cyp2d6 Inhibitors/Propranolol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of propranolol.(1)

CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from propranolol, including hypotension and bradycardia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with propranolol and CYP2D6 inhibitors. The dosage of propranolol may need to be adjusted.(1)

DISCUSSION: In a pharmacokinetic study in 16 healthy volunteers, concurrent use of quinidine 200 mg (a CYP2D6 inhibitor) increased the area-under-curve (AUC) of propranolol by 2.29-fold.(2) In a pharmacokinetic study in 6 healthy subjects, concurrent use of quinidine increased propranolol AUC 2-fold.(3) A retrospective review of concurrent use of propranolol and antidepressants evaluated the risk of hospitalization or emergency room visit within 30 days of concurrent prescription. In patients receiving antidepressants with moderate to strong CYP2D6 inhibitory effects, patient were an increased risk compared to patients receiving no antidepressants (Hazard Ratio (HR) = 1.53; 95% CI 1.03-2.81 vs. HR = 1.24; 95% CI 0.82-1.88).(4) Case reports of bradycardia and cardiac adverse effects have been reported with concurrent use of propranolol and the antidepressants fluoxetine and paroxetine (strong CYP2D6 inhibitors).(5) Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine, mavorixafor, and paroxetine. Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir, berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, levomepromazine, lorcaserin, mirabegron, moclobemide, quinine, ranolazine, and rolapitant. Weak CYP2D6 inhibitors include: desvenlafaxine, diphenhydramine, dimenhydrinate, dronabinol, fedratinib, hydroxychloroquine, imatinib, osilodrostat, ranitidine, and sertraline.(6)

Selected Cyp2d6 Substrates/Desvenlafaxine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Desvenlafaxine is considered a weak inhibitor of CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of desvenlafaxine may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP2D6 pathway.(1) Agents linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

PREDISPOSING FACTORS: With perphenazine and tolterodine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: Reduce the dose of CYP2D6 substrates by up to one-half when coadministered with desvenlafaxine 400 mg.(1) Studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. CYP2D6 substrates should be dosed at the original level when coadministered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued.(1) The manufacturer of desvenlafaxine does not provide recommendations for use of desvenlafaxine at dosages between 100-400 mg concurrently with CYP2D6 substrates. Monitor for toxicity of the CYP2D6 substrate and consider reducing its dosage.

DISCUSSION: In a study, coadministration of desvenlafaxine 100 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 25% and 17%.(1) In a study, coadministration of desvenlafaxine 400 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 50% and 90%.(1) Selected CYP2D6 substrates linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

Selected Moderate To Strong Cyp2d6 Inhibitors/Tramadol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Abiraterone, asunaprevir, berotralstat, bupropion, cinacalcet, dacomitinib, dronedarone, duloxetine, eliglustat, fluoxetine, hydroquinidine, levomepromazine, levomethadone, lorcaserin, mirabegron, paroxetine, quinidine, rolapitant, oral terbinafine, and tipranavir are moderate or strong inhibitors of CYP2D6 and may decrease conversion of tramadol to its more active O-demethylated metabolite (M1).(1-6) M1 is up to 6 times more potent than tramadol in producing analgesia.(1)

CLINICAL EFFECTS: Tramadol analgesic efficacy may be decreased due to lower mu-opioid receptor mediated analgesia.(1,9,10) Higher concentrations of tramadol may be associated with increased inhibition of norepinephrine and serotonin reuptake, increasing risk for seizures and serotonin syndrome.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(7)

PREDISPOSING FACTORS: Risk for seizure may be increased with tramadol doses above the recommended range, in patients with metabolic disorders, alcohol or drug withdrawal, infection of the central nervous system, or with a history of seizures or head trauma.(1) Treatment with multiple medications which increase serotonin levels, or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(1,7) Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer.(14) Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.(14)

PATIENT MANAGEMENT: If a CYP2D6 inhibitor is started in a patient stabilized on long term tramadol therapy, monitor for loss of analgesic efficacy. When initiating tramadol in a patient stabilized on a moderate or strong CYP2D6 inhibitor, anticipate lower analgesic efficacy. Hospitalized patients may need added doses of rescue analgesics to achieve adequate pain control.(9,10) To decrease risk for serotonin syndrome, consider change to an alternative analgesic for patients taking other serotonin increasing drugs in addition to concomitant tramadol and a CYP2D6 inhibitor. If a CYP2D6 inhibitor is discontinued, consider lowering the dose of tramadol until patient achieves stable drug effects. The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(12)

DISCUSSION: Tramadol and its M1 metabolite both contribute to analgesic efficacy. Tramadol inhibits the reuptake of norepinephrine and serotonin with minimal opioid receptor binding. The M1 metabolite has 200 times greater binding affinity for the mu-opioid receptor than tramadol and is 6 times more potent in producing analgesia.(1) CYP2D6 converts tramadol to M1.(1,8) A prospective study evaluated the impact of 2D6 genotype on tramadol analgesia after abdominal surgery. Rescue doses of opioids were required in 47% of poor metabolizers (PM) versus 22% of extensive metabolizers (EM) of 2D6.(9) A follow-up study included 2D6 EM patients who received concomitant treatment with 2D6 inhibitors. Levels of the M1 metabolite were decreased by 80-90% compared with EM patients not taking 2D6 inhibitors. The authors noted some EM patients were converted to the PM phenotype.(10) In both studies, higher M1 levels were associated with greater analgesic efficacy and decreased need for rescue opioid treatment.(9,10) A study in 12 healthy volunteers found that a single dose of tramadol (50 mg) given to patients on terbinafine (a strong CYP2D6 inhibitor) resulted in tramadol AUC and Cmax that were 2.1-fold and 1.5-fold higher, respectively, than tramadol given alone. The AUC and Cmax of M1 were decreased by 64 % and 78 %, respectively.(13) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(12)

Selected Sensitive Cyp2b6 Substrates/Lemborexant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lemborexant may induce the metabolism of CYP2B6 substrates.(1)

CLINICAL EFFECTS: Concurrent lemborexant may result in decreased levels of sensitive CYP2B6 substrates, which may result in a decrease in or failure of clinical response.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lemborexant recommends close monitoring of patients who receive lemborexant with CYP2B6 substrates. Monitor patients receiving concurrent lemborexant for an adequate clinical response. The dosage of the CYP2B6 substrate may need to be adjusted.(1,2) An alternative agent may need to be selected.

DISCUSSION: In a study, lemborexant (10 mg dose) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of a S-bupropion by 49.9% and 45.5%, respectively.(1) Sensitive CYP2B6 substrates linked to this monograph include: bupropion and esketamine.(3,4)

Selected Sensitive Cyp2b6 Substrates/Midostaurin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Midostaurin may induce the metabolism of CYP2B6 substrates.(1)

CLINICAL EFFECTS: Concurrent midostaurin may result in decreased levels of sensitive CYP2B6 substrates, which may result in a decrease in clinical response.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent midostaurin for an adequate clinical response. The dosage of the CYP2B6 substrate may need to be adjusted.(1,2) An alternative agent may need to be selected.

DISCUSSION: In a study, multiple doses of midostaurin (50 mg twice daily) decreased the area-under-curve (AUC) of a single dose of bupropion by 48% and of bupropion's metabolite, hydroxybupropion by 65%.(1) Sensitive CYP2B6 substrates linked to this monograph include: bupropion and esketamine.(3,4)

Selected Strong Cyp2d6 Inhibitors/Flecainide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bupropion, dacomitinib, fluoxetine, and paroxetine are strong CYP2D6 inhibitors and may inhibit the CYP2D6 mediated metabolism of flecainide.(1)

CLINICAL EFFECTS: Concurrent use may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(2-5)

PREDISPOSING FACTORS: Renal and hepatic impairment may increase risk for excessive QTc prolongation as flecainide is renally and hepatically eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, flecainide must be dose adjusted in renal and hepatic insufficiency. The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(6) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(6)

PATIENT MANAGEMENT: Manufacturers of bupropion, fluoxetine, paroxetine recommend caution with concurrent use of flecainide due to the increased risk for ventricular arrhythmias (e.g. torsades de pointes) associated with higher flecainide concentrations.(2-5) Consider use of an alternative antidepressant or antiarrhythmic if possible. If concurrent therapy is deemed medically necessary, consider therapeutic drug monitoring of flecainide levels and obtain serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a drug interaction and pharmacogenomics study in 21 healthy subjects, paroxetine 20 mg daily for 7 days increased flecainide exposure (area-under-curve, AUC) by 28%.(7)

Selected Strong Cyp2d6 Inhibitors/Metoclopramide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of metoclopramide.

CLINICAL EFFECTS: Concurrent use may result in elevated levels of metoclopramide, which may increase the risk of extrapyramidal symptoms such as tardive dyskinesia, which may be permanent. Tardive dyskinesia typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs. Concurrent use may also result in serotonin syndrome. Symptoms of serotonin syndrome include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death.

PREDISPOSING FACTORS: Patients with renal and/or hepatic impairment may have an increased risk from this combination.

PATIENT MANAGEMENT: Concurrent use of a strong 2D6 inhibitor requires a dosage adjustment of metoclopramide. For gastroesophageal reflux, reduce the dosage of metoclopramide to 5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg taken three times daily for a maximum daily dosage of 30 mg in patients taking strong CYP2D6 inhibitors.(1) For acute and recurrent diabetic gastroparesis, reduce the dosage of metoclopramide to 5 mg four times daily (30 minutes before each meal and at bedtime) for a maximum daily dosage of 20 mg in patients taking strong CYP2D6 inhibitors.(1) If concurrent therapy is warranted, patients should be monitored for extrapyramidal symptoms and signs and symptoms of serotonin syndrome. Instruct patients to report any abnormal/uncontrollable muscle movements, muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study in 20 healthy male subjects, concurrent fluoxetine (60 mg daily, another strong CYP2D6 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg single dose) by 42% and 89%, respectively.(1,2) There have been case reports of serotonin syndrome in patients receiving concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(3) sertraline,(5-7) and venlafaxine.(7) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)

Serotonergic Agents/Ziprasidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1)

DISCUSSION: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6)

Strong Cyp1a2 Or Cyp2d6 Inhibitors/Fenfluramine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP1A2 or CYP2D6 inhibitors may decrease the metabolism of fenfluramine.(1) Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of agents that are strong CYP1A2 or CYP2D6 inhibitors may result in elevated levels of and toxicity from fenfluramine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of fenfluramine states that the maximum daily dosage of fenfluramine with a strong CYP1A2 or CYP2D6 inhibitor in patients not on stiripentol is 20 mg. In patients on concomitant stiripentol and clobazam, the maximum fenfluramine dosage with strong CYP1A2 or CYP2D6 inhibitors is 17 mg.(1) If the strong CYP1A2 or CYP2D6 inhibitors is discontinued, consider gradually increasing the fenfluramine dosage to the usual recommended dose without the inhibitor.(1)

DISCUSSION: In a study of healthy volunteers, fluvoxamine 50 mg daily (a strong CYP1A2 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 102% and 22%, respectively, and decreased the AUC and Cmax of norfenfluramine by 22% and 44%, respectively.(1) In a study of healthy volunteers, paroxetine 30 mg daily (a strong CYP2D6 inhibitor) increased the AUC and Cmax of single-dose fenfluramine 0.4 mg/kg by 81% and 13%, respectively, and decreased the AUC and Cmax of norfenfluramine by 13% and 29%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include: Angelica root, ciprofloxacin, enasidenib, vemurafenib, and viloxazine. Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, and quinidine.(1-4)

Strong Cyp2d6 Inhibitors/Codeine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of codeine to its active form, morphine.

CLINICAL EFFECTS: The concurrent administration of codeine and a strong inhibitor of CYP2D6 may result in decreased efficacy of codeine. If a strong CYP2D6 inhibitor is discontinued, the effects of codeine may be increased, including respiratory depression.

PREDISPOSING FACTORS: Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with codeine and a strong CYP2D6 inhibitor should be observed for decreased effectiveness of codeine. Dose increase of codeine may be required, or an alternative analgesic, such as morphine, may need to be considered. After discontinuation of a CYP2D6 inhibitor, consider reducing the dosage of codeine and monitor the patient for signs and symptoms of respiratory depression or sedation.

DISCUSSION: Strong inhibitors of CYP2D6 have been shown to decrease the metabolism of codeine to morphine at CYP2D6. Quinidine has also been shown to decrease cerebrospinal fluid levels of morphine after codeine administration. Concurrent administration resulted in decreased effects of codeine. Strong CYP2D6 inhibitors linked to this monograph are: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.

Strong Cyp2d6 Inhibitors/Deutetrabenazine;Tetrabenazine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: After ingestion, tetrabenazine is rapidly to converted the active agent, dihydrotetrabenazine (HTBZ, a mixture of alpha-HTBZ and beta-HTBZ). Both alpha and beta-HTBZ are metabolized by CYP2D6. Strong inhibitors of CYP2D6 may inhibit the metabolism of tetrabenazine active metabolites.(1) Deutetrabenazine is a deuterated form of tetrabenazine.(2)

CLINICAL EFFECTS: Concurrent use of a strong CYP2D6 inhibitor may result in increased levels of and adverse effects from deutetrabenazine(2) or tetrabenazine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of deutetrabenazine when administered with a strong inhibitor of CYP2D6 is 36 mg daily (tablets: given as 18 mg twice daily; or extended-release tablets: given as 36 mg daily).(2,3) The maximum recommended dose of tetrabenazine when administered with a strong inhibitor of CYP2D6 is 50 mg daily (given as 25 mg twice daily).(1) Monitor patients receiving concurrent deutetrabenazine or tetrabenazine and a strong CYP2D6 inhibitor for adverse effects, including depression, suicidal thoughts, stiff muscles, trouble swallowing, irritability or agitation, shaking, and restlessness. If the CYP2D6 inhibitor is discontinued, the dose of deutetrabenazine or tetrabenazine may need adjustment.

DISCUSSION: In a study in 24 healthy subjects, following the administration of a single oral dose of deutetrabenazine (22.5 mg) after 8 days of paroxetine (20 mg daily), the maximum concentration (Cmax) of alpha-HTBZ and beta-HTBZ increased by 1.2-fold and 2.2-fold, respectively. The area-under-curve (AUC) of alpha-HTBZ and beta-HTBZ increased by 1.9-fold and 6.5-fold, respectively.(2) In a study in 25 healthy subjects, following the administration of a single oral dose of tetrabenazine (50 mg) after 10 days of paroxetine (20 mg daily), the Cmax of alpha-HTBZ and beta-HTBZ increased by 30% and 2.4-fold, respectively. The AUC of alpha-HTBZ and beta-HTBZ increased by 3-fold and 9-fold, respectively.(1) Strong inhibitors of CYP2D6 include: bupropion, dacomitinib, fluoxetine, paroxetine and terbinafine.(1-4)

Strong Cyp2d6 Inhibitors/Mexiletine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine may inhibit the metabolism of mexiletine at CYP2D6.(1-7)

CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from mexiletine, including vertigo, insomnia, and abdominal pain.(1-5)

PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6.(1-5)

PATIENT MANAGEMENT: The UK manufacturer states coadministration of mexiletine with a strong CYP2D6 inhibitor may lead to increased levels and toxicity from mexiletine. Clinical monitoring is recommended during and after concurrent therapy for changes in mexiletine levels.(1) The US manufacturer states if concurrent use is warranted, mexiletine should be slowly titrated to response and closely monitored.(2)

DISCUSSION: Mexiletine is 90% metabolized in the liver, with CYP2D6 as the primary pathway. CYP2D6 phenotypes significantly affect drug levels of mexiletine.(3-5) In an interaction study (8 extensive and 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable.(2) In a pharmacokinetic study in CYP2D6 phenotypes, patients with CYP2D6 extensive metabolizers had a decreased extent of the formation of both metabolites by more than 50% and 85% for the microsomes from CYP2D6*1/*10 and 10/*10 livers, respectively.(3) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine.(6-7)

Strong Cyp2d6 Inhibitors/Oliceridine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Oliceridine is metabolized equally by CYP2D6 and CYP3A4. Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from oliceridine including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Inhibition of both CYP2D6 and CYP3A4 pathways may result in a greater increase in the levels of and toxcity of oliceridine.(1)

PATIENT MANAGEMENT: Caution should be used when administering oliceridine to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4. Dosage adjustments should be made if warranted. Closely monitor these patients for respiratory depression and sedation at frequent intervals and evaluate subsequent doses based on response. If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is necessary, less frequent dosing of oliceridine may be required. If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued, increase of the oliceridine dosage may be necessary. Monitor for signs of opioid withdrawal. Patients receiving concurrent therapy with both a strong or moderate CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse effects. Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and a strong CYP3A4 inhibitor may require less frequent dosing of oliceridine.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: In a study of four healthy subjects who are CYP2D6 poor metabolizers, itraconazole (200 mg daily for 5 days) increased the area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1) In a study of subjects who were not CYP2D6 poor metabolizers, ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the pharmacokinetics of oliceridine.(1) Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(4)

Strong Cyp2d6 Inhibitors/Oxycodone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may alter the metabolism of oxycodone.(1) Oxycodone is primarily metabolized by CYP3A4 to noroxycodone then by CYP2D6 to noroxymorphone as well as by CYP2D6 to oxymorphone. Noroxycodone, oxymorphone, and noroxymorphone are active metabolites.(1-3)

CLINICAL EFFECTS: The concurrent administration of oxycodone and a strong inhibitor of CYP2D6 may result in decreased efficacy or increased effects and toxicity of oxycodone. Parent and metabolite concentrations of oxycodone may be altered.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with oxycodone and a strong CYP2D6 inhibitor should be observed for decreased effectiveness as well as signs of increased effects and opioid toxicity. An alternative analgesic, such as morphine or nonopioid analgesics, may need to be considered.

DISCUSSION: Strong inhibitors of CYP2D6 have been shown to alter the metabolism of oxycodone.(1-3) A study in 10 healthy subjects who were CYP2D6 extensive metabolizers were given oxycodone 20 mg with either quinidine 200 mg or placebo, followed by quinidine 100 mg 6 hours later. Levels of oxymorphone were undetectable at any time point after quinidine administration. The psychomotor or subjective drug effects of oxycodone were unchanged.(4) A study in 10 healthy subjects received a single dose of quinidine 100 mg (a strong CYP2D6 inhibitor) followed by oxycodone 0.2 mg/kg oral drops. Oxymorphone (CYP2D6 dependent metabolite) concentration maximum (Cmax) and area-under-curve (AUC) were both decreased by 40% with quinidine administration compared to oxycodone alone. Oxycodone AUC and AUC at 90 minutes post administration were increased 1.5-fold and 8.5-fold, respectively. Total clearance of oxycodone was decreased by 20-30%. A compensatory 70% increase of noroxycodone (CYP3A4 dependent metabolite) AUC was also observed.(5) A study in 11 healthy subjects evaluated the effects of paroxetine 20 mg daily on single dose oxycodone 10 mg. Paroxetine decreased the mean AUC of CYP2D6 dependent metabolite oxymorphone by 44% (p<0.05) and increased the mean AUC of CYP3A4 dependent metabolite noroxycodone by 68% (p<0.001). Administration of paroxetine increased the VAS score for deterioration of performance for the first 6 hours following oxycodone.(6) A randomized crossover trial in 10 healthy subjects with differing CYP2D6 metabolizer statuses received oxycodone with either placebo, quinidine, ketoconazole, or both quinidine and ketoconazole. CYP2D6 activity correlated with oxymorphone and noroxymorphone AUCs and Cmax.(7) A retrospective cohort study in 111 patients found patients who received oxycodone with either a CYP2D6 or CYP3A4 inhibitor had an increased risk of gastrointestinal, dizziness, and drowsiness adverse reactions. Use of either a CYP2D6 or CYP3A4 inhibitor increase the risk by 20.4 and 25.4 times, respectively. Concurrent use of both a CYP2D6 and CYP3A4 inhibitor increased the risk with an adjusted OR of 48.6.(8) A cohort study evaluated the use of concurrent oxycodone and SSRIs that inhibit CYP2D6 on the risk of opioid overdose. The adjusted incidence rate of opioid overdose in patients on SSRIs that inhibit CYP2D6 when initiated on oxycodone was higher than SSRIs that do not inhibit CYP2D6 (9.47 per 1000 person years vs 7.66 per 1000 person years, respectively).(9) The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that CYP2D6 poor metabolizers have a lower peak concentration of oxymorphone (CYP2D6 dependent metabolite) after a dose of oxycodone compared to extensive metabolizers; however, clinical significance of metabolizer status on analgesia or risk of toxicity is unknown.(10) CPIC recommends selecting alternative drugs other than oxycodone for CYP2D6 poor and intermediate metabolizers, or be alert to insufficient pain relief; for CYP2D6 ultrarapid metabolizers, select an alternative to oxycodone, or be alert for adverse events.(10) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, and quinidine.(11)

Strong Cyp2d6 Inhibitors/Pitolisant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bupropion, dacomitinib, fluoxetine, paroxetine, and terbinafine may inhibit the metabolism of pitolisant at CYP2D6.(1,2)

CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from pitolisant including potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The US manufacturer states the concurrent use of pitolisant with strong CYP2D6 inhibitors requires dose adjustment. - Adult patients currently receiving a strong CYP2D6 inhibitor prior to initiation of pitolisant: start pitolisant at 8.9 mg once daily and increase after 7 days to a maximum dosage of 17.8 mg daily. - Patients 6 years and older weighing <40 kg: start pitolisant at 4.45 mg once daily and increase after 7 days to a maximum dosage of 8.9 mg once daily. - Patients 6 years and older weighing >=40 kg: start pitolisant at 4.45 mg once daily and increase after 7 days to 8.9 mg once daily. May increase after another 7 days to a maximum dosage of 17.8 mg once daily. - All patients who are stable on pitolisant: reduce the dose of pitolisant by half upon initiating a strong CYP2D6 inhibitor.(1) The UK manufacturer states concurrent use of pitolisant with CYP2D6 inhibitors should be done with caution and dose adjustment could be considered.(2) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a clinical study, concurrent use of pitolisant with paroxetine increased the concentration maximum (Cmax) and area-under-curve (AUC) by approximately 1.75 and 2.25, respectively.(1) In two dedicated QT prolongation studies, supra-therapeutic doses of pitolisant at 3-6 times the therapeutic dose (108-216 mg) were seen to cause mild to moderate QTc prolongation (10-13 ms). A study in patients who were CYP2D6 poor metabolizers had higher systemic exposure up to 3-fold compared to CYP2D6 extensive metabolizers.(1) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, paroxetine and terbinafine.(5,6)

Strong Cyp2d6 Inhibitors/Primaquine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of primaquine to its active metabolite.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in reduced antimalarial effect of primaquine due to decreased formation of the active primaquine metabolite.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, consider alternative medications that are not strong CYP2D6 inhibitors. If concurrent therapy is warranted, monitor patients closely for possible relapse.

DISCUSSION: Published clinical reports indicate that primaquine is a CYP2D6 substrate. Reduced CYP2D6 activity may decrease the formation of the active metabolite of primaquine.(1) Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.(2,3)

Strong Cyp2d6 Inhibitors/Valbenazine (<=40 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Valbenazine's active metabolite (alpha-HTBZ) is metabolized by CYP2D6 and CYP3A4.(1) Bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine are strong inhibitors of CYP2D6.(2,3)

CLINICAL EFFECTS: Concurrent use of bupropion, dacomitinib, fluoxetine, paroxetine, quinidine or terbinafine may result in elevated levels and adverse effects of valbenazine such as somnolence and QT prolongation.

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its own metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction.(2) Concurrent use of strong CYP3A4 inhibitors may further increase levels of valbenazine.(1)

PATIENT MANAGEMENT: Reduce the valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP2D6 inhibitor.(1) During concomitant therapy with a strong CYP2D6 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine did not affect valbenazine maximum concentration (Cmax) or area-under-the-curve (AUC). However, Cmax and AUC for the active metabolite of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold, respectively. Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.

*Seizure disorder.

*Current or past diagnosis of bulimia or anorexia nervosa.

*Patients undergoing abrupt discontinuance of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

*Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor. Initiating dextromethorphan/bupropion in patients receiving reversible MAO inhibitors (e.g., linezolid, IV methylene blue) also is contraindicated.

*Known hypersensitivity to bupropion, dextromethorphan, or to any other ingredient in the formulation.

• Alcohol withdrawal syndrome
• Anorexia nervosa
• Bulimia nervosa
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Lactation
• Lower seizure threshold
• Seizure disorder
• Seizure due to abrupt benzodiazepine withdrawal

• Alcohol use disorder
• Angle-closure glaucoma
• Brugada syndrome
• Central nervous system neoplasm
• Cerebral metastases
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• CYp2d6 poor metabolizer
• Hyponatremia
• Opioid dependence
• Risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
• Sedative drug dependence
• Serotonin syndrome
• Stimulant drug dependence
• Suicidal ideation

• Bipolar disorder
• Hypertension
• Psychotic disorder

Adverse effects occurring in >=5% of patients receiving dextromethorphan/bupropion and with an incidence of at least twice that reported with placebo in clinical studies include dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.

More Frequent

• Agitation

Less Frequent

• Cardiac arrhythmia
• Hypertension
• Hypotension
• Infection
• Psychiatric disorder
• Urticaria

Rare or Very Rare

• Abnormal hepatic function tests
• Accidental fall
• Accommodation disorder
• Acquired dystonia
• Acute generalized exanthematous pustulosis
• Acute myocardial infarction
• Akathisia
• Anaphylaxis
• Angioedema
• Atrioventricular block
• Bronchospastic pulmonary disease
• Brugada pattern
• Colitis
• Coma
• Complete atrioventricular block
• Delusional disorder
• Drug-induced psychosis
• Dyskinesia
• Erythema multiforme
• Esophagitis
• Extrasystoles
• Gastric ulcer
• Gastrointestinal hemorrhage
• Gastrointestinal perforation
• Hallucinations
• Hepatitis
• Homicidal ideation
• Hypersensitivity drug reaction
• Leukocytosis
• Leukopenia
• Maculopapular rash
• Manic disorder
• Non-infective meningitis
• Ocular hypertension
• Orthostatic hypotension
• Pancreatitis
• Pancytopenia
• Paranoid disorder
• Parkinsonism
• Pneumonia
• Pulmonary thromboembolism
• Rhabdomyolysis
• Secondary angle-closure glaucoma
• Seizure disorder
• SIADH syndrome
• Stevens-johnson syndrome
• Suicidal
• Suicidal ideation
• Tardive dyskinesia
• Thrombocytopenic disorder
• Unconsciousness
• Vomiting

More Frequent

• Acute abdominal pain
• Anorexia
• Arthralgia
• Concentration difficulty
• Constipation
• Diarrhea
• Dizziness
• Dream disorder
• Headache disorder
• Hyperhidrosis
• Insomnia
• Nausea
• Nervousness
• Palpitations
• Pharyngitis
• Rhinitis
• Symptoms of anxiety
• Tinnitus
• Tremor
• Weight loss
• Xerostomia

Less Frequent

• Abnormal sexual function
• Acute cognitive impairment
• Acute cognitive impairment
• Ataxia
• Blurred vision
• Bronchitis
• Cough
• Drowsy
• Drug-induced hot flash
• Dry skin
• Dyspepsia
• Dysphagia
• Epistaxis
• Fever
• Flatulence
• Flushing
• General weakness
• Hearing disorder
• Increased appetite
• Increased urinary frequency
• Irritability
• Libido changes
• Menstrual disorder
• Migraine
• Myalgia
• Myoclonus
• Neck pain
• Non-cardiac chest pain
• Peripheral edema
• Pruritus of skin
• Skin rash
• Stomatitis
• Vomiting

Rare or Very Rare

• Abdominal pain with cramps
• Abnormal electroencephalogram
• Abnormal vaginal bleeding
• Aggressive behavior
• Alopecia
• Anemia
• Anticholinergic toxicity
• Aphasia
• Behavioral disorders
• Bruxism
• Cramps in legs
• Cystitis
• Delirium
• Depersonalization
• Diplopia
• Disorder of ejaculation
• Dizziness
• Drowsy
• Dry eye
• Dysarthria
• Dysgeusia
• Dyspareunia
• Dyspnea
• Dysuria
• Ecchymosis
• Erectile dysfunction
• Euphoria
• Exfoliative dermatitis
• Facial edema
• Gingival bleeding
• Glycosuria
• Gynecomastia
• Hirsutism
• Hostility
• Hyperglycemia
• Hypoglycemic disorder
• Hypomania
• Hyponatremia
• Increased libido
• Lymphadenopathy
• Malaise
• Muscle rigidity
• Muscle weakness
• Mydriasis
• Nausea
• Nocturia
• Panic disorder
• Paresthesia
• Phlebitis
• Polyuria
• Salpingitis
• Sialorrhea
• Skin photosensitivity
• Syncope
• Tachycardia
• Urinary incontinence
• Urinary retention
• Vaginitis
• Vertigo

No enhanced messaging available.

Safety and efficacy of dextromethorphan/bupropion in pediatric patients have not been established. Antidepressants, including bupropion, increase the risk of suicidal thoughts and behaviors in pediatric patients.

The pharmacokinetics of dextromethorphan/bupropion have not been studied in pediatric patients.

Clinical data on the use of dextromethorphan/bupropion during pregnancy are insufficient to evaluate for a drug-associated risk of major birth malformations, miscarriage, or other adverse maternal or fetal outcomes; however, data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an overall increased risk of congenital malformations. Based on animal studies, dextromethorphan/bupropion may cause fetal harm when administered to women during pregnancy. If a patient becomes pregnant, discontinue dextromethorphan/bupropion and advise the patient of the risk to the fetus.

In studies conducted in rats and rabbits, a combination of dextromethorphan/quinidine demonstrated developmental toxicity, including fetal malformations (rabbits) and embryolethality, when administered to pregnant animals. When bupropion alone was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 21 times the maximum recommended human dose (MRHD) of 210 mg daily. When bupropion alone was given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately 2-5 times the MRHD and greater. Decreased fetal weights were seen at bupropion doses approximately 5 times the MRHD and greater.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Clinicians are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/.

Bupropion and its metabolites are distributed into human milk. The effects of bupropion or its metabolites on milk production are not known. It is not known whether dextromethorphan is distributed into human milk; the effects of dextromethorphan on the breast-fed infant or on milk production also are not known.

Limited data from postmarketing reports of bupropion use in nursing women have not identified a clear association of adverse reactions in the breast-fed infant. Neurotoxicity findings have been observed in juvenile rats treated with dextromethorphan/quinidine on postnatal day 7, which corresponds to the third trimester of gestation through the first few months of life and may extend through the first 3 years of life in humans.

Because of the potential for neurotoxicity in nursing infants, breast-feeding is not recommended during treatment with dextromethorphan/bupropion and for 5 days following the final dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Clinical trials of dextromethorphan/bupropion did not include patients >=65 years of age to determine whether geriatric patients respond differently than younger adults. The pharmacokinetics of dextromethorphan/bupropion have not been studied in geriatric patients.