Paroxetine Hcl (paroxetine HCl)

Dosages of paroxetine hydrochloride and paroxetine mesylate are expressed in terms of paroxetine.

When discontinuing paroxetine hydrochloride, gradually reduce the dosage rather than stopping the drug abruptly whenever possible. Adverse reactions may occur upon discontinuation of paroxetine.

Paroxetine is commercially available in the US as paroxetine hydrochloride conventional, film-coated tablets (e.g., Paxil(R)), extended-release tablets (e.g., Paxil CR(R)), and oral suspension and as paroxetine mesylate capsules. Conventional tablets of Paxil(R) and paroxetine mesylate capsules are not bioequivalent.

Paroxetine hydrochloride and paroxetine mesylate are administered orally.

Paroxetine hydrochloride conventional film-coated tablets, extended-release tablets, and suspension usually are administered once daily in the morning with or without food. Paroxetine hydrochloride oral suspension should be shaken well just prior to administration of each dose. Extended-release tablets of paroxetine hydrochloride should be swallowed whole and should not be chewed or crushed.

Paroxetine mesylate capsules are administered once daily at bedtime with or without food.

Paroxetine hydrochloride conventional tablets should be stored at 15-30degreesC. The oral suspension and extended-release tablets of paroxetine hydrochloride should be stored at or below 25degreesC. Paroxetine hydrochloride extended-release tablets may be exposed to temperatures ranging between 15degrees to 30degreesC.

Paroxetine mesylate conventional capsules should be stored at 20-25degreesC but may be exposed to temperatures ranging from 15-30degreesC; the capsules should be protected from light and humidity.

Paroxetine undergoes extensive hepatic metabolism via the cytochrome P-450 (CYP) 2D6 enzyme. Paroxetine is a strong CYP2D6 inhibitor.

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

P-Glycoprotein (P-GP) Inhibitors/Doxorubicin

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: P-glycoprotein (P-gp) inhibition may increase doxorubicin cellular concentration, as well as decrease biliary or renal elimination.(1)

CLINICAL EFFECTS: Increased cellular or systemic levels of doxorubicin may result in doxorubicin toxicity, including cardiomyopathy, myelosuppression, or hepatic impairment.(1)

PREDISPOSING FACTORS: The interaction magnitude may be greater in patients with impaired renal or hepatic function.

PATIENT MANAGEMENT: Avoid the concurrent use of P-gp inhibitors in patients undergoing therapy with doxorubicin.(1) Consider alternatives with no or minimal inhibition. If concurrent therapy is warranted, monitor the patient closely for signs and symptoms of doxorubicin toxicity. For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Doxorubicin is a substrate of P-gp.(1) Clinical studies have identified and evaluated the concurrent use of doxorubicin and P-gp inhibitors as a target to overcome P-gp mediated multidrug resistance.(3,4) P-gp inhibitors linked to this monograph include: amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, cimetidine, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, istradefylline, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib, propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline, schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, tepotinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(5,6)

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 Ssris; Duloxetine/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: Dapoxetine,(1) duloxetine,(2) fluoxetine,(3-7) and paroxetine(3,4) may inhibit the metabolism of thioridazine by CYP2D6. Fluvoxamine may inhibit the metabolism of thioridazine by CYP2C19 and/or CYP1A2.(8)

CLINICAL EFFECTS: The concurrent administration of dapoxetine, duloxetine, fluoxetine, fluvoxamine, or paroxetine with thioridazine may result in elevated levels of thioridazine. Elevated levels of thioridazine may augment thioridazine-induced prolongation of the QTc interval, which may increase the risk of serious, potentially fatal, cardiac arrhythmias such as torsades de pointes.(3,4)

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. 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.(15) 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. co-administration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(15)

PATIENT MANAGEMENT: Use an alternative antipsychotic agent. The concurrent use of thioridazine with dapoxetine,(1) duloxetine,(2) fluoxetine,(3-5,7) fluvoxamine,(3,4,8) or paroxetine(3,4,9,10) is contraindicated. If thioridazine cannot be discontinued, use an alternative to the interacting SSRI or duloxetine and evaluate patient for predisposing risk factors for QT prolongation. Correct modifiable risk factors and monitor for QT prolongation as appropriate throughout treatment with thioridazine. If alternative treatment is not possible and concurrent therapy is deemed medically necessary, strongly 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. At least 7 days should elapse following the discontinuation of dapoxetine before thioridazine is initiated and at least 14 days should elapse following the discontinuation of thioridazine before dapoxetine is initiated.(1) At least five weeks should elapse following the discontinuation of fluoxetine before thioridazine is initiated.(5-7)

DISCUSSION: In a study, pretreatment with duloxetine (60 mg twice daily) increased the area-under-curve (AUC) of a single dose of desipramine (50 mg) by 3-fold. Desipramine is metabolized by CYP2D6.(2) In a study in 10 patients, concurrent fluvoxamine (25 mg twice daily) resulted in a 3-fold increase in the levels of thioridazine and its two active metabolites, mesoridazine and sulforidazine.(11) A study in six slow and 13 rapid metabolizers of debrisoquin showed that slow metabolizers of debrisoquin had 2.4-fold and 4.5-fold higher thioridazine maximum concentration (Cmax) and AUC, respectively, than rapid metabolizers.(5,6,12) Slow metabolizers of debrisoquin have a genetic defect that results in low levels of CYP2D6.(3) A study in healthy subjects showed a thioridazine dose-related prolongation of the QTc interval.(13) A study in schizophrenic patients found no changes in thioridazine levels following the addition of citalopram.(14)

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.

Serotonergic Agents/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 agents which effect serotonin 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. (1-5)

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 Canadian manufacturer of sibutramine formerly stated that concurrent use with antidepressants or serotonergic agents is contraindicated. At least 14 days should elapse between discontinuation of these agents and initiation of sibutramine. Five weeks is required following the discontinuation of fluoxetine.(1) The Australian(2) and UK(3) manufacturers of sibutramine stated that sibutramine is contraindicated within 2 weeks of antidepressant use and should not be used with other serotonergic agents. The US manufacturer of sibutramine stated that in general, sibutramine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors, sumatriptan or dihydroergotamine. However, if concurrent administration is clinically indicated, the patient should be appropriately observed.(4) 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. Sibutramine inhibits serotonin reuptake and serotonin syndrome has been reported during concomitant use of selective serotonin reuptake inhibitors and other selective serotonin reuptake inhibitors, sumatriptan, and dihydroergotamine(1-4)

Serotonin Reuptake Inhibitors; Snris/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: Serotonin reuptake inhibitors and MAOIs may act synergistically to increase blood pressure and evoke behavioral excitation.

CLINICAL EFFECTS: Concurrent use or switching between agents without a sufficient washout period may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of the selective serotonin reuptake inhibitors, the selective serotonin and norepinephrine reuptake inhibitors, nefazodone, and venlafaxine state that concurrent use with MAOIs is contraindicated. A minimum 5 week washout period should separate the switch of fluoxetine to a MAOI. A washout period of at least 21 days is recommended for the switch from vortioxetine to a MAOI. A washout period of at least 2 weeks is recommended for the switch of citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, or vilazodone to a MAOI. A washout period of 7 days is recommended for the switch of dapoxetine, levomilnacipran, nefazodone, desvenlafaxine, and venlafaxine to a MAOI. A washout period of 5 days is recommended for the switch of duloxetine or milnacipran to a MAOI. Prior to starting any selective serotonin reuptake inhibitor, non-selective serotonin reuptake inhibitor, or duloxetine, allow a 2 week washout period after stopping MAOI therapy. These washout recommendations apply to the selective MAO-B inhibitors rasagiline and selegiline as well. If rasagiline is used in combination with fluvoxamine, patients should receive no more than 0.5mg of rasagiline daily. In emergency situations in patients maintained on SSRIs or SNRIs, weigh the availability and safety of alternatives to linezolid and methylene blue against the risk of serotonin syndrome. If linezolid or methylene blue therapy is required, the patient's SSRI or SNRI should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks (5 weeks in the case of fluoxetine, 21 days in the case of vortioxetine, and 5 days in the case of duloxetine and milnacipran) or until 24 hours after the last dose of linezolid or methylene blue, whichever comes first. In non-emergency situations in patients maintained on SSRIs or SNRIs when linezolid or methylene blue therapy is planned, discontinue the patient's SSRI or SNRI at least 2 weeks (5 weeks in the case of fluoxetine, 21 days in the case of vortioxetine, and 5 days in the case of duloxetine and milnacipran) in advance of linezolid or methylene blue therapy. The patient's SSRI or SNRI therapy may be resumed 24 hours after the last dose of linezolid or methylene blue. Do not initiate SSRI or SNRI therapy in patients receiving linezolid or methylene blue until 24 hours after the last dose of these agents.

DISCUSSION: This serious interaction (serotonin syndrome) has been reported with fluoxetine, sertraline, and venlafaxine. Although this has been not been reported with the fluvoxamine, nefazodone, or paroxetine, current recommendations by their manufacturers indicate that the potential for this interaction should be assumed. Manufacturer's product information for fluoxetine, paroxetine, and venlafaxine state that concurrent administration of these agents with a MAOI is contraindicated. The other selective serotonin reuptake inhibitors and non-selective serotonin reuptake inhibitors have shorter half-lives than fluoxetine. Therefore, the time frame during which the interaction would be expected to occur with agents and MAOIs would not be expected to be as prolonged as with fluoxetine. In a case report, a patient had stopped taking paroxetine 10 days prior to initiating St. John's wort. The evening after initiating St. John's wort, the patient took a paroxetine. At noon the next day, the patient was able to be awakened, but was incoherent, groggy, slow-moving, and almost unable to get up. Two hours later during an examination, she was groggy and lethargic, but able to respond appropriately. She complained of nausea, weakness, and fatigue. Her vital signs and physical exam were normal, except for a slow response time and limp muscle tone. She did not take any additional paroxetine and was normal the next day. The metabolism of rasagiline has been shown to be inhibited by CYP P-450-1A2 inhibitors such as fluvoxamine. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Serotonin syndrome has been reported following administration of methylene blue in patients receiving selective serotonin reuptake inhibitors (SSRIs). Metaxalone is a weak inhibitor of MAO. The FDA AERS contains reports of serotonin syndrome with the concurrent use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine as well as reports of serotonin syndrome with concurrent injectable methylene blue and citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. 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.

Ssris; Nefazodone/Astemizole; Terfenadine

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 the inhibition of the metabolism of astemizole and terfenadine by the SSRIs and nefazodone.

CLINICAL EFFECTS: Concurrent administration may result in increased serum levels of astemizole and terfenadine resulting in possible life-threatening cardiotoxicity including QT prolongation or torsades de pointes.

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.(9) 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).(9)

PATIENT MANAGEMENT: Concomitant administration of terfenadine with either fluvoxamine and nefazodone is contraindicated.(1-3) The manufacturer of terfenadine states that concurrent administration of terfenadine and sertraline is not recommended.(3) Concomitant administration of astemizole with fluvoxamine and nefazodone is contraindicated by the manufacturers of fluvoxamine and nefazodone.(1,2) Concomitant administration of astemizole and fluoxetine, fluvoxamine, nefazodone, paroxetine, or sertraline is not recommended by the manufacturer of astemizole.(4) 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.

DISCUSSION: Elevated plasma levels of the nonsedating antihistamines astemizole or terfenadine can cause QT prolongation and torsades de pointes-type ventricular tachycardia which may be fatal. Both astemizole and terfenadine are metabolized by CYP3A4. Drugs that block the metabolism of astemizole and terfenadine may produce an increase in plasma concentrations of these antihistamines. It has not been demonstrated that fluvoxamine is a potent inhibitor of CYP3A4: however, fluvoxamine is suspected to be. In vitro studies have shown nefazodone to be an inhibitor of CYP3A4. Therefore the manufacturers of fluvoxamine and nefazodone contraindicate concurrent use with either astemizole or or terfenadine.(1,2) The manufacturer of astemizole states that concurrent administration of astemizole and fluoxetine, fluvoxamine, nefazodone, paroxetine, or sertraline is not recommended.(4) In a study, concurrent administration of fluoxetine with a single dose of terfenadine resulted in no changes in terfenadine levels. The manufacturer of fluoxetine states that fluoxetine inhibition of CYP3A4 is unlikely to be of clinical significance.(5) In a study, concurrent administration of paroxetine with terfenadine at steady state resulted in no changes in terfenadine levels. The manufacturer of paroxetine states that paroxetine inhibition of CYP3A4 is unlikely to be of clinical significance.(6,7) In a study, concurrent administration of sertraline with terfenadine at steady state resulted in no changes in terfenadine levels. The manufacturer of sertraline states that sertraline inhibition of CYP3A4 is unlikely to be of clinical significance.(8)

Strong Cyp2d6 Inhibitors/Pimozide

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 CYP2D6 inhibitors may inhibit the metabolism of pimozide at CYP2D6.(1-6)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors that prolong QT may increase the levels and effects of pimozide including additive QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes. Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(8)

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.(7) 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).(7) 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.(8)

PATIENT MANAGEMENT: The concurrent use of pimozide with strong inhibitors of CYP2D6 is contraindicated.(1) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if possible. 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.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a controlled study in healthy subjects, steady-state paroxetine (60 mg daily, a strong inhibitor of CYP2D6) increased the AUC and Cmax of a single dose of pimozide (2 mg) by 151% and 62%, respectively.(2-4) Strong CYP2D6 inhibitors include: dacomitinib, fluoxetine, paroxetine, and terbinafine.(1,9) 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.

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

Clomipramine; Imipramine; Ssris; Snris;/Meperidine

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

MECHANISM OF ACTION: The concurrent administration of meperidine with a selective serotonin reuptake inhibitor or a serotonin/norepinephrine reuptake inhibitor (SNRI) may result in additive blockade of serotonin reuptake, resulting in central serotonergic hyperstimulation.(1,2) The combination of meperidine and selective serotonin reuptake inhibitors or SNRIs may also lower the seizure threshold.

CLINICAL EFFECTS: Concurrent administration may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2)

PREDISPOSING FACTORS: Predisposing factors include renal dysfunction and use of multiple agents which increase central serotonin levels. Chronic use of meperidine or high doses of SSRIs or SNRIs would also be expected to increase the risk for serotonin toxicity.

PATIENT MANAGEMENT: Use an alternative analgesic whenever possible, particularly in patients with renal impairment. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome, seizure activity. 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: Case reports describe the interaction between meperidine and serotonin-increasing agents.(3-5) Meperidine has long been associated with the risk for serotonin syndrome, particularly when used with monoamine oxidase inhibitors (MAOIs).(6) In addition to SSRIs and SNRIs, clomipramine, a tricyclic antidepressant(TCA) with strong serotonin effects and imipramine, a TCA with more moderate serotonin effects are also included in this monograph.(7)

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)

Fluoxetine; Paroxetine/Dextromethorphan And Quinidine

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

MECHANISM OF ACTION: Each product may affect the pharmacokinetics of the other. The combination of dextromethorphan 20 mg and quinidine 10 mg is given twice daily for treatment of pseudobulbar affect.(1) Due to the presence of quinidine, dextromethorphan exposure in this formulation is about 20-fold higher than expected with dextromethorphan alone.(1) Fluoxetine and paroxetine, strong inhibitors of CYP2D6, may also inhibit CYP2D6 mediated metabolism of dextromethorphan, further increasing dextromethorphan systemic concentration.(1-4) Fluoxetine(4) and paroxetine(3) are primarily metabolized by CYP2D6 and so quinidine may inhibit their metabolism as well, resulting in higher systemic concentrations of these SSRIs.(1,2,4)

CLINICAL EFFECTS: Patients may experience increased adverse effects of dextromethorphan and fluoxetine or paroxetine 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.(5) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(5) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(5) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(5)

PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(5) 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.(6)

PATIENT MANAGEMENT: In patients currently stabilized on dextromethorphan-quinidine who require an SSRI, consider use of an agent which is not primarily metabolized by nor a strong inhibitor of CYP2D6 (e.g. sertraline) if clinically appropriate. When both agents are necessary use the lowest effective dose of each medication and closely monitor for serotonin toxicity and other adverse effects. Patients stabilized on fluoxetine or paroxetine and newly starting dextromethorphan-quinidine may require lower than the usual recommended dextromethorphan-quinidine maintenance dose. It may also be necessary to lower the fluoxetine or paroxetine dose. The manufacturer of dextromethorphan-quinidine recommends limiting paroxetine dosage to less than or equal to 35 mg daily.(1) 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. 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: 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. Results: 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 (without quinidine) by 27-fold.(7) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(7,8) and paroxetine.(10)

Fluoxetine; Paroxetine/Higher Strength Tricyclics

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

MECHANISM OF ACTION: Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of CYP2D6.(1) Paroxetine is a strong inhibitor of CYP2D6.(1,2) Doxepin and trimipramine are metabolized by CYP2C19 and CYP2D6.(1) Desipramine and nortriptyline are metabolized by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent administration of fluoxetine or paroxetine with selected cyclic agents which are metabolized by CYP2D6 or CYP2C19 may result in an increase in serum levels, toxicities (e.g. risk for seizures, severe anticholinergic effects), and/or clinical effects of the tricyclic agent. Elevated levels of tricyclics may increase the risk of QT prolongation and the risk for torsades de pointes.

PREDISPOSING FACTORS: Higher doses or higher systemic concentrations of fluoxetine or paroxetine may increase the magnitude of this interaction. 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.(3,4) 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 inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3,4) 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). 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.(5)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds when concurrent therapy with fluoxetine or paroxetine is started or if the dosage of either agent is increased. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If fluoxetine or paroxetine is discontinued in a patient receiving a cyclic antidepressant, the dosage may need to be adjusted upward as the effects of enzyme inhibition wane. The effects of fluoxetine on hepatic metabolism may last for up to 5 weeks after fluoxetine discontinuation. A tricyclic antidepressant started after the discontinuation of fluoxetine should be started at a lower initial dosage. When concurrent therapy may be associated with QT prolongation, 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, and fainting.

DISCUSSION: Case reports have shown that the addition of fluoxetine to a tricyclic compound therapy can result in an increase of 100-300% in the tricyclic compound plasma concentration as well as an increase in adverse effects, including seizures and delirium. In an 83 year-old patient, the combination of clomipramine and fluoxetine resulted in high clomipramine concentrations and cardiac side effects. In a 70 year old patient, the use of venlafaxine, fluoxetine, and nortriptyline was associated with severe anticholinergic side effects. This interaction was thought to be due to increased nortriptyline levels. QTc prolongation also exists with some antidepressants. In a case report, the combination of levofloxacin, imipramine, and fluoxetine was associated with a QTc of 509msec. The authors concluded that this interaction was due to the pharmacodynamic additive effect among fluoxetine, imipramine, and levofloxacin. Cyclic antidepressants included in this monograph are desipramine (all strengths), doxepin (> 25 mg), nortriptyline (> 30 mg), and trimipramine (> 25 mg).

Fluoxetine; Paroxetine/Trazodone (> 75 MG)

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

MECHANISM OF ACTION: Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of CYP2D6.(1) Paroxetine is a strong inhibitor of CYP2D6.(1,2) Trazodone is metabolized by CYP3A4 and its metabolite, mCPP, is pharmacologically active. MCPP is metabolized by CYP2D6 and when it accumulates may be associated with adverse effects.

CLINICAL EFFECTS: Concurrent administration of fluoxetine or paroxetine with trazodone may result in an increase in serum trazodone levels. Elevated levels of trazodone may increase the risk of QT prolongation and the risk for torsades de pointes and serotonin syndrome.

PREDISPOSING FACTORS: Higher systemic concentrations of fluoxetine or paroxetine may increase the magnitude of this interaction. Concurrent use of multiple drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(3) 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.(4,5) 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 inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4,5) 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 and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids).

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of trazodone at the initiation of concurrent therapy with fluoxetine or paroxetine. If fluoxetine or paroxetine is discontinued in a patient receiving trazodone, the dosage may need to be adjusted upward as the effects of enzyme inhibition wane. The effects of fluoxetine on hepatic metabolism may last for up to 5 weeks after fluoxetine discontinuation. If trazodone is started after the discontinuation of fluoxetine, it should be started at a lower initial dosage. Patients receiving fluoxetine or paroxetine and trazodone should be monitored for serotonin syndrome. Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus. Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus. Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity. When concurrent therapy may be associated with QT prolongation, 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, and fainting.

DISCUSSION: There is one case report of serotonin syndrome during concurrent therapy with paroxetine and trazodone.(6) There have also been case reports of serotonin syndrome with trazodone and fluoxetine.(7) In a 24 year-old patient, the use of fluoxetine and trazodone resulted in severe irritability, anger, anxiety, and anorexia.(8) In a study in 11 patients, concurrent administration of trazodone 100 mg/day and fluoxetine 20 mg/day increased the concentrations of trazodone and its active metabolite mCPP by 65% and 231%.(9)

Fluoxetine;Paroxetine/Higher Strength Serotonergic Tcas

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

MECHANISM OF ACTION: Depending upon the interacting combination, pharmacokinetic and/or pharmacodynamic interactions are possible. Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of CYP2D6.(1) Paroxetine is a strong inhibitor of CYP2D6.(1,2) Amitriptyline, clomipramine, and imipramine are metabolized by CYP2C19 and CYP2D6.(1) Fluoxetine, paroxetine, clomipramine, and imipramine significantly increase neuronal serotonin levels. Amitriptyline increases serotonin at higher dosages.

CLINICAL EFFECTS: Concurrent administration of fluoxetine or paroxetine with selected cyclic agents which are metabolized by CYP2D6 or CYP2C19 may result in an increase in serum levels, toxicities (e.g. risk for seizures, severe anticholinergic effects), and/or clinical effects of the tricyclic agent. Concurrent administration of fluoxetine or paroxetine with clomipramine, imipramine, and high dose amitriptyline may increase the risk for serotonin syndrome.

PREDISPOSING FACTORS: Higher doses or higher systemic concentrations of fluoxetine or paroxetine may increase the magnitude of this interaction. Concurrent use of multiple drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(21) 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.(4,5) 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 inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4,5) 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 and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). 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: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds when concurrent therapy with fluoxetine or paroxetine is started or if the dosage of either agent is increased. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If fluoxetine or paroxetine is discontinued in a patient receiving a tricyclic antidepressant, the dosage may need to be adjusted upward as the effects of enzyme inhibition wane. The effects of fluoxetine on hepatic metabolism may last for up to 5 weeks after fluoxetine discontinuation. A cyclic antidepressant started after the discontinuation of fluoxetine should be started at a lower initial dosage. Patients receiving fluoxetine or paroxetine and clomipramine, imipramine, or higher dose amitriptyline should be monitored for serotonin syndrome. Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus. Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus. Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity. When concurrent therapy may be associated with QT prolongation, 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, and fainting.

DISCUSSION: Case reports have shown that the addition of fluoxetine to a tricyclic compound therapy can result in an increase of 100-300% in the tricyclic compound plasma concentration as well as an increase in adverse effects, including seizures and delirium. In an 83 year-old patient, the combination of clomipramine and fluoxetine resulted in high clomipramine concentrations and cardiac side effects. In a 70 year old patient, the use of venlafaxine, fluoxetine, and nortriptyline was associated with severe anticholinergic side effects. This interaction was thought to be due to increased nortriptyline levels. QTc prolongation also exists with some antidepressants. In a case report, the combination of levofloxacin, imipramine, and fluoxetine was associated with a QTc of 509msec. The authors concluded that this interaction was due to the pharmacodynamic additive effect among fluoxetine, imipramine, and levofloxacin. Cyclic antidepressants included in this monograph are amitriptyline (> 40 mg), clomipramine (> 25 mg), and imipramine (> 10 mg).

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

P-Glycoprotein (P-GP) Inhibitors/Bilastine

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibition may increase the absorption of bilastine.(1,2)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may result in elevated levels and toxicities from bilastine, including headache and somnolence.(1,2)

PREDISPOSING FACTORS: The interaction magnitude may be greater in patients with moderate to severe renal impairment.

PATIENT MANAGEMENT: The Canadian manufacturer of bilastine states that concomitant use of P-gp inhibitors with bilastine is not recommended. Coadministration should be avoided in patients with moderate or severe renal impairment.(1) The UK manufacturer of bilastine states that coadministration of bilastine and P-gp inhibitors should be avoided in patients with moderate to severe renal impairment.(2) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(5)

DISCUSSION: In a study, ketoconazole and erythromycin both increased bilastine area-under-curve (AUC) and maximum concentration (Cmax) by 2-fold and 2- to 3-fold, respectively.(1) The UK manufacturer of bilastine states that these changes do not appear to affect the safety of bilastine.(2) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, istradefylline, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline, schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, tepotinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(4,5)

P-Glycoprotein (P-GP) Inhibitors/Relugolix

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

MECHANISM OF ACTION: Relugolix is a substrate of the intestinal P-glycoprotein (P-gp) efflux transporter. Inhibitors of P-gp may increase the absorption of relugolix.(1)

CLINICAL EFFECTS: The concurrent administration of relugolix with an inhibitor of P-glycoprotein may result in elevated levels of relugolix and adverse effects, including hot flashes, skin flushing, musculoskeletal pain, hyperglycemia, acute renal injury, transaminitis, arrhythmias, and hemorrhage.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of relugolix states that the coadministration of relugolix with P-gp inhibitors should be avoided. If the P-gp inhibitor is to be used short-term, relugolix may be held for up to 2 weeks. If treatment with relugolix is interrupted for longer than 7 days, resume relugolix with a loading dose of 360 mg on the first day, followed by 120 mg once daily.(1) If coadministration with a P-gp inhibitor cannot be avoided, relugolix should be taken at least 6 hours before the P-gp inhibitor. Monitor the patient more frequently for adverse events.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Coadministration of relugolix with erythromycin (a P-gp and moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 6.2-fold. Voriconazole (a strong CYP3A4 inhibitor) did not have a clinically significant effect on the pharmacokinetics of relugolix.(1) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, curcumin, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, indinavir, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, lonafarnib, mavorixafor, mibefradil, mifepristone, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quinidine, quinine, ranolazine, ritonavir, sarecycline, schisandra, selpercatinib, simeprevir, sotorasib, telaprevir, telithromycin, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)

Paroxetine/Clozapine

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

MECHANISM OF ACTION: The metabolism of clozapine may be inhibited at CYP2D6 by paroxetine. In addition, due to its anticholinergic activity, paroxetine may compound the anticholinergic and anti-serotonergic effects of clozapine to inhibit gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(1-6)

CLINICAL EFFECTS: The concurrent administration of clozapine with paroxetine may result in elevated levels of clozapine and an increase in clozapine related side effects, orthostatic hypotension, syncope, QT prolongation, profound sedation and seizures. Concurrent use may also increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6)

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.(7) 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).(7) The risk for serious bowel complications is higher with increasing age and in patients on multiple anticholinergic agents.(5)

PATIENT MANAGEMENT: Clozapine levels should be monitored in patients receiving concurrent therapy with clozapine and paroxetine. Patients should be monitored for signs of clozapine toxicity. The dosage of either clozapine or paroxetine may need to be adjusted or one or both agents may need to be discontinued. Clozapine levels should also be monitored following the discontinuation of paroxetine from concurrent therapy. If concurrent therapy is warranted in patients receiving clozapine, 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. In addition, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2)

DISCUSSION: A study(8) in 16 subjects found that the concurrent administration of paroxetine and clozapine resulted in clozapine and norclozapine levels that were 57.4% and 50% higher, respectively, than levels seen in similar patients receiving clozapine alone. In a case report(9), a patient developed anticholinergic syndrome and her clozapine level had doubled into the toxic range 19 days after the addition of paroxetine to her therapy. In contrast, two studies(10,11) found no significant changes in clozapine levels following the addition of paroxetine. Gastrointestinal effects with paroxetine coadministration: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4)

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/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)

Serotonin Reuptake Inhibitors/Linezolid

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

MECHANISM OF ACTION: Serotonin reuptake inhibitors and linezolid, which inhibits MAO, may act synergistically to increase central nervous system (CNS) serotonin concentrations, leading to toxicity.

CLINICAL EFFECTS: Concurrent use or switching between agents without a sufficient washout period may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2) Serotonin syndrome may result in death.

PREDISPOSING FACTORS: High doses of serotonin reuptake inhibitors or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: If linezolid is required for urgent or life threatening treatment, the FDA states the interacting serotonergic drug should be stopped. The FDA has also released a statement that linezolid can be given with serotonergic agents if the "benefit is deemed to outweigh the risk" for conditions including but not limited to vancomycin-resistant Enterococcus (VRE) infections, nosocomial pneumonia, and complicated skin and skin structure infections, including cases caused by methicillin resistant Staphylococcus aureus (MRSA). In these instances, linezolid can be started with serotonergic agents under close monitoring.(1) Serotonergic medications should not preclude the use of linezolid if clinically warranted. If concurrent use of linezolid without a washout is warranted, the patient should be closely monitored.(24-29) If serotonergic agents are discontinued, serotonin toxicity due to the interaction is still possible. Patients should be monitored for CNS serotonin toxicity for two weeks (five weeks if fluoxetine, 3 weeks if vortioxetine, 7 days if desvenlafaxine or venlafaxine, or 5 days if duloxetine was taken) or until 24 hours after the last linezolid dose, whichever comes first. Therapy with the serotonergic agent may be resumed 24 hours after the last dose of linezolid.(1,3-13)

DISCUSSION: Serotonin syndrome has been reported with the use of linezolid and SSRIs including in: four patients receiving concurrent citalopram, one patient receiving concurrent fluoxetine, three patients receiving concurrent sertraline, one patient receiving concurrent venlafaxine, one patient in whom linezolid was initiated 18 days after fluoxetine discontinuation, and one patient in whom linezolid was initiated three days after the discontinuation of paroxetine.(14-23) Literature states that linezolid is a weak MAOI and rarely causes serotonin toxicity. Cases of serotonin toxicity were rapidly reversible with discontinuation of the offending agent(s) and supportive care. Some literature suggests that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(24-29)

Slt Strong 2D6 Inhibitor/Aripiprazole Lauroxil Submicronized

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

MECHANISM OF ACTION: Strong 2D6 inhibitors such as dacomitinib, fluoxetine, paroxetine, and quinidine may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1) Strong CYP2D6 inhibitors linked to this monograph are bupropion, dacomitinib, fluoxetine, paroxetine and quinidine.

PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)

PATIENT MANAGEMENT: The US manufacturer of the extended release aripiprazole lauroxil, submicronized (Aristada Initio) recommends avoiding use of strong CYP2D6 inhibitors with Aristada Initio. Aristada Initio is only available in a single strength as a single-dose pre-filled syringe.

DISCUSSION: Drug interaction studies have not been conducted with Aristada Initio. Aristada Initio has a long half-life (15-18 days). 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)

Ssris; Snris/Selected Anticoagulants (VITAMIN K ANTAGONISTS)

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

MECHANISM OF ACTION: SSRI or SNRI inhibition of platelet serotonin uptake may result in impaired platelet aggregation.(1-11) This effect may be additive or synergistic when combined with other agents which impair hemostasis. Fluvoxamine is an inhibitor of CYP2C9 mediated metabolism of warfarin.(9)

CLINICAL EFFECTS: Concurrent use of selected anticoagulants and SSRIs or SNRIs may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(11) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: For the combination of fluvoxamine and warfarin: when possible change to a SSRI which does not inhibit warfarin metabolism (e.g. citalopram or paroxetine). For patients who require this combination, monitor for an increase in INR when fluvoxamine is started or the dose is increased. The warfarin dose may need to be reduced. For all anticoagulant/SSRI or SNRI combinations, if concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The manufacturer's product information for fluvoxamine reports a study in which the plasma warfarin concentrations increased 98% and prothrombin times were prolonged in patients who received concurrent fluvoxamine and warfarin.(9) In a single study in 24 healthy patients, concurrent administration of paroxetine and warfarin resulted in clinically significant bleeding in five patients. No changes in paroxetine or warfarin disposition were seen.(13) In a review describing the bleeding risk with SRIs, warfarin was associated with an increased rate of hemorrhage among SRI users (adjusted relative risk = 1.41).(14) In a cohort study of patients taking warfarin in combination with an SSRI versus warfarin treatment alone, an analysis including first bleedings revealed a hazard ratio of 3.49 for bleeding during treatment with a combination of SSRI and warfarin compared with warfarin only.(15) A retrospective study of warfarin-treated patients prescribed or not prescribed an antidepressant showed that use of an SSRI with warfarin was significantly associated with increased risk of any bleed (overall risk (OR)=2.6), major bleeding (OR=4.4), and hospitalization secondary to bleeding (OR=7.0) as compared to those not taking an SSRI.(16) A population based study of patient outcomes in 176 primary intracerebral hemorrhage patients showed that 19 patients taking SSRI/SNRIs together with warfarin had an increased 30-day case fatality rate of 78.9% compared to warfarin alone (50.7%).(17) In a study of the Anticoagulation and Risk factors in Atrial fibrillation (ATRIA) cohort, hemorrhage rates were higher during periods of SSRI exposure compared with periods on no antidepressants (2.32 per 100 person-years vs 1.35 per 100 person-years). After adjusting for bleeding risk and time in INR range > 3, SSRI exposure was associated with an increased rate of hemorrhage compared with no antidepressants (adjusted relative risk = 1.41).(18) Increased bleeding risk has been found when patients receive 3 agents which can affect bleeding risk: an anticoagulant, SSRI and NSAID.(19) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a SSRI with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(19) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with SSRIs and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, SSRIs, or both were 3.7, 2.6, or 15.6, respectively.(20) A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 10 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antidepressants (OR=1.54; 95% CI 1.4-1.7). Increased bleeding risk was also seen in subgroup analyses with SSRIs (OR=1.62; 95% CI 1.42-1.85) but not SNRIs. There was an increased case fatality rate for intracerebral hemorrhage with SSRIs and SNRIs (OR=3.64; 95% CI 1.15-11.53).(21) There are two published case reports involving increased effects of warfarin following addition of fluoxetine. Another case report is inconclusive. In a study in seven healthy volunteers, neither single dose or eight days of consecutive therapy resulted in alteration of warfarin clearance.(22, 23) In a parallel group study involving 12 healthy volunteers, the prothrombin time and area-under-curve (AUC) were increased and the normalization of prothrombin time was decreased with concurrent warfarin and sertraline. There was also a clinically insignificant increase in warfarin protein binding.(24) There is one case report of increased INR during concurrent warfarin and duloxetine.(25)

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.

Agents With Hyponatremia Risk/Desmopressin

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

MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics).

PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

Fluoxetine; Paroxetine/Duloxetine

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

MECHANISM OF ACTION: Fluoxetine and paroxetine inhibit CYP2D6 mediated metabolism of duloxetine.(1-3) In addition, duloxetine, fluoxetine and paroxetine are serotonin reuptake inhibitors.

CLINICAL EFFECTS: Higher duloxetine concentrations and concomitant use of two agents which inhibit serotonin reuptake may increase the risk for serotonin syndrome.(1-4) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(4)

PREDISPOSING FACTORS: Concurrent use of a CYP1A2 inhibitor (e.g. ciprofloxacin, fluvoxamine, vemurafenib, zileuton) would block duloxetine's other important metabolic pathway further increasing systemic concentrations and risk for toxicities.(1) High doses of serotonin reuptake inhibitors or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.(4)

PATIENT MANAGEMENT: The prescriber may intend short-term use of this combination when transitioning the patient from one serotonergic agent to another. However, if fluoxetine or paroxetine is used to treat a psychiatric disorder (e.g. depression, PTSD, OCD) and duloxetine is used to treat neuropathic pain, concomitant use may be long term. If the interacting agents are prescribed by different providers, it would be prudent to assure that they are aware of concomitant therapy and monitoring the patient for serotonin toxicities. 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: An interaction study evaluated concomitant use of duloxetine 40 mg once daily with paroxetine 20 mg daily. Paroxetine increased duloxetine AUC 60%. The US manufacturer for duloxetine notes that greater inhibition would be expected with higher doses of paroxetine.(1) Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(4) Monitor patients on multiple serotonergic agents for symptoms of serotonin toxicity. Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor or myoclonus. Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia and clonus. Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity and hypertonicity.

Fluoxetine; Paroxetine/Lower Strength Tricyclics

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

MECHANISM OF ACTION: Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of CYP2D6.(1) Paroxetine is a strong inhibitor of CYP2D6.(1,2) Doxepin, and trimipramine are metabolized by CYP2C19 and CYP2D6.(1) Desipramine, nortriptyline, amoxapine, and protriptyline are metabolized by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent administration of fluoxetine or paroxetine with tricyclics metabolized by CYP2D6 or CYP2C19 may result in an increase in serum levels, toxicities (e.g. risk for seizures, severe anticholinergic effects), and/or clinical effects of the tricyclic. Elevated levels of tricyclics may increase the risk of QT prolongation and the risk for torsades de pointes.

PREDISPOSING FACTORS: Higher doses or higher systemic concentrations of fluoxetine or paroxetine may increase the magnitude of this interaction. 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.(4,5) 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 inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4,5) 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 and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). 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: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds when concurrent therapy with fluoxetine or paroxetine is started or if the dosage of either agent is increased. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If fluoxetine or paroxetine is discontinued in a patient receiving a tricyclic compound, the dosage may need to be adjusted upward as the effects of enzyme inhibition wane. The effects of fluoxetine on hepatic metabolism may last for 3-5 weeks after fluoxetine discontinuation. A cyclic compound started after the discontinuation of fluoxetine should be started at a lower initial dosage. When concurrent therapy may be associated with QT prolongation, 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: Case reports have shown that the addition of fluoxetine to a tricyclic compound therapy can result in an increase of 100-300% in the tricyclic compound plasma concentration as well as an increase in adverse effects, including seizures and delirium. In a 83 year-old patient, the combination of clomipramine and fluoxetine resulted in high clomipramine concentrations and cardiac side effects. In a 70 year old patient, the use of venlafaxine, fluoxetine, and nortriptyline was associated with severe anticholinergic side effects. This interaction was thought to be due to increased nortriptyline levels. In a 50 year-old patient, the use of protriptyline and fluoxetine resulted in anticholinergic delirium. QTc prolongation also exists with some antidepressants. In a case report, the combination of levofloxacin, imipramine, and fluoxetine was associated with a QTc of 509msec. The authors concluded that this interaction was due to the pharmacodynamic additive effect among fluoxetine, imipramine, and levofloxacin. Cyclic agents included in this monograph are amoxapine, doxepin (<=25mg), melitracen, nortriptyline (<=30mg), protriptyline, and trimipramine (<=25mg).

Fluoxetine; Paroxetine/Trazodone (<= 75 MG)

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

MECHANISM OF ACTION: Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of CYP2D6.(1) Paroxetine is a strong inhibitor of CYP2D6.(1,2) Trazodone is metabolized by CYP3A4 and its metabolite, mCPP, is pharmacologically active. MCPP is metabolized by CYP2D6 and when it accumulates may be associated with adverse effects.

CLINICAL EFFECTS: Concurrent administration of fluoxetine or paroxetine with trazodone may result in an increase in trazodone serum levels. Elevated levels of trazodone may increase the risk of QT prolongation and the risk for torsades de pointes and serotonin syndrome.

PREDISPOSING FACTORS: Higher doses or higher systemic concentrations of fluoxetine or paroxetine may increase the magnitude of this interaction. Concurrent use of multiple drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(3) 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.(4,5) 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 inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4,5) 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 and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids).

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of trazodone when concurrent therapy with fluoxetine or paroxetine is started or if the dosage of either agent is increased. If the fluoxetine or paroxetine is discontinued in a patient receiving a trazodone, the dosage may need to be adjusted upward as the effects of enzyme inhibition wane. The effects of fluoxetine on hepatic metabolism may last for 3-5 weeks after fluoxetine discontinuation. A cyclic compound (other than cyclobenzaprine) started after the discontinuation of fluoxetine should be started at a lower initial dosage. Patients receiving fluoxetine or paroxetine and trazodone should be monitored for serotonin syndrome. Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus. Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus. Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(20) When concurrent therapy may be associated with QT prolongation, 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: There is one case report of serotonin syndrome during concurrent therapy with paroxetine and trazodone.(6) There have also been case reports of serotonin syndrome with trazodone and fluoxetine,(7) and trazodone and amitriptyline with lithium. In a 24 year-old patient, the use of fluoxetine and trazodone resulted in severe irritability, anger, anxiety, and anorexia.(8) In a study in 11 patients, concurrent administration of trazodone 100 mg/day and fluoxetine 20 mg/day increased the concentrations of trazodone and its active metabolite mCPP by 65% and 231%.(9)

Fluoxetine;Paroxetine/Lower Strength Serotonergic Tricyclics

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

MECHANISM OF ACTION: Depending upon the interacting combination, pharmacokinetic and/or pharmacodynamic interactions are possible. Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of CYP2D6.(1) Paroxetine is a strong inhibitor of CYP2D6.(1,2) Amitriptyline, clomipramine, and imipramine are metabolized by CYP2C19 and CYP2D6.(1) Cyclobenzaprine is metabolized by CYP1A2 and CYP3A4 and so a pharmacokinetic interaction is not expected.(3) Fluoxetine, paroxetine, clomipramine and imipramine significantly increase neuronal serotonin levels. Amitriptyline increases serotonin at higher dosages.

CLINICAL EFFECTS: Concurrent administration of fluoxetine or paroxetine with tricyclics metabolized by CYP2D6 or CYP2C19 may result in an increase in serum levels, toxicities (e.g. risk for seizures, severe anticholinergic effects), and/or clinical effects of the tricyclic. Concurrent administration of fluoxetine or paroxetine with clomipramine and perhaps with imipramine, cyclobenzaprine, or high dose amitriptyline may increase the risk for serotonin syndrome.

PREDISPOSING FACTORS: Higher doses or higher systemic concentrations of fluoxetine or paroxetine may increase the magnitude of this interaction. 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.(4,5) 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 inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4,5) Concurrent use of multiple drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(6) 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). 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: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds when concurrent therapy with fluoxetine or paroxetine is started or if the dosage of either agent is increased. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If the fluoxetine or paroxetine is discontinued in a patient receiving a tricyclic compound other than cyclobenzaprine the dosage may need to be adjusted upward as the effects of enzyme inhibition wane. The effects of fluoxetine on hepatic metabolism may last for 3-5 weeks after fluoxetine discontinuation. A cyclic compound (other than cyclobenzaprine) started after the discontinuation of fluoxetine should be started at a lower initial dosage. Patients receiving fluoxetine or paroxetine and clomipramine, imipramine, higher dose amitriptyline, or cyclobenzaprine should be monitored for serotonin syndrome. Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus. Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus. Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(20) When concurrent therapy may be associated with QT prolongation, 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: Case reports have shown that the addition of fluoxetine to a tricyclic compound therapy can result in an increase of 100-300% in the tricyclic compound plasma concentration as well as an increase in adverse effects, including seizures and delirium. In a 83 year-old patient, the combination of clomipramine and fluoxetine resulted in high clomipramine concentrations and cardiac side effects. The manufacturer of cyclobenzaprine reports that serotonin syndrome has been reported when combined with other serotonergic agents.(3) QTc prolongation also exists with some antidepressants. In a case report, the combination of levofloxacin, imipramine, and fluoxetine was associated with a QTc of 509msec. The authors concluded that this interaction was due to the pharmacodynamic additive effect among fluoxetine, imipramine, and levofloxacin. Cyclic agents included in this monograph are amitriptyline (<=40mg), clomipramine (<=25mg), cyclobenzaprine (structurally similar to amitriptyline), and imipramine (<=10mg).

Paroxetine/Asenapine

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

MECHANISM OF ACTION: Asenapine is a weak inhibitor of CYP2D6 and may convert patients from the extensive metabolizer to poor metabolizer phenotype for this enzyme. Asenapine may enhance the inhibitory effects of paroxetine on its own metabolism by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of asenapine may result in increased serum levels and adverse effects of paroxetine.

PREDISPOSING FACTORS: 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 asenapine recommends that the paroxetine dose be reduced by half when it is used in combination with asenapine. (1)

DISCUSSION: Concomitant use of paroxetine with asenapine increased the paroxetine systemic exposure and maximum plasma concentration (Cmax) by 2-fold as compared to use of paroxetine alone. (1)

Paroxetine/Levomethadone; Methadone

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

MECHANISM OF ACTION: The mechanism of this interaction is unknown but may involve CYP2D6 inhibition by paroxetine. Levomethadone is the active (R)-enantiomer of methadone.(1)

CLINICAL EFFECTS: Concurrent administration of paroxetine may result in increased levels and clinical effects of levomethadone and methadone,(2) which may result in QTc prolongation and life-threatening arrhythmias. Elevated levels can also cause profound sedation, respiratory depression, coma, and/or death. The discontinuation of paroxetine in patients maintained on levomethadone or methadone may result in symptoms of opiate withdrawal. Levomethadone, methadone and paroxetine have been associated with serotonin syndrome.(1,3,4) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

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 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)

PATIENT MANAGEMENT: If concomitant use of levomethadone or methadone and paroxetine is necessary, closely monitor the patient when paroxetine is initiated or withdrawn. The dosage of levomethadone or methadone may need to be adjusted.(3) 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. 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 agents that may increase opioid drug levels.(6) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. 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. Discuss an opioid reversal agent (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).(7)

DISCUSSION: A study of patients in a methadone maintenance program found that paroxetine 20 mg daily for 12 days significantly increased concentrations of (R)-methadone and (S)-methadone by 26% and 49%, respectively. Most of this increase was driven by patients who were CYP2D6 extensive metabolizers, who experienced a 32% and 53% increase in (R)-methadone and (S)-methadone levels, respectively. Poor CYP2D6 metabolizers did not have an increase in (R)-methadone concentrations, but (S)-methadone concentrations were increased by 36%.(2)

Paroxetine/Pravastatin

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

MECHANISM OF ACTION: The specific combination of pravastatin and paroxetine increases the risk for hyperglycemia. The mechanism of action is not clear.

CLINICAL EFFECTS: Use of pravastatin or paroxetine separately has been associated with minor or no elevations in random glucose measurements. Concurrent use of pravastatin and paroxetine has been associated with a mean glucose increase of 18.5 mg/dl in non-diabetic subjects and 48.1 mg/dl in diabetic subjects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor diabetic patients newly started on this combination for elevated glucose measurements. Consider changing to a different statin or SSRI if needed to maintain control of diabetes. For non-diabetic patients with elevated random glucose measurements, test fasting glucose concentration. If significantly elevated, change to a different statin or SSRI.

DISCUSSION: Study authors evaluated the FDA Adverse Event Reporting System (FAERS) for potential drug-drug interaction signals and found a potential signal for a pravastatin - paroxetine interaction. To follow up on this finding, they performed data mining of electronic medical records (EMRs) at 3 academic medical centers. Pre and post treatment random blood glucose levels were evaluated for patients started on paroxetine only, pravastatin only, or on the combination of paroxetine and pravastatin.(1) In the combined site analysis: - use of paroxetine only, or pravastatin only was not associated with an increase in glucose levels. - in non-diabetic subjects taking both paroxetine and pravastatin, post treatment increase in random glucose levels was 18.5 mg/dl (CI: 9.2,27.8) - in diabetic subjects receiving the combination, post treatment increase in random glucose levels was 48.1 mg/dl (CI: 35.1,61.1)(1) A further evaluation of 324 patients who received any SSRI (except paroxetine) and any statin (other than pravastatin) found an increase in glucose levels of 1.7 mg/dl. Analysis of 115 patients on paroxetine and any other statin found no significant effect on glucose levels. However, analysis of 38 pravastatin patients on any other SSRI found an increase in random glucose levels of 9.5 mg/dl (P = 0.008).(1) A pharmacovigilance study of web searches looked for signals of this interaction prior to the 2011 study cited above. They found that people who performed both paroxetine and pravastatin searches during the study period were about twice as likely to also search for hyperglycemia-related search terms compared with users who performed only paroxetine or pravastatin searches.(2)

Select Serotonergic Agents/Fentanyl

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

MECHANISM OF ACTION: Although the exact mechanism is not known, fentanyl is thought to have mild serotonergic effects.(1,7) Concurrent administration with one or more potent serotonergic agents may increase serotonin effects, leading to toxicity.

CLINICAL EFFECTS: Concurrent use of serotonergic agents and fentanyl may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

PREDISPOSING FACTORS: Based upon case reports, high fentanyl doses in the perioperative period, concomitant use of multiple serotonergic agents, or a recent increase in dosage of either agent may be risk factors for this interaction.(2-6)

PATIENT MANAGEMENT: Most patients tolerate the combination of fentanyl with serotonin-increasing agents. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(1) Monitor patients on multiple serotonergic agents for symptoms of serotonin toxicity. 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: Health Canada recently reported 5 cases of serotonin syndrome associated with patients receiving fentanyl and at least one other serotonergic agent.(2) Additional cases have been reported in the medical literature.(3-6) Serotonin increasing agents linked to this monograph are: centanafadine, citalopram, clomipramine, desvenlafaxine, duloxetine, fluoxetine, imipramine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone and vortioxetine.

Select Strong Cyp2d6 Inhibitors/Aripiprazole Lauroxil

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 aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: The 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 be affected by this interaction.(1)

PATIENT MANAGEMENT: 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 tolerated. If the patient is a poor metabolizer of CYP2D6, no dose adjusment 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) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)

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/Terbinafine

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

MECHANISM OF ACTION: Terbinafine is a strong inhibitor of CYP2D6 and may convert patients from the extensive metabolizer to poor metabolizer phenotype for this enzyme.(1)

CLINICAL EFFECTS: Concurrent use of terbinafine may result in increased serum levels and adverse effects of drugs primarily metabolized by or sensitive to changes in the activity of the CYP2D6 metabolic pathway.(1,2)

PREDISPOSING FACTORS: 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.(3)

PATIENT MANAGEMENT: Terbinafine has a serum half-life of approximately 36 hours, so the maximal effect of this interaction may be delayed for one to two weeks. Extended monitoring may be necessary. Patients receiving therapy with agents primarily metabolized by CYP2D6 need increased monitoring for adverse effects and may need a dose reduction. Plasma level monitoring should be considered in patients receiving flecainide.(4) The effect of terbinafine on CYP2D6 substrates may last for up to four weeks after terbinafine discontinuation. Over time, patients previously stabilized on the combination of terbinafine and a selected CYP2D6 substrate may need an increase in the dose of the CYP2D6 metabolized drug.

DISCUSSION: In a randomized, placebo-controlled trial in 12 healthy subjects, terbinafine (150 mg daily for 6 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of paroxetine (20 mg) by 2.9-fold and 1.9-fold, respectively.(6) In a placebo-controlled trial in 12 healthy males, terbinafine (250 mg for 4 days) increased the Cmax and AUC of a single dose of venlafaxine (75 mg) by 2.67-fold and 4.9-fold, respectively.(7) CYP2D6 substrates linked to this monograph are: dapoxetine, flecainide, metoprolol, nebivolol, paroxetine, perphenazine, propafenone, propranolol, venlafaxine 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 Ssris That Inhibit Cyp1a2 Or Cyp2d6/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) Concurrent administration may also result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: Concurrent use of agents that are strong CYP1A2 or CYP2D6 inhibitors may result in elevated levels of and toxicity from fenfluramine, including CNS depression, hypertension, and serotonin syndrome.(1) Serotonin syndrome is 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.(2)

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 inhibitor is discontinued, consider gradually increasing the fenfluramine dosage to the usual recommended dose without the inhibitor.(1) The manufacturer of fenfluramine states that fenfluramine should be used with caution with other serotonergic agents such as selective serotonin reuptake inhibitors. 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 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: fluvoxamine.(3,4) Strong CYP2D6 inhibitors linked to this monograph include: fluoxetine and paroxetine.(3,4)

Selected Ssris That Inhibit Cyp2d6/Dextromethorphan

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.(1-4)

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.(5) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(5) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(5) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(5)

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: 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, and/or severe diarrhea.

DISCUSSION: 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. Results: 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.(1) Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of dextromethorphan by 27-fold.(4) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(6,7) and paroxetine.(8)

Selected Ssris; Snris/Clopidogrel

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-5) or a serotonin-norepinephrine reuptake inhibitor(7-9) and agents that affect coagulation may result in bleeding.(12)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(13) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-5) or serotonin-norepinephrine reuptake inhibitors(6-8) and agents that affect coagulation should be used concurrently with caution. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue antiplatelet agents in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(9) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(10)

Selected Ssris;Snris/Cilostazol; Ticlopidine

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-4) or a serotonin-norepinephrine reuptake inhibitor(5-7) and agents that affect coagulation may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(8) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-4) or serotonin-norepinephrine reuptake inhibitors(5-7) and agents that affect coagulation should be used concurrently with caution. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(9) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(10) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(11) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ration 1.57).(12) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(13)

Selected Strong Cyp2d6 Inhibitors/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 may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)

PATIENT MANAGEMENT: 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 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) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(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/Iloperidone

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

MECHANISM OF ACTION: Strong CYP2D6 inhibitors(1) such as dacomitinib, fluoxetine, paroxetine, and terbinafine may inhibit the metabolism of iloperidone.(2)

CLINICAL EFFECTS: Concurrent administration of iloperidone with dacomitinib, fluoxetine, paroxetine, or terbinafine may result in elevated iloperidone levels and toxicities, including the risk for QTc prolongation.(2)

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, advanced age, and with concurrent use of inhibitors of CYP3A4, which metabolizes iloperidone.(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 US manufacturer of iloperidone states that the dose of iloperidone should be reduced to one-half of its normal dose when strong CYP2D6 inhibitors such as dacomitinib, fluoxetine or paroxetine are coadministered.(2) Due to its long half-life it may take 2 or more weeks to see the full effects of fluoxetine CYP2D6 inhibition on iloperidone exposure and tolerance. Maximal CYP2D6 inhibitory effects due to paroxetine coadministration are generally expected within one week after initiation or increase in the paroxetine dosage. When the inhibitor is discontinued iloperidone exposure will wane and the dose of iloperidone should be increased.(2) Concurrent administration of iloperidone with both a CYP2D6 inhibitor and CYP3A4 inhibitor does not have additive inhibitory effects compared to either inhibitor alone. The dose of iloperidone should be reduced to one-half of its normal dose, and further dose reduction is not required.(2) 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: In a study in 23 healthy subjects, fluoxetine (20 mg twice daily for 21 days) increased the AUC of iloperidone (3 mg single dose) and its P88 metabolite by 2-3-fold. The AUC of iloperidone's P95 metabolite decreased by 50%.(2) In a study in patients with schizophrenia, paroxetine (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%.(2) 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.(2) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(2)

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)

Selected Strong Cyp2d6 Inhibitors/Risperidone

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 risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: 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 risperidone (Risperdal) recommends that when CYP2D6 inhibitors are co-administered with risperidone that the dose should be reduced. The risperidone dose should not exceed 8 mg per day when co-administered with CYP2D6 inhibitors. When initiating therapy with risperidone, the dose of risperidone should be titrated slowly. It may be necessary to increase the risperidone dose, when CYP2D6 inhibitors are discontinued.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(2)

DISCUSSION: 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.(3) 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.(4) 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.(5) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(5) 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.(6) 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.(2) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(2) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(7)

Serotonergic Agents/Centanafadine

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

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

CLINICAL EFFECTS: Concurrent use of centanafadine with other serotonergic agents may increase the risk of 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.(1,2)

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: If concurrent use of centanafadine with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue centanafadine and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin.(1)

Serotonergic Agents/Gepirone

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

MECHANISM OF ACTION: Gepirone is a serotonin receptor agonist. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of gepirone with other serotonergic agents may increase the risk of hypertensive crisis and 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.(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: If concurrent use of gepirone with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue gepirone and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Gepirone and its 3'-OH metabolite act as agonists at 5HT1A receptors. Use with other agents that also increase serotonin in the body must be undertaken with caution and monitored closely due to the risk of serotonin syndrome.(1)

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)

Slt Ssris That Inhibit Cyp2d6/Dextromethorphan-Bupropion

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)

Slt Strong 2D6 Inhibitors/Risperidone Im Every 2 Weeks

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 risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: 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 dosage of risperidone should be re-evaluated.(1) 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.(1) When initiating the product in patients maintained on fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of this dose has not been confirmed in clinical trials.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(2)

DISCUSSION: 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.(3) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(3) 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.(4) 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.(2) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(2) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)

Slt Strong Cyp2d6 Inhibitors/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 may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)

PATIENT MANAGEMENT: 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) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)

Slt Strong Cyp2d6 Inhibitors/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 may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)

PATIENT MANAGEMENT: 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, fluoxetine, paroxetine and quinidine 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(s) is(are) 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) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)

Slt Strong Cyp2d6 Inhibitors/Risperidone Sq Every 1-2 Months

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 risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms.(2) 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.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(3)

DISCUSSION: 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.(4) 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.(5) 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.(6) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(6) 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.(7) 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.(3) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(3) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)

Snris; Ssris/Bupropion

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)

Ssris; Snris/Amphetamines; Phentermine

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

MECHANISM OF ACTION: Amphetamines may affect serotonin release and/or reuptake, depending on their molecular structure. Ring substitution tends to increase amphetamine-induced release of endogenous serotonin. However, the effect on serotonin release may also be dose related and is more likely if the amphetamine is taken in doses greater than those approved and generally employed in treating Attention-deficit-hyperactivity-disorder, or if abused, especially over long periods of time.(1) Amphetamines, phentermine and serotonin-norepinephrine reuptake inhibitors(SNRIs) may have additive effects on blood pressure.

CLINICAL EFFECTS: Concurrent use of amphetamines with agents that affect serotonin may increase the risk of serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(8) Concurrent use of amphetamines or phentermine and a SNRI may increase the risk for high blood pressure or make hypertension more difficult to control. SSRIs and SNRIs linked to this monograph are: citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone and vortioxetine.

PREDISPOSING FACTORS: High doses or long-term abuse of amphetamines may increase the risk of this interaction.

PATIENT MANAGEMENT: The concurrent use of amphetamines with SSRIs or SNRIs should be approached with appropriate monitoring. Instruct patients receiving concurrent therapy to report any signs or symptoms of serotonin syndrome immediately. Monitor blood pressure during concurrent therapy and adjust dosage or change medication for persistent increases in blood pressure. 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 case report, a 13 year-old female experienced tachycardia when amphetamine was added to her sertraline regimen.(2) Increased side effects have also been reported in patients maintained on fluoxetine who ingested illicit amphetamines.(3) In a case report, a 22 year-old female had previously been taking phentermine and oral contraceptive agents. The patient stopped taking phentermine and, after an undetermined length of time, started taking fluoxetine (20 mg daily). The patient discontinued her fluoxetine after three months. Eight days later, she took one dose of phentermine (30 mg). Within several hours, she developed jitteriness, stomach cramps, dry eyes, palpitations, and tremors. The patient received once dose of lorazepam (1.5 mg) and her symptoms resolved over night.(4) In a case report, a 32 year-old male developed agitation, anxiety, shivering, tremors, and diaphoresis two weeks after adding venlafaxine to his dexamphetamine.(5) There have also been reports of safe and effective use of amphetamines with fluoxetine,(6) dextroamphetamine and sertraline,(6) and dextroamphetamine with fluoxetine.(7)

Ssris; Snris/Selected Nsaids; Aspirin

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-7,13) or a serotonin-norepinephrine reuptake inhibitor(8-10) and a NSAID may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, antiplatelets, or corticosteroids. Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(15)

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-7,13) or serotonin-norepinephrine reuptake inhibitors(8-10) and NSAIDs should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.(1-11,13) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anti-platelet agents in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(11) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(12)

Ssris; Snris/Tapentadol

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

MECHANISM OF ACTION: The concurrent administration of tapentadol(1) with a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine reuptake inhibitor (SNRI) may result in additive blockade of serotonin reuptake, leading to central serotonergic hyperstimulation.(1) The combination of tapentadol and SSRIs or SNRIs may impact seizure control.(1)

CLINICAL EFFECTS: Concurrent administration may increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2) Concurrent administration may increase the risk for seizures, especially in susceptible individuals.(1)

PREDISPOSING FACTORS: 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.(2)

PATIENT MANAGEMENT: If concurrent therapy of tapentadol with a SSRI or SNRI is warranted, patients should be closely monitored for signs and symptoms of serotonin syndrome or increased seizure frequency. Tapentadol may need to be discontinued.

DISCUSSION: Concurrent use of tapentadol with SSRIs or SNRIs may result in additive blockage of serotonin reuptake, leading to central serotonergic hyperstimulation. Cases of serotonin syndrome have been reported with tapentadol in combination with other serotonergic drugs.(1) Use of tapentadol has been associated with increased seizure frequency in patients with seizure disorders.(1) SSRIs and SNRIs linked to this monograph are: citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, sibutramine, venlafaxine, vilazodone, and vortioxetine.

Ssris; Vilazodone/Flurbiprofen

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a SSRI(1-8) or vilazodone(9) and flurbiprofen may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(13) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-8) or vilazodone(9) and flurbiprofen should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.(1-10) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anti-platelet agents in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a SSRI with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(10) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(11)

Ssris; Vilazodone/Selected Nsaids

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a SSRI(1-8) or vilazodone(9) and a NSAID may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, antiplatelets, or corticosteroids. Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(13)

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-8) or vilazodone(9) and NSAIDs should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.(1-10) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anti-platelet agents in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a SSRI with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(10) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(11)

Ssris;Snris/Slt Anticoagulants;Antiplatelets;Thrombolytics

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-6) or a serotonin-norepinephrine reuptake inhibitor(7-9) and agents that affect coagulation may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(15) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-6) or serotonin-norepinephrine reuptake inhibitors(7-9) and agents that affect coagulation should be used concurrently with caution. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(10) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(11) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(12) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ratio 1.57).(13) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(14) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of 1.69 (1.11-2.57).(16) A systematic review and meta-analysis of 22 cohort and case-controlled studies including over 1 million patients found 1.55-fold higher odds of upper gastrointestinal (GI) bleeding in SSRI users compared with non-SSRI users (95% CI, 1.35-1.78). In subgroup analyses, the risk was found to be greatest among participants taking SSRIs concurrently with NSAIDs or antiplatelet medications.(17)

Strong Cyp2d6 Inhibitors/Brexpiprazole

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 brexpiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor may result in elevated levels of and toxicity from brexpiprazole.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are receiving concomitant treatment with a strong or moderate CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor. Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to increase brexpiprazole levels 5.1-fold in extensive metabolizers of CYP2D6.(1)

PATIENT MANAGEMENT: The US manufacturer of brexpiprazole recommends the following dose adjustments for patients who are receiving a strong CYP2D6 inhibitor: - in patients with major depressive disorder who are taking a strong CYP2D6 inhibitor WITHOUT a strong or moderate CYP3A4 inhibitor, no dosage adjustment is required. - in patients with major depressive disorder who are taking a strong CYP2D6 inhibitor AND who are receiving a strong or moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual dose. - in patients with schizophrenia who are taking a strong CYP2D6 inhibitor WITHOUT a strong or moderate CYP3A4 inhibitor, administer half the usual dosage of brexpiprazole. - in patients with schizophrenia who are taking a strong CYP2D6 inhibitor AND who are receiving a strong or moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual dose. The dose of brexpiprazole should be adjusted to its original level if the CYP2D6 inhibitor is discontinued.(1)

DISCUSSION: Coadministration of quinidine, a strong inhibitor of CYP2D6, increased the area-under-curve (AUC) of brexpiprazole approximately 2-fold.(1) Strong CYP2D6 inhibitors include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(2,3)

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/Milsaperidone

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 milsaperidone.(1)

CLINICAL EFFECTS: Concurrent administration of milsaperidone with strong CYP2D6 inhibitors may result in elevated milsaperidone levels and toxicities, including the risk for QTc prolongation.(1)

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, advanced age, and with concurrent use of inhibitors of CYP3A4, which metabolizes milsaperidone.(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 US manufacturer of milsaperidone states that the maintenance dose of milsaperidone should be reduced to one-half of its normal dose when initiating a strong CYP2D6 inhibitor. If starting milsaperidone with a stable dose of a strong CYP2D6 inhibitor, follow the recommended titration schedule in the labeling.(1) Further dose reduction is not required for concurrent administration of milsaperidone with both a CYP2D6 inhibitor and CYP3A4 inhibitor. The maintenance dose of milsaperidone should be reduced to one-half of its normal dose when initiating a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor. If starting milsaperidone with a stable dose of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor, follow the recommended titration schedule in the labeling.(1) Due to its long half-life it may take 2 or more weeks to see the full effects of fluoxetine CYP2D6 inhibition on milsaperidone exposure and tolerance. Maximal CYP2D6 inhibitory effects due to paroxetine coadministration are generally expected within one week after initiation or increase in the paroxetine dosage. When the inhibitor is discontinued milsaperidone exposure will wane and the dose of milsaperidone should be titrated to the recommended dose in the labeling.(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.

DISCUSSION: In a study in healthy subjects, fluoxetine (20 mg twice daily for 21 days) increased the area-under-curve (AUC) of iloperidone (3 mg single dose) and milsaperidone by 2-3-fold. The AUC of iloperidone's P95 metabolite decreased by 50%.(1) In a study in patients with schizophrenia, paroxetine (20 mg daily for 5-8 days) increased the maximum concentration (Cmax) of iloperidone and milsaperidone by about 1.6-fold. The Cmax of iloperidone's P95 metabolite decreased by 50%.(1) 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.(1) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(2) Coadministration of ketoconazole (200 mg twice daily, an inhibitor of CYP3A4) 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.(1) Coadministration of paroxetine (20 mg daily, an inhibitor of CYP2D6) 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.(1) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, paroxetine, and terbinafine.(3)

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/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 may inhibit the metabolism of risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: 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 risperidone for monthly intramuscular injection (Risvan) makes the following recommendations for patients who receive a strong CYP2D6 inhibitor: - 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.(1)

DISCUSSION: 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.(2) 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.(3) 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.(4) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)

Strong Cyp2d6 Inhibitors/Risperidone Sq Monthly

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 risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: 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: 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.(2) 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.(3) 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.(4) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)

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.

*Concomitant use of monoamine oxidase inhibitors (MAOIs) (including linezolid and IV methylene blue) or use within 14 days of discontinuing an MAOI, due to an increased risk of serotonin syndrome.

*Concomitant use of thioridazine, due to the risk of QT prolongation.

*Concomitant use of pimozide, due to the risk of QT prolongation.

*Known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any of the inactive ingredients of the formulation.

*Paroxetine mesylate only: Pregnancy; vasomotor symptoms do not occur during pregnancy and paroxetine can cause fetal harm.

• Serotonin syndrome

• Angle-closure glaucoma
• Bipolar disorder
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
• Suicidal ideation
• Upper GI bleed

• Akathisia
• Hyponatremia
• Increased risk of bleeding
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Manic disorder
• Pathological fracture
• Seizure disorder
• SIADH syndrome

The most common adverse effects with paroxetine hydrochloride conventional tablets and suspension (>=5% and at least twice placebo) are abnormal ejaculation, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, infection, insomnia, libido decreased, male genital disorder, nausea, nervousness, somnolence, sweating, tremor, and yawn.

The most common adverse effects with paroxetine hydrochloride extended-release tablets (>=5% and at least twice placebo) are abnormal ejaculation, abnormal vision, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, insomnia, libido decreased, nausea, somnolence, sweating, and tremor.

The most common adverse effects with paroxetine mesylate capsules (>=2% and at a higher incidence that placebo) are headache, fatigue, malaise, lethargy, nausea, and vomiting.

Less Frequent

• Acute cognitive impairment
• Hypertension
• Infection
• Myoclonus
• Myopathy

Rare or Very Rare

• Abnormal hepatic function tests
• Acquired dystonia
• Acute myocardial infarction
• Agranulocytosis
• Akathisia
• Anaphylaxis
• Anemia
• Angina
• Aplastic anemia
• Atrial fibrillation
• Bone marrow depression
• Bradycardia
• Bundle branch block
• Cerebral ischemia
• Cerebrovascular accident
• Colitis
• DRESS syndrome
• Drug-induced hepatitis
• Dyskinesia
• Extrapyramidal disease
• Fracture
• Guillain-barre syndrome
• Heart block
• Heart failure
• Hemolytic anemia
• Hemorrhage
• Hepatic failure
• Hypersensitivity pneumonitis
• Hypomania
• Hyponatremia
• IgA vasculitis
• Increased risk of bleeding
• Leukocytosis
• Leukopenia
• Lymphocytosis
• Manic disorder
• Myocardial ischemia
• Neuroleptic malignant syndrome
• Optic neuritis
• Pancreatitis
• Pancytopenia
• Peritonitis
• Porphyria
• Priapism
• Pulmonary hypertension
• Pulmonary thromboembolism
• Rectal bleeding
• Secondary angle-closure glaucoma
• Seizure disorder
• Serotonin syndrome
• SIADH syndrome
• Stevens-johnson syndrome
• Suicidal ideation
• Supraventricular premature beats
• Thrombocytopenic disorder
• Thrombocytosis
• Torsades de pointes
• Toxic epidermal necrolysis
• Trismus
• Vasculitis
• Ventricular fibrillation
• Ventricular tachycardia

More Frequent

• Abnormal sexual function
• Anorexia
• Constipation
• Diarrhea
• Disorder of ejaculation
• Dizziness
• Drowsy
• Dysuria
• Erectile dysfunction
• General weakness
• Headache disorder
• Hyperhidrosis
• Insomnia
• Libido changes
• Nausea
• Nervousness
• Tremor
• Urinary retention
• Visual changes
• Xerostomia

Less Frequent

• Acute abdominal pain
• Aggressive behavior
• Agitation
• Arthralgia
• Back pain
• Blurred vision
• Chest pain
• Cough
• Dysgeusia
• Dyspepsia
• Fatigue
• Flatulence
• Hypertonia
• Increased appetite
• Increased urinary frequency
• Lethargy
• Malaise
• Mood changes
• Muscle weakness
• Myalgia
• Orgasm disorder
• Palpitations
• Paresthesia
• Pruritus of skin
• Rhinitis
• Sinusitis
• Skin rash
• Symptoms of anxiety
• Tachycardia
• Urinary tract infection
• Vasodilation of blood vessels
• Vertigo
• Vomiting
• Weight gain
• Weight loss
• Yawning

Rare or Very Rare

• Accidental fall
• Anticholinergic toxicity
• Aphthous stomatitis
• Bruxism
• Candidiasis
• Chills
• Dysarthria
• Dysphagia
• Eczema
• Edema
• Eosinophilia
• Exophthalmos
• Facial edema
• Gait abnormality
• Galactorrhea not associated with childbirth
• Glossitis
• Hallucinations
• Hypercholesterolemia
• Hyperkinesis
• Hyperprolactinemia
• Hypokinesia
• Hypotension
• Laryngismus
• Loss of sense of smell
• Lymphadenopathy
• Lymphedema
• Memory impairment
• Menorrhagia
• Migraine
• Mydriasis
• Neck pain
• Orthostatic hypotension
• Pallor
• Phlebitis
• Restless leg syndrome
• Skin photosensitivity
• Syncope
• Tinnitus
• Vaginitis

No enhanced messaging available.

The safety and effectiveness of paroxetine in pediatric patients have not been established. Effectiveness was not established in 3 studies comparing paroxetine to placebo in pediatric patients with MDD. The main safety concern is the increased risk of suicidal thoughts and behaviors.

Paroxetine mesylate capsules are not indicated for use in the pediatric population.

Paroxetine mesylate capsules are contraindicated for use in pregnant women because menopausal vasomotor symptoms do not occur during pregnancy and paroxetine can cause fetal harm.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including paroxetine, during pregnancy. Advise patients to register by calling the National Pregnancy Registry for Antidepressants 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi stry/antidepressants/.

Paroxetine is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester. There are risks of persistent pulmonary hypertension of the newborn (PPHN) and/or poor neonatal adaptation with exposure during pregnancy. Use of paroxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. There also are risks associated with untreated depression in pregnancy. Additionally, women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. For women who intend to become pregnant or who are in their first trimester of pregnancy, initiate paroxetine only after consideration of the other available treatment options.

Data from the published literature report the presence of paroxetine in human milk. There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to paroxetine through breast milk. Monitor for these symptoms in infants exposed to paroxetine. There are no data on the effect of paroxetine on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for paroxetine and any potential adverse effects on the breast-fed child from paroxetine or from the underlying maternal condition.

Paroxetine hydrochloride conventional tablets or suspension: For elderly patients, the recommended initial dosage is 10 mg daily. Do not exceed 40 mg daily.

Paroxetine hydrochloride extended-release tablets: In elderly patients, the recommended initial dosage is 12.5 mg daily; if necessary, reduce the initial dose and increase the intervals between upward titration of the dosage. Do not exceed 50 mg daily for MDD or PD treatment. Do not exceed 37.5 mg daily for SAD treatment.

Paroxetine mesylate capsules: No dosage adjustment is necessary.

In premarketing clinical trials with paroxetine, 17% of patients treated with paroxetine (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose of paroxetine hydrochloride is recommended; however, no overall differences in safety or effectiveness were observed between elderly and younger patients. SSRIs including paroxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction.

Clinical studies of paroxetine mesylate capsules did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently from younger subjects. Elderly patients may have elevated paroxetine plasma concentrations compared to younger patients. However, no dosage adjustment of paroxetine mesylate capsules is considered necessary in elderly patients.