Symbyax

Drug overview for SYMBYAX (olanzapine/fluoxetine hcl):

Generic name: OLANZAPINE/FLUOXETINE HCL (oh-LAN-za-peen/floo-OX-e-teen)
Drug class: Antidepressants
Therapeutic class: Central Nervous System Agents

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is an antidepressant. Olanzapine is considered an atypical or second-generation antipsychotic agent.

Fluoxetine is used in the treatment of major depressive disorder, obsessive-compulsive disorder, premenstrual dysphoric disorder, bulimia nervosa, and panic disorder with or without agoraphobia. In addition, fluoxetine has been used for the treatment of depression associated with bipolar disorder+; obesity+; anorexia nervosa+; myoclonus+; cataplexy+; alcohol dependence+; and premature ejaculation+. Olanzapine is used orally for the symptomatic management of psychotic disorders (e.g., schizophrenia) in adults and adolescents 13-17 years of age.

In addition, oral olanzapine is used alone in adults and adolescents 13-17 years of age or in conjunction with lithium or valproate in adults for the management of acute manic or mixed episodes associated with bipolar I disorder; the drug also is used for longer-term maintenance monotherapy in patients with this disorder. Short-acting olanzapine injection is used IM for the management of acute agitation in patients with bipolar disorder or schizophrenia. Long-acting olanzapine pamoate injection is used IM for the management of schizophrenia in adults.

Olanzapine is used orally in combination with fluoxetine for the treatment of acute depressive episodes associated with bipolar I disorder in adults and pediatric patients 10-17 years of age. The drug also is used orally in combination with fluoxetine for the acute and maintenance therapy of treatment-resistant depression. Olanzapine has been used orally in combination with other antiemetic agents for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy+, including high-dose cisplatin therapy in adults. The drug also has been used as rescue antiemetic therapy in patients with breakthrough cancer chemotherapy-induced nausea and vomiting+.

DRUG IMAGES

SYMBYAX 6-25 MG CAPSULE
SYMBYAX 12-50 MG CAPSULE
SYMBYAX 3-25 MG CAPSULE

The following indications for SYMBYAX (olanzapine/fluoxetine hcl) have been approved by the FDA:

Indications:
Depression associated with bipolar disorder
Major depressive disorder

Professional Synonyms:
Depression associated with bipolar affective disorder
Depression associated with manic depressive disorder
Depressive episode associated with bipolar disorder
Depressive phase of bipolar disorder
Major unipolar illness
Unipolar mood disorder

The following dosing information is available for SYMBYAX (olanzapine/fluoxetine hcl):

Dosing
Administration
Dosing Information
OLANZAPINE-FLUOXETINE HCL

Olanzapine is commercially available as the base and as the pamoate salt; the dosage of olanzapine pamoate is expressed in terms of olanzapine.

Conventional olanzapine tablets and orally disintegrating tablets of the drug are bioequivalent. However, IM administration of a 5-mg dose of the commercially available short-acting olanzapine injection results in a maximum plasma olanzapine concentration that is about fivefold higher than that resulting from a 5-mg oral dose of the drug.

Dosage of olanzapine for psychiatric indications (e.g., psychotic disorders, bipolar disorder, treatment-resistant depression) must be adjusted carefully according to individual requirements and response, using the lowest possible effective dosage.

Dosage of fluoxetine hydrochloride is expressed in terms of fluoxetine.

In titrating dosage of or discontinuing fluoxetine therapy, the prolonged elimination half-life of fluoxetine and norfluoxetine should be considered. Several weeks will be required before the full effect of such alterations is realized.

The manufacturers and some clinicians recommend that an interval of at least 5 weeks elapse between discontinuance of fluoxetine therapy and initiation of monoamine oxidase (MAO) inhibitor therapy, and that at least 2 weeks elapse following discontinuance of an MAO inhibitor prior to initiation of fluoxetine therapy. For additional information on potentially serious drug interactions that may occur between fluoxetine and MAO inhibitors or other serotonergic agents, see Cautions: Precautions and Contraindications and also see Drug Interactions: Serotonergic Drugs.

Because withdrawal effects may occur with discontinuance of fluoxetine, other selective serotonin-reuptake inhibitors (SSRIs), and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), abrupt discontinuance of these drugs should be avoided whenever possible. When fluoxetine therapy is discontinued, the dosage should be reduced gradually (e.g., over a period of several weeks) and the patient monitored for possible withdrawal symptoms. If intolerable symptoms occur following a dosage reduction or upon discontinuance of therapy, the drug may be reinstituted at the previously prescribed dosage.

Subsequently, the clinician may continue decreasing the dosage, but at a more gradual rate. Plasma concentrations of fluoxetine and norfluoxetine (the principal metabolite) decline gradually after cessation of therapy, which may minimize the risk of withdrawal symptoms. (See Withdrawal Reactions under Cautions: Nervous System Effects and also see Chronic Toxicity.)

Patients receiving fluoxetine should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment. (See Cautions: Precautions and Contraindications.)

For the management of major depression, the recommended initial dosage of fluoxetine in adults is 20 mg daily administered in the morning. However, some clinicians suggest that fluoxetine therapy be initiated with lower dosages (e.g., 5 mg daily or 20 mg every 2 or 3 days). Although symptomatic relief may be apparent within the first 1-3 weeks of fluoxetine therapy, optimum antidepressant effect usually requires at least 4 weeks or more of therapy with the drug.

If insufficient clinical improvement is apparent after several weeks of fluoxetine therapy at 20 mg daily, an increase in dosage may be considered. Efficacy of fluoxetine for major depression was demonstrated in clinical trials employing 10-80 mg daily. Studies comparing fluoxetine 20, 40, and 60 mg daily to placebo indicate that a dosage of 20 mg daily is sufficient to obtain a satisfactory response in most adults with major depression.

Fluoxetine dosages up to 80 mg daily have been administered in some patients, and dosages as low as 5 mg daily may be effective in some patients with depression. In addition, in a study in moderately depressed patients, increasing the dosage of fluoxetine from 20 mg to 40 or 60 mg daily did not result in substantial improvement in depression but was associated with an increase in certain adverse effects (e.g., nausea, anxiety, diarrhea, dry mouth, weight loss). The manufacturer states that the maximum dosage of fluoxetine in adults with major depression should not exceed 80 mg daily; however, somewhat higher dosages (e.g., 100-120 mg daily) occasionally have been used in patients who did not respond adequately to lower dosages.

When fluoxetine hydrochloride delayed-release capsules are used for the continuing management of major depressive disorder, the recommended dosage of fluoxetine is 90 mg once weekly beginning 7 days after the last dose of fluoxetine 20 mg daily. If a satisfactory response is not maintained with once weekly administration, consideration may be given to reestablishing a daily dosage schedule.

As with the use of fluoxetine for other indications, lower dosages or less frequent dosing regimens should be considered for geriatric patients, patients with concurrent disease, and patients receiving multiple concomitant drug therapies.

For the management of major depressive disorder in children and adolescents 8-18 years of age, the recommended initial dosage of fluoxetine is 10 or 20 mg daily. If therapy is initiated at 10 mg daily, it should be increased after 1 week to 20 mg daily. Because higher plasma fluoxetine concentrations occur in lower weight children, the manufacturer states that both the initial and target dosage in lower weight children may be 10 mg daily.

An increase in dosage to 20 mg daily may be considered after several weeks in lower weight children if insufficient clinical improvement is observed. Because a rare but serious drug interaction may occur in depressed children and adolescents with comorbid attention-deficit hyperactivity disorder (ADHD) who receive stimulants and selective serotonin-reuptake inhibitors concomitantly, some experts recommend a maximum fluoxetine dosage of 20 mg daily in such patients. (See Tramadol and Other Serotonergic Drugs under Drug Interactions: Serotonergic Drugs.)

For the management of obsessive-compulsive disorder, the recommended initial dosage of fluoxetine in adults is 20 mg daily administered in the morning. Because a possible dose-response relationship for effectiveness was suggested in one clinical study, an increase in dosage may be considered following several weeks of therapy if insufficient clinical improvement is observed. The manufacturer recommends fluoxetine dosages of 20-60 mg daily for the treatment of obsessive-compulsive disorder; dosages up to 80 mg daily have been well tolerated in clinical studies evaluating the drug in adults with obsessive-compulsive disorder.

The manufacturer states that fluoxetine dosage should not exceed 80 mg daily. Like fluoxetine's antidepressant effect, the full therapeutic effect of the drug in patients with obsessive-compulsive disorder may be delayed until 5 weeks of fluoxetine therapy or longer.

The manufacturer states that because only minimal amounts of olanzapine For the management of obsessive-compulsive disorder, the recommended (about 7%) are excreted in urine and because the pharmacokinetics of initial dosage of fluoxetine in children and adolescents 7-17 years of age olanzapine appear not to be altered in patients with renal or hepatic is 10 mg once daily. In adolescents and higher weight children, the dosage impairment, dosage adjustment is not necessary in such patients. should be increased to 20 mg daily after 2 weeks; additional dosage

increases may be considered after several more weeks if insufficient The manufacturer states that the extended-release IM formulation of clinical improvement is observed. In lower weight children, dosage olanzapine pamoate (Zyprexa(R) Relprevv) has not been specifically studied increases may be considered after several weeks if insufficient clinical in patients with renal and/or hepatic impairment. improvement is observed.

The manufacturer recommends fluoxetine dosages of

20-60 mg daily for adolescents and higher weight children and fluoxetine dosages of 20-30 mg daily for lower weight children for the treatment of obsessive-compulsive disorder. In lower weight children, the manufacturer states that clinical experience with fluoxetine dosages exceeding 20 mg daily is minimal and that there is no experience with dosages exceeding 60 mg daily in such patients.

In depressed patients on hemodialysis, chronic fluoxetine administration produced steady-state plasma fluoxetine and norfluoxetine concentrations that were comparable with those observed in patients with normal renal function. The manufacturer therefore states that a reduction in dosage and/or frequency of administration of fluoxetine is not routinely required in patients with renal impairment. Supplemental doses of fluoxetine during hemodialysis also do not appear to be necessary since the drug and its active metabolite norfluoxetine are not removed substantially by hemodialysis.

(See Pharmacokinetics: Elimination.)

Since fluoxetine is extensively metabolized in the liver, elimination may be prolonged in patients with hepatic impairment. Therefore, the manufacturer and some clinicians recommend a reduction in dosage and/or frequency of administration of fluoxetine in patients with hepatic impairment. Some clinicians recommend a 50% reduction in initial fluoxetine dosage for patients with well-compensated cirrhosis; however, patients with more substantial hepatic impairment, particularly those with severe disease, will require careful individualization of dosage. Subsequent dosage adjustment based on the tolerance and therapeutic response of the patient has been recommended in patients with hepatic impairment.

Fluoxetine hydrochloride is administered orally without regard to meals. Fluoxetine hydrochloride conventional capsules, tablets, and solution are administered once or twice daily; the delayed-release capsules are administered once weekly. For the initial management of depression, obsessive-compulsive disorder, premenstrual dysphoric disorder, or bulimia nervosa, the drug generally is administered once daily in the morning.

If the dosage exceeds 20 mg daily, the manufacturer and some clinicians state that fluoxetine should be administered in 2 divided doses daily (preferably in the morning and at noon). However, limited evidence suggests that no clinically important differences in either the efficacy or incidence of adverse effects exist with once-daily (in the morning) versus twice-daily (in the morning and at noon) administration of the drug. If sedation occurs during fluoxetine therapy, administering the second dose at bedtime rather than at noon may be useful.

Because fluoxetine and its principal active metabolite have relatively long half-lives, the drug has been administered less frequently than once daily (e.g., every 2-7 days), particularly during maintenance therapy. Fluoxetine delayed-release capsules are administered once weekly as maintenance therapy in the management of major depressive disorder in patients who have responded to daily administration of the drug. Some clinicians have suggested that conventional fluoxetine preparations administered less frequently than once daily (i.e., three 20-mg capsules once weekly) may also be effective as maintenance therapy in the management of major depressive disorder, but such dosing regimens should be considered investigational at this time and require additional study to confirm their safety and efficacy. Because of the prolonged elimination of fluoxetine and its active metabolite from the body, missing a dose of the drug once steady-state concentrations have been achieved is unlikely to result in substantial alterations in plasma fluoxetine or norfluoxetine concentrations.

No dosing information available.

Generic dosing information for OLANZAPINE-FLUOXETINE HCL
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
OLANZAPINE-FLUOXETINE 3-25 MG	Maintenance	Adults take 1 capsule by oral route once daily in the evening
OLANZAPINE-FLUOXETINE 6-25 MG	Maintenance	Adults take 1 capsule by oral route once daily in the evening
OLANZAPINE-FLUOXETINE 12-50 MG	Maintenance	Adults take 1 capsule by oral route once daily in the evening

The following drug interaction information is available for SYMBYAX (olanzapine/fluoxetine hcl):

Contraindicated
Severe
Moderate

There are 7 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
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. Furazolidone is also known to be a monoamine oxidase inhibitor. 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.	AZILECT, EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METAXALONE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, RASAGILINE MESYLATE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE, XADAGO, ZELAPAR
Thioridazine/Selected SSRIs; Duloxetine 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)	THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE
Iomeprol/Neuroleptics 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: Neuroleptics may lower seizure threshold.(1) CLINICAL EFFECTS: Use of iomeprol in a patient receiving a neuroleptic may increase the risk of seizure.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of iomeprol states that neuroleptics should be discontinued 48 hours before iomeprol use. Treatment with a neuroleptic should not be resumed until 24 hours post-procedure.(1) DISCUSSION: Because neuroleptics may lower seizure threshold, neuroleptics should be discontinued 48 hours before iomeprol use. Treatment with a neuroleptic should not be resumed until 24 hours post-procedure.(1)	IOMERON 350
Pimozide/Strong CYP2D6 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: 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 and 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.	PIMOZIDE
Mavacamten/Strong CYP2C19 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong CYP2C19 inhibitors may decrease the metabolism of mavacamten.(1-3) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP2C19 increases plasma exposure of mavacamten which may increase the incidence and severity of adverse reactions of mavacamten.(1-3) PREDISPOSING FACTORS: CYP2C19 rapid and ultrarapid metabolizers may experience an increased incidence or severity of adverse effects.(1-3) PATIENT MANAGEMENT: The US and Canadian manufacturers of mavacamten state concomitant use with a strong CYP2C19 inhibitor is contraindicated.(1,2) The UK manufacturer of mavacamten states concomitant use with strong CYP2C19 inhibitors is dependent on CYP2C19 phenotype. Labeling recommends: -In patients who are CYP2C19 poor metabolizers, strong CYP2C19 inhibitors may be used concurrently without dose adjustment of mavacamten. Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume usual monitoring schedule. -In patient who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers: When used concurrently with strong CYP2C19 inhibitors, initiate mavacamten at 2.5 mg daily. If starting a strong CYP2C19 inhibitor, reduce mavacamten dose from 15 mg to 5 mg, 10 mg to 2.5 mg, 5 mg to 2.5 mg, or discontinue 2.5 mg. Monitor LVEF in 4 weeks then resume usual monitoring schedule. -If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily. If starting a strong CYP2C19 inhibitor, reduce mavacamten dose from 5 mg to 2.5 mg or discontinue mavacamten if on 2.5 mg. Monitor LVEF in 4 weeks then resume usual monitoring schedule.(3) DISCUSSION: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg), a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve (AUC) by 48% with no effect on maximum concentration (Cmax) in healthy CYP2C19 normal metabolizers and rapid metabolizers.(1) Strong CYP2C19 inhibitors linked to this monograph include: fluoxetine and ticlopidine.(4,5)	CAMZYOS
Cilostazol (Greater Than 50 mg BID)/Strong CYP2C19 Inhibitors that Cause Bleeding 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: Fluoxetine and fluvoxamine are strong CYP2C19 inhibitors. Strong CYP2C19 inhibitors may inhibit the metabolism of cilostazol.(1-3) In addition, serotonin release by platelets plays a role in hemostasis.(2,3) This may result in an increased risk of bleeding due to a decrease in serotonin reuptake by platelets. CLINICAL EFFECTS: Concurrent use of cilostazol and strong CYP2C19 inhibitors may result in elevated levels and increased effects of cilostazol.(1) Concurrent use of a selective serotonin reuptake inhibitor(2,3) and cilostazol 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.(5) 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: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong CYP2C19 inhibitors.(1) Selective serotonin reuptake inhibitors 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: A study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4) 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.(5) 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.(6) 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).(7) 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).(8) 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.(9)	CILOSTAZOL
Valbenazine (Greater Than 40 mg)/Strong CYP2D6 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: 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.	INGREZZA, INGREZZA INITIATION PK(TARDIV), INGREZZA SPRINKLE

There are 20 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Cabergoline/Selected Dopamine Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Dopamine (D2) blockers such as the phenothiazines, butyrophenones, thioxanthenes and atypical antipsychotics may decrease the effects of cabergoline, a dopamine agonist.(1) CLINICAL EFFECTS: Concurrent administration of cabergoline with dopamine blockers (e.g. phenothiazines, butyrophenones, or thio xanthines) may decrease the effectiveness of cabergoline.(1) Cabergoline may decrease the effectiveness of antipsychotic treatment. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of cabergoline states cabergoline(1) should not be administered concurrently with dopamine antagonists. Avoid concurrent use when possible. If cabergoline is started in a patient receiving long term antipsychotic treatment, monitor closely for loss of antipsychotic efficacy. If an antipsychotic is required for a patient on long term cabergoline therapy, consider use of a shorter half-life, less potent dopamine (D2) blocking atypical antipsychotic (e.g. clozapine, quetiapine) and monitor closely. DISCUSSION: The manufacturer of cabergoline state that it should not be administered concurrently with dopamine antagonists.	CABERGOLINE
Selected Anticoagulants (Vitamin K antagonists)/SSRIs; SNRIs 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)	ANISINDIONE, JANTOVEN, WARFARIN SODIUM
Atomoxetine; Vortioxetine/Strong 2D6 Inhibitors 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)	ATOMOXETINE HCL, STRATTERA, TRINTELLIX
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. Although 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 SSRI may be resumed 24 hours after the last dose of linezolid.(1,3-13) DISCUSSION: Serotonin syndrome has been reported in four patients receiving concurrent citalopram and linezolid, in a patient in whom linezolid was initiated 18 days after fluoxetine discontinuation, in a patient receiving concurrent linezolid and fluoxetine, in a patient in whom linezolid was initiated three days after the discontinuation of paroxetine, in three patients receiving concurrent linezolid and sertraline, and in a patient receiving concurrent linezolid and venlafaxine. Many authors state 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 authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(24-29)	LINEZOLID, LINEZOLID-0.9% NACL, LINEZOLID-D5W, ZYVOX
Tamoxifen/Selected Strong CYP2D6 Inhibitors 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 breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(16) 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.(17) 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).(18-19) 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.(20-22) 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,(23-27) 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.(28-29)	SOLTAMOX, TAMOXIFEN CITRATE
Metoclopramide/SSRIs; SNRIs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Both metoclopramide and serotonin reuptake inhibitors (SSRIs, SNRIs) may be associated with extrapyramidal side effects (EPS).(1-7) Some SSRIs or SNRIs may also inhibit the metabolism of metoclopramide by CYP2D6, further increasing the risk for EPS.(8) A few case reports have reported serotonin syndrome with this combination.(9,10) The mechanism of action is not clear. CLINICAL EFFECTS: Concurrent use may result in extrapyramidal side effects (EPS) such as acute dystonia, Parkinsonism, akathisia, neuroleptic malignant syndrome, or tardive dyskinesia. Tardive dyskinesia may be permanent. Serotonin syndrome has been reported infrequently with this combination. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity. Adverse effects may be may be more frequent or severe with SSRIs or SNRIs which inhibit CYP2D6 mediated metabolism of metoclopramide. CYP2D6 inhibitors linked to this monograph and their strength of inhibition(8) (S=strong, M=moderate, W=weak) are: fluoxetine(S), paroxetine(S), duloxetine(M), desvenlafaxine(W), fluvoxamine(W), sertraline(W), escitalopram(W), and venlafaxine(magnitude unclear). Agents linked to this monograph which are not known to inhibit CYP2D6 are levomilnacipran, milnacipran, and vilazodone. PREDISPOSING FACTORS: Patients with renal and/or hepatic impairment may have an increased risk from this combination. The risk of extrapyramidal symptoms is also increased in patients on metoclopramide for longer than 12 weeks. Elderly patients, especially elderly women, and diabetics are at higher risk of developing tardive dyskinesia. Other extrapyramidal symptoms, like acute dystonia, have occurred more frequently in patients younger than 30 years old.(1) PATIENT MANAGEMENT: If possible, consider alternatives to metoclopramide in patients receiving SSRI or SNRI therapy. If concurrent therapy is warranted, monitor patients for signs of extrapyramidal side effects (acute dystonic reaction, Parkinsonian symptoms, akathisia, tardive dyskinesia) and neuroleptic malignant syndrome. Symptoms unique to serotonin syndrome may include diaphoresis, hyperreflexia, and clonus.(11) The manufacturer of metoclopramide says to avoid treatment with metoclopramide for longer than 12 weeks, and to use the lowest possible dose.(1) For gastroesophageal reflux, the manufacturer recommends reduction in 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 fluoxetine or paroxetine.(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 fluoxetine or paroxetine.(1) DISCUSSION: In a study in 20 healthy male subjects, concurrent fluoxetine (60 mg daily for 9 days to simulate steady-state levels of 20 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg single dose) by 42% and 89%, respectively.(2) There have been case reports of extrapyramidal side effects(EPS) in patients receiving concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(4) sertraline,(5) and venlafaxine.(9) A review of a review of EPS associated with SSRIs or SNRIs, with or without other precipitating agents has been published.(6) Case reports have described serotonin syndrome with the combination of sertraline or venlafaxine with metoclopramide.(9,10)	GIMOTI, METOCLOPRAMIDE HCL, REGLAN
Clopidogrel/Fluoxetine; Fluvoxamine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Fluoxetine and fluvoxamine may inhibit the metabolism of clopidogrel to its active form by CYP2C19.(1) CLINICAL EFFECTS: Concurrent use of fluoxetine and fluvoxamine may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19, such as fluoxetine and fluvoxamine, are poor metabolizers of this isoenzyme. Consider alternatives to fluoxetine and fluvoxamine in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on fluoxetine or fluvoxamine. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity. DISCUSSION: In an open-label, cross-over study in 8 health male volunteers, a loading dose of clopidogrel (600 mg) was administered alone and after 5 days of fluoxetine (20 mg). The maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel were decreased by 25.3% and 20.6%, respectively. There was an average decrease of approximately 25% in the antiplatelet effects of clopidogrel when administered with fluoxetine.(2) However, it is likely that this study significantly underestimates the magnitude of this interaction. Both fluoxetine and its norfluoxetine metabolite inhibit CYP2C19 and have long half-lives of 4 to 9 days and so and is an irreversible inhibitor of CYP2C19. In a randomized, cross-over study in healthy subjects, ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the Cmax of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The AUC of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(4) In a cross-over study in 72 healthy subjects, simultaneous administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300 mg loading dose, followed by 75 mg daily) decreased the AUC of the active metabolite of clopidogrel by 46% following the loading dose and by 42% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 47% following the loading dose and by 30% during the maintenance dose. In a cross-over study in 72 healthy subjects, administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12 hours after clopidogrel (300 mg loading dose, followed by 75 mg daily) produced similar effects.(1)	CLOPIDOGREL, CLOPIDOGREL BISULFATE, PLAVIX
Metoclopramide/Antipsychotics; Phenothiazines; Rivastigmine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: These agents block dopamine (D2) receptors. D2 blockade can cause extrapyramidal reactions, such acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia. Neuroleptic malignant syndrome may also occur in patients receiving D2 blockers. The risk of these adverse effects may be increased by concurrent use.(1-3) CLINICAL EFFECTS: Concurrent use may increase the risk of extrapyramidal reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome. Tardive dyskinesia, which may be permanent, 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.(1-3) Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle rigidity, altered mental status, an autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias), elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.(1) PREDISPOSING FACTORS: Patients with Parkinson's or Lewy Body Disease may be more likely to have extrapyramidal reactions or unmasking of their primary disease symptoms. The risk of extrapyramidal symptoms is also increased in patients on metoclopramide for longer than 12 weeks. Elderly patients, especially elderly women, and diabetics are at higher risk of developing tardive dyskinesia. Other extrapyramidal symptoms, like acute dystonia, have occurred more frequently in patients younger than 30 years old.(1) PATIENT MANAGEMENT: The concurrent use of metoclopramide and agents likely to cause extrapyramidal reactions should be avoided.(1) If concurrent use is warranted, monitor patients closely for extrapyramidal reactions and neuroleptic malignant syndrome. The manufacturer of metoclopramide says to avoid treatment with metoclopramide for longer than 12 weeks, and to use the lowest possible dose.(1) Discontinue therapy if symptoms occur. Instruct patients to seek immediate medical attention if symptoms develop. Symptoms of extrapyramidal reactions, including tardive dyskinesia, include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech, trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.(3) DISCUSSION: Both metoclopramide and phenothiazines can cause extrapyramidal reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome. The risk may be increased by concurrent use.(1,2) Extrapyramidal symptoms have been reported with concurrent metoclopramide and neuroleptics, prochlorperazine, and chlorpromazine.(4-6)	GIMOTI, METOCLOPRAMIDE HCL, REGLAN
Ioflupane I 123/Dopamine Transporter Binders 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) 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)	DATSCAN, IOFLUPANE I-123
Citalopram (Greater Than 20 mg)/Select CYP2C19 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1) CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5) 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, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) 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. PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(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. 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: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, and tecovirimat.(7,8)	CELEXA, CITALOPRAM HBR
Selected Dopamine Agonists/Selected Antipsychotics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Selected dopamine agonists are used to treat neurologic conditions such as Parkinson Disease (PD)or restless legs syndrome, and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1-5) CLINICAL EFFECTS: The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(4,7) Compared with Parkinson patients not receiving antipsychotic therapy, Parkinson patients receiving antipsychotics appear to have an increased mortality risk.(6) Patients with other conditions such as restless legs syndrome or a psychotic disorder may also experience symptom exacerbation due to this combination. PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics. PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing or stopping the dopamine agonist. The US manufacturer of ropinirole recommends treatment with dopamine agonists only if potential benefits outweigh risks.(1) The US manufacturer of entacapone states it should not ordinarily be used in patients with major psychotic disorders as entacapone may lead to an exacerbation of psychosis.(4) DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic They found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(6,7)	APOKYN, APOMORPHINE HCL, BROMOCRIPTINE MESYLATE, CARBIDOPA-LEVODOPA, CARBIDOPA-LEVODOPA ER, CARBIDOPA-LEVODOPA-ENTACAPONE, CREXONT, CYCLOSET, DHIVY, DUOPA, INBRIJA, LEVODOPA, MIRAPEX ER, NEUPRO, ONAPGO, PRAMIPEXOLE DIHYDROCHLORIDE, PRAMIPEXOLE ER, ROPINIROLE ER, ROPINIROLE HCL, RYTARY, SINEMET, VYALEV
Sodium Oxybate/Agents that May Cause Respiratory Depression SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3) CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3) PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3) PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(4) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(5) DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)	LUMRYZ, LUMRYZ STARTER PACK, SODIUM OXYBATE, XYREM, XYWAV
Meperidine/Clomipramine; Imipramine; SSRIs; SNRIs; 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)	DEMEROL, MEPERIDINE HCL, MEPERIDINE HCL-0.9% NACL
Dextromethorphan and Quinidine/Fluoxetine; Paroxetine 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)	NUEDEXTA
Higher Strength Tricyclics;Trazodone/Fluoxetine; Paroxetine 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, doxepin, imipramine and trimipramine are metabolized by CYP2C19 and CYP2D6.(1) Desipramine and nortriptyline are metabolized by CYP2D6.(1) 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. Fluoxetine, paroxetine, clomipramine, and imipramine significantly increase neuronal serotonin levels. 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 or trazodone. Elevated levels of tricyclics and trazodone may increase the risk of QT prolongation and the risk for torsades de pointes. Concurrent administration of fluoxetine or paroxetine with clomipramine, and perhaps with imipramine, high dose amitriptyline, or trazodone 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.(20) 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).(20) 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.(22) PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds or trazodone at the initiation of concurrent therapy with fluoxetine or paroxetine. Plasma concentrations of the tricyclic compound (e.g. imipramine/desipramine, amitriptyline/nortriptyline) 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 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. There is one case report of serotonin syndrome during concurrent therapy with paroxetine and trazodone.(23) There have also been case reports of serotonin syndrome with trazodone and fluoxetine,(25) trazodone and amitriptyline with lithium, and cyclobenzaprine(structurally related to the TCAs) with duloxetine. In a 24 year-old patient, the use of fluoxetine and trazodone resulted in severe irritability, anger, anxiety, and anorexia.(24) 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%.(25) 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), desipramine (all strengths), doxepin (> 25 mg), imipramine (> 10 mg), nortriptyline (> 30 mg), trazodone (> 75 mg), and trimipramine (> 25 mg).	AMITRIPTYLINE HCL, ANAFRANIL, CLOMIPRAMINE HCL, DESIPRAMINE HCL, DOXEPIN HCL, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, NORPRAMIN, NORTRIPTYLINE HCL, PAMELOR, PERPHENAZINE-AMITRIPTYLINE, RALDESY, TRAZODONE HCL, TRIMIPRAMINE MALEATE
Eliglustat/Strong & Moderate CYP2D6 Inhibitors 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, levomethadone, mirabegron, moclobemide, and rolapitant.(1,3,4)	CERDELGA
Opioids (Cough and Cold)/Antipsychotics; Phenothiazines SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as antipsychotics, including phenothiazine derivatives.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)	HYCODAN, HYDROCODONE-CHLORPHENIRAMNE ER, HYDROCODONE-HOMATROPINE MBR, HYDROMET, PROMETHAZINE-CODEINE, TUXARIN ER
Aripiprazole Lauroxil Submicronized (Aristada Initio)/Selected Strong CYP2D6 Inhibitors 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)	ARISTADA INITIO
Iobenguane I 123/Agents that Affect Catecholamines 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)	ADREVIEW
Sofpironium/Strong CYP2D6 Inhibitors 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 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)	SOFDRA

There are 61 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Selected Benzodiazepines/Fluoxetine; Nefazodone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fluoxetine, a strong CYP2C19 inhibitor, and nefazodone, a strong CYP3A4 inhibitor, may decrease the metabolism of Phase I hepatically metabolized benzodiazepines. Benzodiazepines linked to this monograph are metabolized by both CYP2C19 and CYP3A4. CLINICAL EFFECTS: Concurrent use of fluoxetine or nefazodone and selected benzodiazepines may result in increased systemic levels and clinical effects of the benzodiazepine. Toxic effects of increased benzodiazepine levels include profound sedation, respiratory depression, coma, and/or death. Benzodiazepines linked to this monograph are chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam and quazepam. PREDISPOSING FACTORS: Patients receiving a medication regimen which includes inhibitors of both major benzodiazepine metabolic pathways (i.e. CYP2C19 and CYP3A4). PATIENT MANAGEMENT: Benzodiazepines that do not undergo extensive Phase I metabolism (lorazepam, oxazepam) may be an alternative to interacting benzodiazepines in patients receiving fluoxetine or nefazodone. The benzodiazepine dose may need to be decreased during concurrent therapy with fluoxetine or nefazodone. If nefazodone or fluoxetine is started in a patient already receiving a benzodiazepine metabolized by CYP2C19 and CYP3A4, then monitor closely and anticipate the need to reduce the benzodiazepine dose. If on review of medication therapy the patient is found to be taking both a strong CYP2C19 and a strong CYP3A4 inhibitor, it would be prudent to convert patient to an alternative benzodiazepine or to an alternative to the inhibiting agent(s). Counsel patient to report excess drowsiness, confusion, memory problems including sleep-driving behaviors, loss of coordination, slowed or difficult breathing, or unresponsiveness. DISCUSSION: Fluoxetine has been shown to increase the area-under-curve (AUC) and half-life (T1/2) of diazepam and to decrease the plasma clearance and formation of N-desmethyldiazepam. Benzodiazepines such as lorazepam, oxazepam, which do not undergo extensive Phase I hepatic metabolism, would not be expected to interact with fluoxetine or nefazodone. Citalopram has been shown not to have clinically significant effects on triazolam. Sertraline has been shown not to have clinically significant effects on diazepam. A statistically significant interaction has been shown to occur between venlafaxine and diazepam. However, the magnitude of the effects does not appear to be sufficient to be clinically important.	CHLORDIAZEPOXIDE HCL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CHLORDIAZEPOXIDE-CLIDINIUM, CLORAZEPATE DIPOTASSIUM, DIAZEPAM, DORAL, FLURAZEPAM HCL, LIBRAX, QUAZEPAM, VALIUM, VALTOCO
Carbamazepine/Selected SSRIs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. The SSRIs may inhibit the metabolism of carbamazepine, although evidence is conflicting. CLINICAL EFFECTS: Possible increased levels of carbamazepine and clinical toxicity. PREDISPOSING FACTORS: One set of authors speculated that the interaction may be less prevalent in long-term recipients of carbamazepine in whom carbamazepine has resulted in enzyme induction. Carbamazepine-induced enzyme induction could possibly decrease the amount of SSRI available to interact with carbamazepine.(1) PATIENT MANAGEMENT: Consider monitoring carbamazepine levels when SSRI therapy is initiated or withdrawn. Patients receiving concurrent therapy should be monitored for clinical signs of toxicity. DISCUSSION: Information on this interaction is conflicting. In a study in subjects maintained on carbamazepine (CBZ), the addition of fluoxetine or fluvoxamine to their regimens resulted in no changes in either CBZ or carbamazepine-10,11-epoxide (CBZ-E).(1) Another study compared subjects receiving concurrent therapy with CBZ and fluoxetine to subjects receiving CBZ therapy alone. There were no differences in the ratios of CBZ to CBZ-E levels between the groups, although there was a trend towards lower CBZ clearance in the group receiving concurrent therapy. The in-vitro section of this study found that fluoxetine did not inhibit the metabolism of CBZ until fluoxetine reached levels 20 times greater than those found clinically. In contrast, another study in healthy subjects found a 30% increase in area-under-curve (AUC) of CBZ and CBZ-E during concurrent therapy with fluoxetine.(3) There have been four case reports of parkinsonism developing after the addition of fluoxetine to CBZ therapy. (4-6) There have been two case reports of increased CBZ levels(7) and one report of serotonin syndrome(8) following the addition of fluoxetine therapy. Information on fluvoxamine is also conflicting. Although the addition of fluvoxamine to carbamazepine regimens resulted in no changes in either CBZ or CBZ-E levels in one study,(1) there have been five case reports of increases in CBZ levels, with clinical toxicity in two reports, during concurrent therapy.(9-10) Information on sertraline is also conflicting. Although the addition of sertraline to carbamazepine regimens resulted in no changes in either CBZ or CBZ-E levels in one study,(11) there has been one case report of increased CBZ levels with clinical toxicity during concurrent therapy.(12) One study has demonstrated that paroxetine had no effect on CBZ levels or effectiveness.(13)	CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, EPITOL, EQUETRO, TEGRETOL, TEGRETOL XR
Hydantoins/Fluoxetine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Hydantoins are metabolized by CYP2C9 and 2C19.(1) Fluoxetine is a moderate inhibitor of CYP2C19.(2) CLINICAL EFFECTS: The pharmacological and toxic effects of hydantoins may be increased due to elevated plasma hydantoin concentrations.(1,3) Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be fatal. PREDISPOSING FACTORS: Renal impairment, hepatic impairment, or hypoalbuminemia. PATIENT MANAGEMENT: Serum hydantoin concentrations should be monitored and the patient should be observed for changes in seizure control if therapy with fluoxetine is started, stopped or altered. Monitor patients for hydantoin toxicity if fluoxetine treatment is started or if dose is increased (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting). Adjust the hydantoin dose as indicated. If long term fluoxetine therapy is discontinued, the hydantoin concentration may decrease. As fluoxetine is slowly eliminated over 4 to 6 weeks after discontinuation, extended monitoring for potential hydantoin dosage increases is recommended.(3) DISCUSSION: In one case, a patient stabilized on phenytoin for two months developed elevated phenytoin serum concentrations (133% increase) as well as signs and symptoms of phenytoin toxicity within 5 days of starting fluoxetine. In another case, a patient stabilized on phenytoin for one year had a 309% increase in plasma phenytoin concentration and signs of phenytoin toxicity 10 days after initiation of treatment with fluoxetine. Similar cases have been reported to the FDA through the Spontaneous Reporting System.	CEREBYX, DILANTIN, DILANTIN-125, FOSPHENYTOIN SODIUM, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED
Tapentadol/SSRIs; SNRIs 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.	NUCYNTA, NUCYNTA ER
Codeine/Strong CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of 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.	ACETAMINOPHEN-CODEINE, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, CARISOPRODOL-ASPIRIN-CODEINE, CODEINE PHOSPHATE, CODEINE SULFATE, FIORICET WITH CODEINE, PROMETHAZINE-CODEINE, TUXARIN ER
Propafenone/Fluoxetine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fluoxetine may inhibit propafenone metabolism by CYP2D6.(1) CLINICAL EFFECTS: The concurrent administration of fluoxetine and propafenone may result in elevated levels of propafenone and increased clinical and toxic effects of propafenone.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent therapy with fluoxetine and propafenone should be carefully monitored for increased propafenone effects and toxicity. The dosage of propafenone may need to be decreased. DISCUSSION: A study in nine healthy, extensive CYP2D6 metabolizers examined the effects of fluoxetine (20 mg daily for 10 days) on a single dose of propafenone (400 mg). Fluoxetine increased the half-life (T1/2, from 3.44+/-0.74 hours to 4.47+/-1.00 hours), the maximum concentration (Cmax, from 435.71+/-37.1 ng/ml to 580.41+/-43.2 ng/ml), and area-under-curve (AUC, from 2238.37+/-25.2 mcg x h/L to 3371.29+/-86.7 mcg x h/L) of S-propafenone when compared to baseline. S-propafenone clearance decreased from 75.01+/-17.69 L/h to 49.36+/-8.62 L/h. Fluoxetine increased the T 1/2 (from 3.24+/-0.9 hours to 3.98+/-0.58 hours), Cmax (from 304.71+/-09.9 ng/ml to 461.91+/-34.8 ng/ml) and AUC (from 1576.35+/-73.1 mcg x h/L to 2370.7+/-704.5 mcg x h/L) of R-propafenone when compared to baseline. R-propafenone clearance decreased from 107.62+/-33.82 L/h to 70.60+/-12.42 L/h.(1)	PROPAFENONE HCL, PROPAFENONE HCL ER
Risperidone/Selected Strong CYP2D6 Inhibitors 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)	RISPERDAL, RISPERIDONE, RISPERIDONE ODT
Aripiprazole Immediate Release/Slt Strong CYP2D6 Inhibitors 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)	ABILIFY, ARIPIPRAZOLE, ARIPIPRAZOLE ODT, OPIPZA
Bupropion/Antipsychotics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Both bupropion and the antipsychotics are known to lower the seizure threshold.(1,2) Bupropion is also a strong inhibitor of CYP2D6.(3) CLINICAL EFFECTS: Concurrent use of bupropion and an antipsychotic may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2) PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1,2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3) PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1)	APLENZIN, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CONTRAVE, FORFIVO XL, WELLBUTRIN SR, WELLBUTRIN XL
Amphetamines; Phentermine/SSRIs; SNRIs 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)	ADDERALL, ADDERALL XR, ADIPEX-P, ADZENYS XR-ODT, AMPHETAMINE SULFATE, DESOXYN, DEXEDRINE, DEXTROAMPHETAMINE SULFATE, DEXTROAMPHETAMINE SULFATE ER, DEXTROAMPHETAMINE-AMPHET ER, DEXTROAMPHETAMINE-AMPHETAMINE, DYANAVEL XR, EVEKEO, HYDROXYAMPHETAMINE HBR, LISDEXAMFETAMINE DIMESYLATE, LOMAIRA, METHAMPHETAMINE HCL, MYDAYIS, PHENTERMINE HCL, PROCENTRA, QSYMIA, VYVANSE, XELSTRYM, ZENZEDI
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)	ACETYL SALICYLIC ACID, ANAPROX DS, ANJESO, ARTHROTEC 50, ARTHROTEC 75, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, ASPIRIN, ASPIRIN-DIPYRIDAMOLE ER, BUPIVACAINE-KETOROLAC-KETAMINE, BUTALBITAL-ASPIRIN-CAFFEINE, CALDOLOR, CAMBIA, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CELEBREX, CELECOXIB, COMBOGESIC, COMBOGESIC IV, CONSENSI, COXANTO, DAYPRO, DICLOFENAC, DICLOFENAC POTASSIUM, DICLOFENAC SODIUM, DICLOFENAC SODIUM ER, DICLOFENAC SODIUM MICRONIZED, DICLOFENAC SODIUM-MISOPROSTOL, DIFLUNISAL, DOLOBID, DURLAZA, EC-NAPROSYN, ELYXYB, ETODOLAC, ETODOLAC ER, FELDENE, FENOPROFEN CALCIUM, FENOPRON, HYDROCODONE-IBUPROFEN, IBU, IBUPAK, IBUPROFEN, IBUPROFEN LYSINE, IBUPROFEN-FAMOTIDINE, INDOCIN, INDOMETHACIN, INDOMETHACIN ER, INFLAMMACIN, INFLATHERM(DICLOFENAC-MENTHOL), KETOPROFEN, KETOPROFEN MICRONIZED, KETOROLAC TROMETHAMINE, KIPROFEN, LODINE, LOFENA, MECLOFENAMATE SODIUM, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NABUMETONE MICRONIZED, NALFON, NAPRELAN, NAPROSYN, NAPROTIN, NAPROXEN, NAPROXEN SODIUM, NAPROXEN SODIUM CR, NAPROXEN SODIUM ER, NAPROXEN-ESOMEPRAZOLE MAG, NEOPROFEN, NORGESIC, NORGESIC FORTE, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, OXAPROZIN, PIROXICAM, R.E.C.K.(ROPIV-EPI-CLON-KETOR), RELAFEN DS, ROPIVACAINE-CLONIDINE-KETOROLC, ROPIVACAINE-KETOROLAC-KETAMINE, SPRIX, SULINDAC, SUMATRIPTAN SUCC-NAPROXEN SOD, SYMBRAVO, TOLECTIN 600, TOLMETIN SODIUM, TORONOVA II SUIK, TORONOVA SUIK, TOXICOLOGY SALIVA COLLECTION, TRESNI, TREXIMET, VIMOVO, VIVLODEX, YOSPRALA, ZIPSOR, ZORVOLEX, ZYNRELEF
Olanzapine/Fluvoxamine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of olanzapine by CYP1A2.(1-5) CLINICAL EFFECTS: Concurrent use of fluvoxamine may result in elevated levels of and toxicity from olanzapine. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for olanzapine side effects. The dose of olanzapine may need to be adjusted if fluvoxamine is initiated or discontinued. DISCUSSION: In a study in 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(1) In a study in 8 schizophrenic patients, the addition of fluvoxamine (100 mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from 12-112%. N-desmethylolanzapine levels were not significantly affected.(2) In a retrospective review, 10 patients receiving concurrent fluvoxamine and olanzapine were compared to 134 patients receiving olanzapine alone. The ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients receiving concurrent fluvoxamine.(3) Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and by 52%, respectively, in female nonsmokers. Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male smokers.(4,5)	FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER
Nebivolol/Fluoxetine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fluoxetine may inhibit the metabolism of nebivolol by CYP2D6.(1) CLINICAL EFFECTS: Concurrent fluoxetine may result in elevated levels of and increased effects from nebivolol.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent fluoxetine should be closely monitored and their dosage of nebivolol should be adjusted according to blood pressure response.(1) DISCUSSION: In a study in 10 healthy subjects, pretreatment with fluoxetine (20 mg daily for 21 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of nebivolol (10 mg) by 8-fold and 3-fold, respectively.(1) In a study in 10 healthy extensive metabolizers, pretreatment with fluoxetine (20 mg daily for 21 days) increased the AUC and Cmax of a single dose of nebivolol (10 mg) by 6-fold and 2.3-fold.(3) 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.	BYSTOLIC, NEBIVOLOL HCL
Deutetrabenazine;Tetrabenazine/Strong CYP2D6 Inhibitors 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)	AUSTEDO, AUSTEDO XR, AUSTEDO XR TITRATION KT(WK1-4), TETRABENAZINE, XENAZINE
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)	ACD-A, ACTIVASE, AGGRASTAT, ARGATROBAN, ARGATROBAN-0.9% NACL, ARIXTRA, ASPIRIN-DIPYRIDAMOLE ER, BRILINTA, CATHFLO ACTIVASE, CITRATE PHOSPHATE DEXTROSE, DABIGATRAN ETEXILATE, DEFITELIO, DICUMAROL, DIPYRIDAMOLE, EFFIENT, ELIQUIS, ELMIRON, ENOXAPARIN SODIUM, ENOXILUV, EPTIFIBATIDE, FONDAPARINUX SODIUM, FRAGMIN, HEPARIN SODIUM, HEPARIN SODIUM IN 0.45% NACL, HEPARIN SODIUM-0.45% NACL, HEPARIN SODIUM-0.9% NACL, HEPARIN SODIUM-D5W, KENGREAL, LOVENOX, PENTOSAN POLYSULFATE SODIUM, PHENINDIONE, PRADAXA, PRASUGREL HCL, RIVAROXABAN, SAVAYSA, TICAGRELOR, TIROFIBAN HCL, TNKASE, XARELTO, ZONTIVITY
Citalopram (Less than or Equal To 20 mg)/Selected CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1) CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5) 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, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) 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. PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(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. 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: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, and tecovirimat.(7,8)	CELEXA, CITALOPRAM HBR
Tramadol/Selected Moderate to Strong CYP2D6 Inhibitors 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, escitalopram, fluoxetine, hydroquinidine, 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)	CONZIP, QDOLO, TRAMADOL HCL, TRAMADOL HCL ER, TRAMADOL HCL-ACETAMINOPHEN
Clobazam/Selected Moderate CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Clobazam's active metabolite, N-desmethylclobazam, is metabolized by the CYP2C19 isoenzyme.(1) CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP2C19 may result in elevated levels of and toxicity from the active metabolite of clobazam, including profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The dosage of clobazam may need to be adjusted when initiating or discontinuing a moderate inhibitor of CYP2C19.(1) When initiating clobazam in a patient maintained on a moderate inhibitor of CYP2C19, it would be prudent to follow the manufacturer's recommendations for dosage adjustments in patients who are CYP2C19 poor metabolizers. In these patients, consider a starting dose of 5 mg/day and reduce weekly dosage adjustments to half the normal increase. Based on clinical response, the dosage may be titrated to normal dosage levels based on weight group at Day 21.(1) When initiating a moderate inhibitor of CYP2C19 in a patient maintained on clobazam monitor for increased effects from clobazam until inhibitor concentration reaches steady-state and adjust dose accordingly.(1-4) DISCUSSION: The active metabolite of clobazam, N-desmethylclobazam, is metabolized by CYP2C19. Levels of N-desmethylclobazam are 3-5 times higher in poor metabolizers of CYP2C19 and 2 times higher in intermediate metabolizers of CYP2C19. Thus, moderate inhibitors of CYP2C19 are expected to result in a 2-fold or higher increase in levels of N-desmethylclobazam as well.(1) Selected moderate inhibitors of CYP2C19 include: abrocitinib, cannabidiol, cenobamate, fluoxetine, moclobemide, and voriconazole.(5) 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.	CLOBAZAM, ONFI, SYMPAZAN
Haloperidol/Fluoxetine; Fluvoxamine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Haloperidol is metabolized via many metabolic pathways. The contributions of CYP2D6, CYP3A4 and possibly CYP1A2 pathways are most clearly defined. Concomitant use of haloperidol with inhibitors of one or more of these pathways may lead to clinically significant increases in haloperidol levels. Fluoxetine is a strong CYP2D6 inhibitor and a weak CYP3A4 inhibitor. Fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19 and is a weak inhibitor of CYP2C8, CYP2C9, and CYP3A4. CLINICAL EFFECTS: The concurrent administration of fluoxetine or fluvoxamine may result in elevated levels of haloperidol and lead to toxicities such as orthostatic hypotension, akathisia, acute dystonia, or Parkinsonism. PREDISPOSING FACTORS: Elderly patients, particularly those with a history of falls or swallowing disorders, and patients with Parkinson Disease, Lewy Body Disease, or other dementias are more sensitive to antipsychotics and have a greater risk for adverse effects. Younger patients, patients on low doses of haloperidol, or on a dose targeted to lower-therapeutic serum levels, have a lower interaction risk. PATIENT MANAGEMENT: Monitor patient for extrapyramidal side effects and orthostatic hypotension if fluoxetine or fluvoxamine is added to haloperidol therapy and lower haloperidol dose if needed. The onset and peak effects of an interaction with fluoxetine may be delayed 1 to 2 weeks due to its long 3 to 7 day half-life. DISCUSSION: Although it is an older agent, the complex pharmacokinetics of haloperidol are not yet fully understood.	HALDOL DECANOATE 100, HALDOL DECANOATE 50, HALOPERIDOL, HALOPERIDOL DECANOATE, HALOPERIDOL DECANOATE 100, HALOPERIDOL LACTATE
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: citalopram, clomipramine, desvenlafaxine, duloxetine, fluoxetine, imipramine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone and vortioxetine.	FENTANYL, FENTANYL CITRATE, FENTANYL CITRATE-0.9% NACL, FENTANYL CITRATE-D5W, FENTANYL CITRATE-STERILE WATER, FENTANYL CITRATE-WATER, FENTANYL-BUPIVACAINE-0.9% NACL, FENTANYL-BUPIVACAINE-NACL, FENTANYL-ROPIVACAINE-0.9% NACL, FENTANYL-ROPIVACAINE-NACL
Escitalopram (Greater Than 15 mg)/Selected CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3) PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) 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. PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. 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: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, and tipranavir.(4)	ESCITALOPRAM OXALATE, LEXAPRO
Duloxetine/Fluoxetine; Paroxetine 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.	CYMBALTA, DRIZALMA SPRINKLE, DULOXETINE HCL, DULOXICAINE
Dextromethorphan/Selected SSRIs that Inhibit CYP2D6 SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fluoxetine and paroxetine, strong inhibitors of CYP2D6, may inhibit the metabolism of dextromethorphan.(1-4) 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, 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)	AUVELITY, BROMFED DM, BROMPHENIRAMINE-PSEUDOEPHED-DM, DEXTROMETHORPHAN HBR, PROMETHAZINE-DM
Lower Strength Tricyclics; Trazodone/Fluoxetine; Paroxetine 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, doxepin, imipramine and trimipramine are metabolized by CYP2C19 and CYP2D6.(1) Desipramine, nortriptyline, amoxapine, and protriptyline are metabolized by CYP2D6.(1) Trazodone is metabolized to mCPP, an active metabolite with potential adverse effects, by CYP2D6. Cyclobenzaprine is metabolized by CYP1A2 and CYP3A4 and so a pharmacokinetic interaction is not expected. Fluoxetine, paroxetine, and clomipramine significantly increase neuronal serotonin levels. 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 or trazodone. Elevated levels of tricyclics and trazodone may increase the risk of QT prolongation and the risk for torsades de pointes. Concurrent administration of fluoxetine or paroxetine with clomipramine and perhaps with imipramine, cyclobenzaprine, high dose amitriptyline, or trazodone 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.(19) 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).(19) Concurrent use of multiple drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(20) 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.(21) PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds or trazodone when concurrent therapy with fluoxetine or paroxetine is started or if the dosage of either agent is increased. Plasma concentrations of the tricyclic compound (e.g. amitriptyline/nortriptyline, imipramine/desipramine) should be monitored and the dosage adjusted accordingly. If the fluoxetine or paroxetine is discontinued in a patient receiving a trazodone or 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, and perhaps cyclobenzaprine, higher dose amitriptyline, or 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: 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. There is one case report of serotonin syndrome during concurrent therapy with paroxetine and trazodone.(24) There have also been case reports of serotonin syndrome with trazodone and fluoxetine,(28) 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.(25) 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%.(27) In a 50 year-old patient, the use of protriptyline and fluoxetine resulted in anticholinergic delirium.(26) The manufacturer of cyclobenzaprine reports that serotonin syndrome has been reported when combined with other serotonergic agents.(23) 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), amoxapine, clomipramine (<=25mg), cyclobenzaprine (structurally similar to amitriptyline), doxepin (<=25mg), imipramine (<=10mg), melitracen, nortriptyline (<=30mg), protriptyline, trazodone (<=75mg), and trimipramine (<=25mg).	AMITRIPTYLINE HCL, AMOXAPINE, AMRIX, ANAFRANIL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CLOMIPRAMINE HCL, CYCLOBENZAPRINE HCL, CYCLOBENZAPRINE HCL ER, CYCLOPAK, CYCLOTENS, DOXEPIN HCL, FEXMID, IMIPRAMINE HCL, NORTRIPTYLINE HCL, PAMELOR, PERPHENAZINE-AMITRIPTYLINE, PROTRIPTYLINE HCL, SILENOR, TRAZODONE HCL, TRIMIPRAMINE MALEATE
Iloperidone/Selected Strong CYP2D6 Inhibitors 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, 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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) 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)	FANAPT
Brexpiprazole/Strong CYP2D6 Inhibitors 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)	REXULTI
Olanzapine/Ciprofloxacin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ciprofloxacin may inhibit the CYP1A2 mediated metabolism of olanzapine.(1-6) CLINICAL EFFECTS: Concurrent use of ciprofloxacin may result in elevated levels of and toxicity from olanzapine. PREDISPOSING FACTORS: Cytokines or other immune modulators secreted in response to infection or inflammation may also inhibit CYP1A2, resulting in additive suppression of CYP1A2 activity.(3-5) PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for olanzapine side effects. The dose of olanzapine may need to be adjusted if ciprofloxacin is initiated or discontinued. DISCUSSION: In a study with fluvoxamine, another CYP1A2 inhibitor, 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(6) In a study in 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(1) In a study in 8 schizophrenic patients, the addition of fluvoxamine (100 mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from 12-112%. N-desmethylolanzapine levels were not significantly affected.(7) In a retrospective review, 10 patients receiving concurrent fluvoxamine and olanzapine were compared to 134 patients receiving olanzapine alone. The ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients receiving concurrent fluvoxamine.(8) Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and by 52%, respectively, in female nonsmokers. Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male smokers.(9,10)	CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W
Flecainide/Selected Strong CYP2D6 Inhibitors 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: This interaction may be more severe in patients who are CYP2D6 extensive or intermediate metabolizers. 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)	FLECAINIDE ACETATE
Alprazolam/Fluoxetine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Alprazolam is primarily metabolized by CYP3A4.(1) Fluoxetine and its long-acting active metabolite norfluoxetine are both weak inhibitors and inducers of CYP3A4.(2) While the onset of enzyme inhibition is an early effect, the onset of induction may take weeks for maximal effect. CLINICAL EFFECTS: Addition of fluoxetine to existing alprazolam therapy may be associated with increased alprazolam concentrations and clinical effects, including profound sedation, respiratory depression, coma, and/or death. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If fluoxetine is started in a patient already receiving alprazolam, the alprazolam dose may need to be decreased. With continued (i.e. chronic) fluoxetine therapy the interaction may wane due to the counteracting effect of weak CYP3A4 induction by fluoxetine. Monitor and adjust the alprazolam dose as needed. If clinically appropriate, a benzodiazepine which does not undergo extensive Phase I metabolism (lorazepam, oxazepam), or clonazepam(3) may be an alternative to alprazolam in patients receiving fluoxetine. Counsel patient to report excess drowsiness, confusion, memory problems including sleep-driving behaviors, loss of coordination, slowed or difficult breathing, or unresponsiveness. DISCUSSION: Manufacturer prescribing information describes an interaction study where fluoxetine increased the maximum concentration (Cmax) of alprazolam by 46%, decreased clearance by 21% and increased half-life by 17% leading to decreased measured psychomotor performance.(1) Details regarding the patient population, drug dosage, and duration of therapy were not provided. The effect of fluoxetine on the pharmacokinetics of a single dose of alprazolam was studied in 11 male volunteers. Subjects received fluoxetine 20 mg every 12 hours for 9 days followed by a single dose of alprazolam 1 mg. The mean elimination half-life of alprazolam increased from 17.4 to 20.3 hours, area-under-curve (AUC) increased 26%. Clinical effects, e.g. impairment of memory or psychomotor performance were not measured.(3) A study was performed to better understand the interactions of chronic fluoxetine therapy on the activity of CYP2D6, CYP2C19 and CYP3A4 enzymes. In this study chronic fluoxetine therapy did significantly affect the AUC, clearance or half-life of the following CYP3A4 substrates: midazolam, lovastatin, cortisone or 6-beta-hydroxycortisol. Evaluation of this outcome revealed that fluoxetine (and its active metabolite) both inhibit and induce CYP3A4 to a similar degree. During chronic fluoxetine therapy, these two opposing activities were balanced, resulting in no clinical effect.	ALPRAZOLAM, ALPRAZOLAM ER, ALPRAZOLAM INTENSOL, ALPRAZOLAM ODT, ALPRAZOLAM XR, XANAX, XANAX XR
Opioids (Extended Release)/Antipsychotics; Phenothiazines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)	BUPRENORPHINE, BUTRANS, CONZIP, FENTANYL, HYDROCODONE BITARTRATE ER, HYDROMORPHONE ER, HYSINGLA ER, MORPHINE SULFATE ER, MS CONTIN, NUCYNTA ER, OXYCODONE HCL ER, OXYCONTIN, OXYMORPHONE HCL ER, TRAMADOL HCL ER, XTAMPZA ER
Slt Opioids (Immediate Release)/Antipsychotics;Phenothiazine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)	APADAZ, BELBUCA, BELLADONNA-OPIUM, BENZHYDROCODONE-ACETAMINOPHEN, BUPRENORPHINE HCL, BUTORPHANOL TARTRATE, DILAUDID, DSUVIA, DURAMORPH, ENDOCET, FENTANYL CITRATE, FENTANYL CITRATE-0.9% NACL, FENTANYL CITRATE-D5W, FENTANYL CITRATE-STERILE WATER, FENTANYL CITRATE-WATER, FENTANYL-BUPIVACAINE-0.9% NACL, FENTANYL-BUPIVACAINE-NACL, FENTANYL-ROPIVACAINE-0.9% NACL, FENTANYL-ROPIVACAINE-NACL, HYDROCODONE BITARTRATE, HYDROCODONE-ACETAMINOPHEN, HYDROCODONE-IBUPROFEN, HYDROMORPHONE HCL, HYDROMORPHONE HCL-0.9% NACL, HYDROMORPHONE HCL-D5W, HYDROMORPHONE HCL-NACL, HYDROMORPHONE HCL-WATER, INFUMORPH, MITIGO, MORPHINE SULFATE, MORPHINE SULFATE-0.9% NACL, MORPHINE SULFATE-NACL, NALBUPHINE HCL, NALOCET, NUCYNTA, OLINVYK, OPIUM TINCTURE, OXYCODONE HCL, OXYCODONE HYDROCHLORIDE, OXYCODONE-ACETAMINOPHEN, OXYMORPHONE HCL, PENTAZOCINE-NALOXONE HCL, PERCOCET, PRIMLEV, PROLATE, REMIFENTANIL HCL, ROXICODONE, ROXYBOND, SUFENTANIL CITRATE, ULTIVA
Olanzapine/Selected CYP1A2 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inducers of CYP1A2 may increase the metabolism of olanzapine.(1,2) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inducer may result in decreased levels and effectiveness of olanzapine.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Patients receiving concurrent therapy with olanzapine and a CYP1A2 inducer may require increased dosages of olanzapine. The dosage of olanzapine may need to be adjusted if concurrent therapy with a CYP1A2 inducer is initiated or discontinued.(1,2) If a CYP1A2 inducer is initiated in a patient maintained on olanzapine, monitor for decreased effectiveness of olanzapine. If a CYP1A2 inducer is discontinued in a patient maintained on olanzapine, monitor for olanzapine toxicity. DISCUSSION: Concurrent use of carbamazepine, a CYP1A2 inducer, increased olanzapine clearance by 50%.(1,2)	ARAVA, AUBAGIO, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, EPITOL, EQUETRO, FOSPHENYTOIN SODIUM, KALETRA, LEFLUNICLO, LEFLUNOMIDE, LOPINAVIR-RITONAVIR, NORVIR, PAXLOVID, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, RIFADIN, RIFAMPIN, RITONAVIR, TEGRETOL, TEGRETOL XR, TERIFLUNOMIDE, VIRACEPT
Valbenazine (Less Than or Equal To 40 mg)/Strong CYP2D6 Inhibitors 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.	INGREZZA, INGREZZA SPRINKLE
Oxycodone/Strong CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may 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)	ENDOCET, NALOCET, OXYCODONE HCL, OXYCODONE HCL ER, OXYCODONE HYDROCHLORIDE, OXYCODONE-ACETAMINOPHEN, OXYCONTIN, PERCOCET, PRIMLEV, PROLATE, ROXICODONE, ROXYBOND, XTAMPZA ER
Desmopressin/Agents with Hyponatremia Risk 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)	DDAVP, DESMOPRESSIN ACETATE, NOCDURNA
Selected Opioids for MAT/Antipsychotics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics may result in additive CNS depression.(1-3) Levomethadone is an enantiomer of methadone.(4) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, may result in profound sedation, respiratory depression, coma, and/or death.(1-3) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine, diacetylmorphine, or methadone is not contraindicated in patients taking CNS depressants; however, gradual tapering or decreasing to the lowest effective dose of the CNS depressant may be appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine, diacetylmorphine, or methadone treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(6) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(7) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(8) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(9) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(10) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(11) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(12) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(13)	BRIXADI, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, DISKETS, METHADONE HCL, METHADONE INTENSOL, METHADOSE, SUBLOCADE, SUBOXONE, ZUBSOLV
Escitalopram (Less Than or Equal To 15 mg)/Selected CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3) PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) 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. PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. 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: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, and tipranavir.(4)	ESCITALOPRAM OXALATE, LEXAPRO
Bupropion/SNRIs; SSRIs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Both bupropion and the SSRIs and SNRIs are known to lower the seizure threshold.(1,2) In addition, bupropion, a strong inhibitor of CYP2D6, may inhibit the metabolism of SSRIs and SNRIs metabolized by CYP2D6. The potential for bupropion to inhibit the metabolism of the antidepressant differs. Antidepressants that are very sensitive to CYP2D6 inhibition have a greater potential for increased effects. Antidepressants which are very sensitive to CYP2D6 inhibition and have the greatest potential for increased effects are: fluoxetine,(3) paroxetine,(4) and venlafaxine.(5) Antidepressants which are moderately sensitive to CYP2D6 inhibition are: fluvoxamine.(6) Antidepressants which are metabolized by CYP2D6 but less susceptible to CYP2D6 inhibition and therefore have a lower potential for increased effects are: citalopram(7) and duloxetine.(8) CLINICAL EFFECTS: Concurrent use of bupropion and a SSRI or SNRI may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2) Concurrent use may also increase levels of and side effects from antidepressants metabolized by CYP2D6, such as citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine, and venlafaxine.(3-10) PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids).(1,2) With paroxetine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(11) PATIENT MANAGEMENT: The concurrent use of bupropion and SSRIs or SNRIs should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) In a study in 15 male subjects who were extensive metabolizers of CYP2D6, bupropion (150 mg twice daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine (50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2) In a clinical study, citalopram steady state levels were not significantly different in poor metabolizers and extensive metabolizers of CYP2D6. Coadministration of a drug that inhibits CYP2D6 with citalopram is unlikely to have clinically significant effects on citalopram metabolism, based on the study results in CYP2D6 poor metabolizers.(7) Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the AUC of duloxetine by about 60%.(8) An in vivo study of single-dose fluvoxamine evaluated pharmacokinetic changes in 13 poor metabolizers (PM) compared to 16 extensive metabolizers (EM). The mean Cmax, AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group.(6) Fluoxetine, paroxetine, and venlafaxine are classified as sensitive CYP2D6 substrates with an increase in AUC >= 5-fold.(9) The FDA defines sensitive substrates as drugs that have an increase in AUC >= 5-fold and moderate sensitive substrates have an increase in AUC >= 2-fold to <5-fold when administered with strong inhibitors.(10)	APLENZIN, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CONTRAVE, FORFIVO XL, WELLBUTRIN SR, WELLBUTRIN XL
Metoprolol/Selected CYP2D6 Inhibitors 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.	KAPSPARGO SPRINKLE, LOPRESSOR, METOPROLOL SUCCINATE, METOPROLOL TARTRATE, METOPROLOL-HYDROCHLOROTHIAZIDE, TOPROL XL
Meperidine (IR)/Selected Antipsychotics; Phenothiazines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids such as meperidine and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids such as meperidine and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as meperidine with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)	DEMEROL, MEPERIDINE HCL, MEPERIDINE HCL-0.9% NACL
Codeine; Levorphanol (IR)/Slt Antipsychotics; Phenothiazines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids such as codeine and levorphanol and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids such as codeine and levorphanol and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as codeine and levorphanol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)	ACETAMIN-CAFF-DIHYDROCODEINE, ACETAMINOPHEN-CODEINE, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, CARISOPRODOL-ASPIRIN-CODEINE, CODEINE PHOSPHATE, CODEINE SULFATE, DIHYDROCODEINE BITARTRATE, FIORICET WITH CODEINE, HYDROCODONE BITARTRATE, LEVORPHANOL TARTRATE, TREZIX
Methadone (non MAT)/Selected Antipsychotics; Phenothiazines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids such as methadone and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids such as methadone and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as methadone with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)	METHADONE HCL, METHADONE HCL-0.9% NACL, METHADONE HCL-NACL
Tramadol (IR)/Selected Antipsychotics; Phenothiazines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids such as tramadol and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids such as tramadol and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as tramadol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)	QDOLO, TRAMADOL HCL, TRAMADOL HCL-ACETAMINOPHEN
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)	FLURBIPROFEN, LURBIPR
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)	BROMFENAC SODIUM, PHENYLBUTAZONE
Clozapine/Fluoxetine; Sertraline SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The metabolism of clozapine may be inhibited at CYP1A2, 2D6 or 3A4 by fluoxetine or sertraline.(1) CLINICAL EFFECTS: The concurrent administration of clozapine with fluoxetine or sertraline may result in elevated levels of clozapine and an increase in clozapine related side effects, orthostatic hypotension, syncope, QT prolongation, profound sedation and seizures. PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(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: Clozapine levels should be monitored in patients receiving concurrent therapy with clozapine and fluoxetine or sertraline. Patients should be monitored for signs of clozapine toxicity. The dosage of either clozapine, fluoxetine or sertraline 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 fluoxetine or sertraline 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. DISCUSSION: Two studies compared subjects receiving concurrent clozapine and fluoxetine to subjects receiving clozapine alone. In the first,(3) the clozapine level-to-dose and norclozapine level-to-dose ratios were 75% and 50% higher, respectively, in subjects receiving concurrent fluoxetine. In the second study(4), clozapine and norclozapine levels were 30.2% and 33.5% higher, respectively, in subjects receiving concurrent fluoxetine. A study (5) in 10 subjects found that the concurrent administration of fluoxetine and clozapine resulted in increases of 58%, 36%, and 38% in clozapine, norclozapine, and clozapine-N-oxide, respectively. One case report(6) documented the development of myoclonic jerks following the addition of fluoxetine to clozapine therapy. A study(4) in 16 subjects found that the concurrent administration of sertraline and clozapine resulted in clozapine and norclozapine levels that were 30.2% and 52.1% higher, respectively, than levels seen in similar patients receiving clozapine alone.	CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ
Pitolisant/Strong CYP2D6 Inhibitors 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 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.(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)	WAKIX
Oliceridine/Strong CYP2D6 Inhibitors 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. Consider this risk when using concurrently with agents that may increase opioid drug levels.(2) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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)	OLINVYK
Mexiletine/Strong CYP2D6 Inhibitors 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 CYP2D61/10 and 10/*10 livers, respectively.(3) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine.(6-7)	MEXILETINE HCL
Belzutifan/Strong CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Belzutifan is primarily metabolized by CYP2C19 and UGT2B17, and to a lesser extent by CYP3A4. Agents that are inhibitors of CYP2C19 may inhibit the metabolism of belzutifan.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP2C19 increases plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions of belzutifan. This may increase the incidence or severity of anemia or hypoxia that can require a blood transfusion.(1) PREDISPOSING FACTORS: UGT2B17 and CYP2C19 ultrarapid metabolizers may increase the incidence or severity of adverse effects, including anemia.(1) PATIENT MANAGEMENT: The manufacturer of belzutifan states concurrent administration of CYP2C19 inhibitors with belzutifan increases plasma exposure which may increase the incidence and severity of anemia or hypoxemia. Monitor patients closely for anemia or hypoxemia and reduce the dose of belzutifan as recommended.(1) Monitor for anemia before initiation of, and periodically throughout, treatment with belzutifan. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia.(1) For patients with hemoglobin <9 g/dL, withhold belzutifan until the hemoglobin is greater than or equal to 9 g/dL, then resume at reduced dose or permanently discontinue belzutifan, depending on the severity of anemia.(1) See full prescribing information for dose modifications and recommendations.(1) DISCUSSION: The effect of concurrent administration inhibitors of CYP2C19 may cause an increase in plasma levels that can increase side effects, including anemia.(1) In clinical studies, patients who are poor metabolizers of UGT2B17 and CYP2C19 had higher belzutifan area-under-curve (AUC). The belzutifan AUC increased by 2-fold, 1.6-fold, and 3.2-fold in patients who were UGT2B17, CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolizers, respectively.(1) Strong CYP2C19 inhibitors linked to this monograph include: fluconazole, fluoxetine, fluvoxamine, and ticlopidine.(2,3)	WELIREG
Abrocitinib/Selected Strong CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Abrocitinib is primarily metabolized by CYP2C19 and CYP2C9. Agents that are inhibitors of CYP2C19 may inhibit the metabolism of abrocitinib.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP2C19 increases plasma exposure of abrocitinib which may increase the incidence and severity of adverse reactions of abrocitinib. This may increase the risk of infections, major adverse cardiovascular events, or thrombosis.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of abrocitinib states that the dose of abrocitinib in patients who are taking strong CYP2C19 inhibitors should be reduced to 50 mg once daily. If an adequate response is not achieved after 12 weeks, consider increasing the dose to 100 mg once daily. If the response remains inadequate, discontinue therapy with abrocitinib.(1) DISCUSSION: In a study, fluvoxamine (50 mg daily for 9 days), a strong CYP2C19 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of abrocitinib (100 mg) by 1.33-fold and 1.91-fold, respectively.(1) Strong CYP2C19 inhibitors linked to this monograph include: fluoxetine and fluvoxamine.(2,3)	CIBINQO
Fenfluramine/Selected SSRIs that Inhibit CYP1A2 or CYP2D6 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)	FINTEPLA
Aripiprazole Lauroxil (Aristada)/Select Strong CYP2D6 Inhibitors 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)	ARISTADA
Cilostazol (Less Than or Equal to 50 mg BID)/Strong CYP2C19 Inhibitors that Cause Bleeding SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fluoxetine and fluvoxamine are strong CYP2C19 inhibitors. Strong CYP2C19 inhibitors may inhibit the metabolism of cilostazol.(1-3) In addition, serotonin release by platelets plays a role in hemostasis.(2,3) This may result in an increased risk of bleeding due to a decrease in serotonin reuptake by platelets. CLINICAL EFFECTS: Concurrent use of cilostazol and strong CYP2C19 inhibitors may result in elevated levels and increased effects of cilostazol.(1) Concurrent use of a selective serotonin reuptake inhibitor(2,3) and cilostazol 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.(5) 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: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong CYP2C19 inhibitors.(1) Selective serotonin reuptake inhibitors 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: A study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4) 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.(5) 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.(6) 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).(7) 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).(8) 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.(9)	CILOSTAZOL
Risperidone Intramuscular Every 2 Weeks (Consta)/Slt Strong 2D6 Inhibitors 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)	RISPERDAL CONSTA, RISPERIDONE ER, RYKINDO
Risperidone Subcutaneous Every 1-2 Months (Uzedy)/Slt Strong 2D6 Inhibitors 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)	UZEDY
Risperidone Subcutaneous Injection Monthly (Perseris)/Strong CYP2D6 Inhibitors 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)	PERSERIS
Aripiprazole IM Monthly (Abilify Maintena)/Selected Strong CYP2D6 Inhibitors 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)	ABILIFY MAINTENA
Aripiprazole IM Every 2 Months (Abilify Asimtufii)/Slt Strong CYP2D6 Inhibitors 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)	ABILIFY ASIMTUFII
Propranolol/Selected CYP2D6 Inhibitors 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, lorcaserin, mirabegron, moclobemide, quinine, ranolazine, and rolapitant. Weak CYP2D6 inhibitors include: celecoxib, desvenlafaxine, diphenhydramine, dimenhydrinate, dronabinol, fedratinib, hydroxychloroquine, imatinib, osilodrostat, ranitidine, and sertraline.(6)	HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID
Ziprasidone/Serotonergic Agents 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)	GEODON, ZIPRASIDONE HCL, ZIPRASIDONE MESYLATE

The following contraindication information is available for SYMBYAX (olanzapine/fluoxetine hcl):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

The manufacturer states that there are no contraindications associated with oral or short-acting IM olanzapine monotherapy. When olanzapine is used in combination with fluoxetine, the usual contraindications associated with fluoxetine must be considered. When olanzapine is used as adjunctive therapy with lithium or valproate, the manufacturer advises clinicians to refer to prescribing information for those other drugs. The manufacturer states that there are no contraindications associated with use of the long-acting IM formulation of olanzapine pamoate.

There are 5 contraindications. Absolute contraindication.

Contraindication List
Congenital long QT syndrome
Neuroleptic malignant syndrome
Parkinsonism
Serotonin syndrome
Torsades de pointes

There are 30 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
30 day risk period post-myocardial infarction
Acute myocardial infarction
Angle-closure glaucoma
Anorexia
Benign prostatic hyperplasia
Bipolar disorder
Cardiac arrhythmia
Cerebrovascular disorder
Chronic heart failure
Dehydration
Diabetes mellitus
Disease of liver
Esophageal dysmotility
Hypotension
Hypovolemia
Leukopenia
Lower seizure threshold
Myocardial ischemia
Neutropenic disorder
Orthostatic hypotension
Paralytic ileus
Predisposition to aspiration
Restless leg syndrome
Risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
Seizure disorder
Senile dementia
Suicidal ideation
Tardive dyskinesia
Transient cerebral ischemia
Upper GI bleed

There are 21 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Abnormal sexual function
Acute decompensated heart failure
Bradycardia
CYp2d6 poor metabolizer
Diabetes mellitus
Disease of liver
Hypercholesterolemia
Hyperlipidemia
Hyperprolactinemia
Hypertriglyceridemia
Hypomania
Hyponatremia
Increased risk of bleeding
Manic disorder
Obesity
Prolonged QT interval
Seizure disorder
SIADH syndrome
Sinus tachycardia
Tobacco smoker
Weight gain

The following adverse reaction information is available for SYMBYAX (olanzapine/fluoxetine hcl):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 89 severe adverse reactions.

More Frequent	Less Frequent
Akathisia Parkinsonism Personality disorders	Altered mental status Chest pain Euphoria Extrapyramidal disease Fever Hypertension Memory impairment Peripheral edema Tardive dyskinesia

Rare/Very Rare
Abnormal hepatic function tests Accidental fall Accommodation disorder Acquired dystonia Acquired hemolytic anemia Agranulocytosis Anaphylaxis Angioedema Aplastic anemia Atrial fibrillation Bronchospastic pulmonary disease Cerebrovascular accident Cholestatic hepatitis Diabetes mellitus Diabetic ketoacidosis DRESS syndrome Drug-induced hepatitis Dysphagia Dyspnea Eosinophilia Eosinophilic pneumonia Erythema multiforme Erythema nodosum Esophageal dysmotility Exfoliative dermatitis Facial edema Gastrointestinal hemorrhage Gastrointestinal ulcer Heat stroke Hemorrhage Hepatic failure Hepatitis Hyperbilirubinemia Hyperglycemia Hyperlipidemia Hyperosmolar hyperglycemic state Hypomania Hyponatremia Ileus Increased risk of bleeding Jaundice Laryngeal edema Laryngismus Leukopenia Lymphadenopathy Manic disorder Menstrual disorder Neuroleptic malignant syndrome Neutropenic disorder Obstructive hyperbilirubinemia Oculogyric crisis Optic neuritis Osteoporosis Pancreatitis Pancytopenia Priapism Prolonged QT interval Pulmonary hypertension Pulmonary thromboembolism Purpura Renal failure Rhabdomyolysis Secondary angle-closure glaucoma Seizure disorder Serotonin syndrome Serum sickness Skin rash Sleep apnea Steatosis of liver Stevens-johnson syndrome Suicidal ideation Thrombocytopenic disorder Thromboembolic disorder Thrombotic thrombocytopenic purpura Torsades de pointes Urinary retention Visual changes

Rare/Very Rare

Abnormal hepatic function tests
Accidental fall
Accommodation disorder
Acquired dystonia
Acquired hemolytic anemia
Agranulocytosis
Anaphylaxis
Angioedema
Aplastic anemia
Atrial fibrillation
Bronchospastic pulmonary disease
Cerebrovascular accident
Cholestatic hepatitis
Diabetes mellitus
Diabetic ketoacidosis
DRESS syndrome
Drug-induced hepatitis
Dysphagia
Dyspnea
Eosinophilia
Eosinophilic pneumonia
Erythema multiforme
Erythema nodosum
Esophageal dysmotility
Exfoliative dermatitis
Facial edema
Gastrointestinal hemorrhage
Gastrointestinal ulcer
Heat stroke
Hemorrhage
Hepatic failure
Hepatitis
Hyperbilirubinemia
Hyperglycemia
Hyperlipidemia
Hyperosmolar hyperglycemic state
Hypomania
Hyponatremia
Ileus
Increased risk of bleeding
Jaundice
Laryngeal edema
Laryngismus
Leukopenia
Lymphadenopathy
Manic disorder
Menstrual disorder
Neuroleptic malignant syndrome
Neutropenic disorder
Obstructive hyperbilirubinemia
Oculogyric crisis
Optic neuritis
Osteoporosis
Pancreatitis
Pancytopenia
Priapism
Prolonged QT interval
Pulmonary hypertension
Pulmonary thromboembolism
Purpura
Renal failure
Rhabdomyolysis
Secondary angle-closure glaucoma
Seizure disorder
Serotonin syndrome
Serum sickness
Skin rash
Sleep apnea
Steatosis of liver
Stevens-johnson syndrome
Suicidal ideation
Thrombocytopenic disorder
Thromboembolic disorder
Thrombotic thrombocytopenic purpura
Torsades de pointes
Urinary retention
Visual changes

There are 125 less severe adverse reactions.

More Frequent	Less Frequent
Anorexia Back pain Constipation Diarrhea Disorder of ejaculation Disturbance of attention Dizziness Dream disorder Drowsy Dyspepsia Erectile dysfunction Fatigue Flu-like symptoms General weakness Headache disorder Hyperhidrosis Hyperprolactinemia Hypertriglyceridemia Increased appetite Insomnia Nausea Nervousness Orthostatic hypotension Pharyngitis Rhinitis Sedation Sinusitis Skin rash Symptoms of anxiety Toxic amblyopia Tremor Vasodilation of blood vessels Weight gain Xerostomia Yawning	Abdominal pain with cramps Abnormal hepatic function tests Abnormal sexual function Acute cognitive impairment Agitation Alopecia Arthralgia Cardiac arrhythmia Chest pain Chills Constipation Cough Dysarthria Dysgeusia Dyspepsia Ecchymosis Edema Erectile dysfunction Fever Flatulence Gait abnormality Hyperkinesis Hypersomnia Hypertension Hypertonia Hypotension Increased urinary frequency Insomnia Libido changes Muscle rigidity Nausea Nervousness Pain in extremities Palpitations Paresthesia Pharyngitis Polydipsia Pruritus of skin Sialorrhea Sleep disorder Tachycardia Tinnitus Urinary incontinence Urinary tract infection Urticaria Visual changes Vomiting Weight loss

More Frequent

Less Frequent

Anorexia
Back pain
Constipation
Diarrhea
Disorder of ejaculation
Disturbance of attention
Dizziness
Dream disorder
Drowsy
Dyspepsia
Erectile dysfunction
Fatigue
Flu-like symptoms
General weakness
Headache disorder
Hyperhidrosis
Hyperprolactinemia
Hypertriglyceridemia
Increased appetite
Insomnia
Nausea
Nervousness
Orthostatic hypotension
Pharyngitis
Rhinitis
Sedation
Sinusitis
Skin rash
Symptoms of anxiety
Toxic amblyopia
Tremor
Vasodilation of blood vessels
Weight gain
Xerostomia
Yawning

Abdominal pain with cramps
Abnormal hepatic function tests
Abnormal sexual function
Acute cognitive impairment
Agitation
Alopecia
Arthralgia
Cardiac arrhythmia
Chest pain
Chills
Constipation
Cough
Dysarthria
Dysgeusia
Dyspepsia
Ecchymosis
Edema
Erectile dysfunction
Fever
Flatulence
Gait abnormality
Hyperkinesis
Hypersomnia
Hypertension
Hypertonia
Hypotension
Increased urinary frequency
Insomnia
Libido changes
Muscle rigidity
Nausea
Nervousness
Pain in extremities
Palpitations
Paresthesia
Pharyngitis
Polydipsia
Pruritus of skin
Sialorrhea
Sleep disorder
Tachycardia
Tinnitus
Urinary incontinence
Urinary tract infection
Urticaria
Visual changes
Vomiting
Weight loss

Rare/Very Rare
Abnormal uterine bleeding Abnormal vaginal bleeding Accidental fall Acute cognitive impairment Allergic dermatitis Alopecia Anticholinergic toxicity Ataxia Bruxism Cataracts Depersonalization Dyskinesia Dysuria Earache Ecchymosis Epistaxis Exophthalmos Fecal incontinence Galactorrhea not associated with childbirth Gastritis Gastroenteritis Gynecomastia Hyperprolactinemia Hypoglycemic disorder Hypotension Hypothyroidism Increased urinary frequency Libido changes Mastalgia Memory impairment Mood changes Mydriasis Orgasm disorder Petechiae Pruritus of skin Restless leg syndrome Skin photosensitivity Sleep walking disorder Stuttering Urticaria Vasodilation of blood vessels Vomiting

Rare/Very Rare

Abnormal uterine bleeding
Abnormal vaginal bleeding
Accidental fall
Acute cognitive impairment
Allergic dermatitis
Alopecia
Anticholinergic toxicity
Ataxia
Bruxism
Cataracts
Depersonalization
Dyskinesia
Dysuria
Earache
Ecchymosis
Epistaxis
Exophthalmos
Fecal incontinence
Galactorrhea not associated with childbirth
Gastritis
Gastroenteritis
Gynecomastia
Hyperprolactinemia
Hypoglycemic disorder
Hypotension
Hypothyroidism
Increased urinary frequency
Libido changes
Mastalgia
Memory impairment
Mood changes
Mydriasis
Orgasm disorder
Petechiae
Pruritus of skin
Restless leg syndrome
Skin photosensitivity
Sleep walking disorder
Stuttering
Urticaria
Vasodilation of blood vessels
Vomiting

The following precautions are available for SYMBYAX (olanzapine/fluoxetine hcl):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Some neonates exposed to fluoxetine and other selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special care nurseries. Such complications can arise immediately upon delivery and usually last several days or up to 2-4 weeks. Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying.

These clinical features appear to be consistent with either a direct toxic effect of the SSRI or SNRI or, possibly, a drug withdrawal syndrome. It should be noted that, in some cases, the clinical picture was consistent with serotonin syndrome (see Drug Interactions: Serotonergic Drugs). Infants exposed to SSRIs in late pregnancy may have an increased risk of persistent pulmonary hypertension of the newborn (PPHN).

PPHN is a rare heart and lung condition occurring in an estimated 1-2 infants per 1000 births in the general population; it occurs when a neonate does not adapt to breathing outside the womb. Some experts have suggested that respiratory distress in neonates exposed to SSRIs may occur along a spectrum of seriousness in association with maternal use of SSRIs, with PPHN among the most serious consequences. Neonates with PPHN may require intensive care support, including mechanical ventilation; in severe cases, multiple organ damage, including brain damage, and even death may occur.

Although several epidemiologic studies have suggested an increased risk of PPHN with SSRI use during pregnancy, other studies did not demonstrate a statistically significant association. Thus, the FDA states that it is currently unclear whether the use of SSRIs, including fluoxetine, during pregnancy can cause PPHN and recommends that clinicians not alter their current clinical practice of treating depression during pregnancy. When treating a pregnant woman with fluoxetine, the clinician should carefully consider the potential risks and benefits of such therapy.

Clinicians should consider that in a prospective longitudinal study of 201 women with a history of recurrent major depression who were euthymic in the context of antidepressant therapy at the beginning of pregnancy, women who discontinued their antidepressant medication (SSRIs, tricyclic antidepressants, or others) during pregnancy were found to be substantially more likely to have a relapse of depression than were women who continued to receive their antidepressant therapy while pregnant. Consideration may be given to cautiously tapering fluoxetine therapy in the third trimester prior to delivery if the drug is administered during pregnancy. (See Dosage and Administration: Treatment of Pregnant Women during the Third Trimester.) Fluoxetine and its principal metabolite norfluoxetine have been shown to cross the placenta in animals.

There are no adequate and controlled studies to date using fluoxetine in pregnant women, and the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to notify their clinician if they are or plan to become pregnant. FDA states that women who are pregnant or thinking about becoming pregnant should not discontinue any antidepressant, including fluoxetine, without first consulting their clinician.

The decision whether or not to continue antidepressant therapy should be made only after careful consideration of the potential benefits and risks of antidepressant therapy for each individual pregnant patient. If a decision is made to discontinue treatment with fluoxetine or other SSRIs before or during pregnancy, discontinuance of therapy should be done in consultation with the clinician in accordance with the prescribing information for the antidepressant, and the patient should be closely monitored for possible relapse of depression. In addition, the prolonged elimination of the drug and its active metabolite from the body after discontinuance of therapy should be considered when a woman of childbearing potential receiving fluoxetine plans to become pregnant.

For additional information on the management of depression in women prior to conception and during pregnancy, including treatment algorithms, the FDA advises clinicians to consult the joint American Psychiatric Association and American College of Obstetricians and Gynecologists guidelines (at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103063/pdf/nihms293836.pdf). Results of a number of epidemiologic studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. Although more than 10 cohort studies and case-control studies failed to demonstrate an increased risk of congenital malformations with fluoxetine overall, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women exposed to fluoxetine during the first trimester of pregnancy compared with those born to women who were not exposed to the drug.

There was no specific pattern of cardiovascular malformations observed in this trial. Overall, a causal relationship between fluoxetine exposure during early pregnancy and congenital malformations has not been established. However, the results of epidemiologic studies indicate that exposure to paroxetine during the first trimester of pregnancy may increase the risk for congenital malformations, particularly cardiovascular malformations.

(See Pregnancy, under Cautions: Pregnancy, Fertility, and Lactation, in Paroxetine 28:16.04.20.) Additional epidemiologic studies are needed to more thoroughly evaluate the relative safety of fluoxetine and other SSRIs during pregnancy, including their potential teratogenic risks and possible effects on neurobehavioral development. The effect of fluoxetine on labor and delivery is not known. Limited experience to date with olanzapine administration during pregnancy has been encouraging and has not revealed evidence of any obvious teratogenic risks; however, additional cases of olanzapine exposure during pregnancy need to be evaluated to more fully determine the relative safety of olanzapine and other antipsychotic agents when administered during pregnancy.

The manufacturer states that there have been 7 pregnancies reported during clinical trials with olanzapine, including 2 resulting in normal births, one resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and one spontaneous abortion. In a separate compilation of pregnancy exposures to olanzapine reported to the manufacturer during clinical trials and from spontaneous reports worldwide, outcomes were available from 23 prospectively collected, olanzapine-exposed pregnancies. Spontaneous abortion occurred in 13% of these pregnancies, stillbirth in 5%, major malformations in 0%, and prematurity in 5%; these rates were all within the range of normal historical control rates.

In 11 retrospectively collected, olanzapine-exposed pregnancies, there was one case of dysplastic kidney, one case of Down's syndrome, and one case of heart murmur and sudden infant death syndrome at 2 months of age. In another study, the majority of women with schizophrenia receiving atypical antipsychotic agents were found to be overweight and to have reduced folate intake and low serum folate concentrations, which may increase the potential risk of neural tube defects. In a prospective, comparative trial assessing pregnancy outcome in women receiving atypical antipsychotic agents (olanzapine, clozapine, risperidone, and quetiapine) during pregnancy, atypical antipsychotics did not appear to be associated with an increased risk of major congenital malformations.

In addition, several case reports have described healthy infants born to women without complications despite prenatal exposure to olanzapine. Neonates exposed to antipsychotic agents, including olanzapine, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates.

The majority of cases were also confounded by other factors, including concomitant use of other drugs known to be associated with withdrawal symptoms, prematurity, congenital malformations, and obstetrical and perinatal complications; however, some cases suggested that neonatal extrapyramidal and withdrawal symptoms may occur with exposure to antipsychotic agents alone. Some of the cases described time of symptom onset, which ranged from birth to one month after birth. Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored.

Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization. For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.

The manufacturer and some clinicians state that there are no adequate and well-controlled studies to date using olanzapine in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the potential risks to the fetus. Women should be advised to notify their clinician if they become pregnant or plan to become pregnant during therapy with the drug. In addition, clinicians should advise women of childbearing potential about the benefits and risks of using antipsychotic agents during pregnancy.

Patients should also be advised not to stop taking their antipsychotic agent if they become pregnant without first consulting with their clinician, since abruptly discontinuing the drugs can cause clinically important complications. Parturition in rats was not affected by olanzapine. The effect of olanzapine on labor and delivery is unknown.

In oral reproduction studies in rats receiving dosages of up to 18 mg/kg daily and in rabbits at dosages of up to 30 mg/kg daily (equivalent to 9 and 30 times the maximum recommended human daily oral dosage on a mg/m2 basis, respectively), no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dosage of 18 mg/kg daily (9 times the maximum recommended human daily oral dosage on a mg/m2 basis), and gestation was prolonged at a dosage of 10 mg/kg daily (equivalent to 5 times the maximum recommended human daily oral dosage on a mg/m2 basis). In an oral rabbit teratology study, fetal toxicity, which was manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dosage of 30 mg/kg daily (equivalent to 30 times the maximum recommended human daily oral dosage on a mg/m2 basis).

Fluoxetine and its metabolites distribute into human milk. Limited data indicate that fluoxetine and norfluoxetine concentrations are 20-30% of concurrent maternal plasma drug concentrations. Crying, sleep disturbance, vomiting, and watery stools developed in an infant who nursed from a woman receiving fluoxetine; plasma fluoxetine and norfluoxetine concentrations in the infant on the second day of feeding were 340 and 208 ng/mL, respectively.

Therefore, fluoxetine should not be used in nursing women, and women should be advised to notify their physician if they plan to breast-feed. In addition, the slow elimination of fluoxetine and norfluoxetine from the body after discontinuance of the drug should be considered. Olanzapine is distributed into milk.

The mean dosage received by an infant at steady state is estimated to be about 1.8% of the maternal dosage. The manufacturer recommends that women receiving olanzapine not breast-feed.

No enhanced Geriatric Use information available for this drug.

The following icd codes are available for SYMBYAX (olanzapine/fluoxetine hcl)'s list of indications:

Depression associated with bipolar disorder
F31.3	Bipolar disorder, current episode depressed, mild or moderate severity
F31.30	Bipolar disorder, current episode depressed, mild or moderate severity, unspecified
F31.31	Bipolar disorder, current episode depressed, mild
F31.32	Bipolar disorder, current episode depressed, moderate
F31.4	Bipolar disorder, current episode depressed, severe, without psychotic features
F31.5	Bipolar disorder, current episode depressed, severe, with psychotic features
Major depressive disorder
F32.0	Major depressive disorder, single episode, mild
F32.1	Major depressive disorder, single episode, moderate
F32.2	Major depressive disorder, single episode, severe without psychotic features
F32.3	Major depressive disorder, single episode, severe with psychotic features
F32.4	Major depressive disorder, single episode, in partial remission
F32.5	Major depressive disorder, single episode, in full remission
F32.9	Major depressive disorder, single episode, unspecified
F33	Major depressive disorder, recurrent
F33.0	Major depressive disorder, recurrent, mild
F33.1	Major depressive disorder, recurrent, moderate
F33.2	Major depressive disorder, recurrent severe without psychotic features
F33.3	Major depressive disorder, recurrent, severe with psychotic symptoms
F33.4	Major depressive disorder, recurrent, in remission
F33.40	Major depressive disorder, recurrent, in remission, unspecified
F33.41	Major depressive disorder, recurrent, in partial remission
F33.42	Major depressive disorder, recurrent, in full remission
F33.9	Major depressive disorder, recurrent, unspecified