Sertraline Hcl

Drug overview for SERTRALINE HCL (sertraline hcl):

Generic name: SERTRALINE HCL (SER-truh-leen)
Drug class: Antidepressants
Therapeutic class: Central Nervous System Agents

Sertraline, a selective serotonin-reuptake inhibitor (SSRI), is an antidepressant agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

SERTRALINE HCL 100 MG TABLET
SERTRALINE HCL 25 MG TABLET
SERTRALINE HCL 50 MG TABLET

The following indications for SERTRALINE HCL (sertraline hcl) have been approved by the FDA:

Indications:
Major depressive disorder
Obsessive-compulsive disorder
Panic disorder
Post traumatic stress disorder
Premenstrual dysphoric disorder
Social phobia

Professional Synonyms:
Major unipolar illness
Obsessive compulsive neurosis
Panic reaction
Panic-like sensation
Post-traumatic stress syndrome
Posttraumatic stress disorder
Social anxiety disorder
Unipolar mood disorder

The following dosing information is available for SERTRALINE HCL (sertraline hcl):

Dosing
Administration
SERTRALINE HCL
SERTRALINE HCL

Dosage of sertraline hydrochloride is expressed in terms of sertraline. The capsule formulation is only approved for use in the treatment of major depressive disorder in adults and obsessive-compulsive disorder in adults and pediatric patients >=6 years of age.

Sertraline is administered orally as tablets, capsules, or oral solution. The drug usually is administered once daily in the morning or evening, with or without food. Commercially available sertraline hydrochloride concentrate for oral solution is a clear, colorless solution with a menthol scent containing 20 mg of sertraline per mL and 12% alcohol.

When the oral solution is used, measure the dose carefully using the calibrated dropper provided by the manufacturer. The dropper has 25 mg and 50 mg graduation marks only. Dilute the appropriate dose in 4 ounces (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade, or orange juice before administration.

Mix the diluted solution and administer immediately. A slight haze may occasionally appear in the diluted oral solution, but the manufacturer states that this is normal. Sertraline hydrochloride oral solution should be diluted only in the liquids specified by the manufacturer, and should be used immediately after dilution.

Swallow sertraline capsules whole; do not open, crush, or chew the capsules. Store sertraline tablets, capsules, and concentrate for oral solution at 20-25degreesC (excursions permitted between 15-30degreesC).

Dosing information for SERTRALINE HCL
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
SERTRALINE HCL 25 MG TABLET	Maintenance	Adults take 1 tablet (25 mg) by oral route once daily
SERTRALINE HCL 50 MG TABLET	Maintenance	Adults take 1 tablet (50 mg) by oral route once daily
SERTRALINE HCL 100 MG TABLET	Maintenance	Adults take 1 tablet (100 mg) by oral route once daily

Generic dosing information for SERTRALINE HCL
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
SERTRALINE HCL 25 MG TABLET	Maintenance	Adults take 1 tablet (25 mg) by oral route once daily
SERTRALINE HCL 50 MG TABLET	Maintenance	Adults take 1 tablet (50 mg) by oral route once daily
SERTRALINE HCL 100 MG TABLET	Maintenance	Adults take 1 tablet (100 mg) by oral route once daily

The following drug interaction information is available for SERTRALINE HCL (sertraline hcl):

Contraindicated
Severe
Moderate

There are 2 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
Pimozide/SSRIs; Nefazodone 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: Fluvoxamine,(1) nefazodone,(2,3) may inhibit the metabolism of pimozide at CYP3A4. The mechanisms for the interactions between citalopram,(4) escitalopram,(5) and sertraline(6) and pimozide are unknown. CLINICAL EFFECTS: Concurrent use may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(1-9) Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(7) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(8) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increased systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(8) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(9) PATIENT MANAGEMENT: The concurrent use of pimozide with citalopram,(3-5) escitalopram,(3-5) fluvoxamine,(1,3) nefazodone,(2,3) or sertraline(3,6) is contraindicated. If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: An in vitro study indicates that pimozide is metabolized at CYP3A4.(7) In a controlled study, the administration of a single dose of pimozide (2 mg) with citalopram (40 mg daily for 11 days) increased mean QTc values by 10 msec compared to pimozide administered alone. There was no change in pimozide area-under-curve (AUC) or maximum concentration (Cmax).(4,5) In a controlled study, the administration of sertraline (200 mg daily) with a single dose of pimozide (2 mg) resulted in 40% increases in both the AUC and Cmax of pimozide, but was not associated with EKG changes. However, given the narrow therapeutic index of pimozide, their concurrent use is contraindicated by the manufacturer of sertraline.(6) 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

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

Pimozide/SSRIs; Nefazodone

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: Fluvoxamine,(1) nefazodone,(2,3) may inhibit the metabolism of pimozide at CYP3A4. The mechanisms for the interactions between citalopram,(4) escitalopram,(5) and sertraline(6) and pimozide are unknown.

CLINICAL EFFECTS: Concurrent use may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(1-9) Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(7)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(8) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increased systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(8) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(9)

PATIENT MANAGEMENT: The concurrent use of pimozide with citalopram,(3-5) escitalopram,(3-5) fluvoxamine,(1,3) nefazodone,(2,3) or sertraline(3,6) is contraindicated. If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: An in vitro study indicates that pimozide is metabolized at CYP3A4.(7) In a controlled study, the administration of a single dose of pimozide (2 mg) with citalopram (40 mg daily for 11 days) increased mean QTc values by 10 msec compared to pimozide administered alone. There was no change in pimozide area-under-curve (AUC) or maximum concentration (Cmax).(4,5)

In a controlled study, the administration of sertraline (200 mg daily) with a single dose of pimozide (2 mg) resulted in 40% increases in both the AUC and Cmax of pimozide, but was not associated with EKG changes. However, given the narrow therapeutic index of pimozide, their concurrent use is contraindicated by the manufacturer of sertraline.(6) 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

There are 6 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
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
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
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
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
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
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

There are 27 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
Dexfenfluramine; Fenfluramine/Serotoninergic Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent administration may result in additive effects on serotonin, resulting in serotonin syndrome. CLINICAL EFFECTS: May result in serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of fenfluramine states that fenfluramine should be used with caution with other serotonergic agents such as the selective serotonin reuptake inhibitors, sumatriptan, or dihydroergotamine. 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: This interaction is based on FDA mandated class labeling for these agents. Although there is no clinical documentation for an interaction between dexfenfluramine or fenfluramine and either the selective serotonin reuptake inhibitors, sumatriptan, or dihydroergotamine, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents, including sumatriptan and dihydroergotamine.	FINTEPLA
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
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
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
Tamoxifen/Selected Weak CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the 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 weak CYP2D6 inhibitors in patients who are CYP2D6 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 National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) 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.(16) 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).(17-18) 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.(19-21) 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,(22-26) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, cimetidine, clobazam, cobicistat, delavirdine, diltiazem, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, fedratinib, felodipine, fluvoxamine, gefitinib, hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat, ranitidine, ritonavir, sertraline, verapamil and viloxazine.(27)	SOLTAMOX, TAMOXIFEN CITRATE
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
Selected SSRIs; SNRIs/Clopidogrel SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets. CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-5) or a serotonin-norepinephrine reuptake inhibitor(7-9) and agents that affect coagulation may result in bleeding.(12) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(13) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-5) or serotonin-norepinephrine reuptake inhibitors(6-8) and agents that affect coagulation should be used concurrently with caution. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue antiplatelet agents in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(9) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(10)	CLOPIDOGREL, CLOPIDOGREL BISULFATE, PLAVIX
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
Flecainide/Sertraline SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Sertraline is a weak inhibitor of CYP2D6.(1,2) Higher sertraline doses are more likely to be associated clinically significant 2D6 inhibition. A substantial portion of flecainide elimination is via CYP 2D6 and flecainide has a narrow therapeutic range. Higher serum flecainide concentrations are associated with a greater risk for proarrhythmic effects.(3) CLINICAL EFFECTS: Concurrent use of sertraline may result in increased serum levels of flecainide and risk for potentially fatal ventricular arrhythmias.(2,3) PREDISPOSING FACTORS: Pre-existing medical conditions which increase the risk for a proarrhythmic event due to flecainide include history of myocardial infarction, chronic atrial fibrillation, chronic heart failure, hypokalemia and hyperkalemia.(3) Patients with severe renal or hepatic disease may have impaired elimination of flecainide.(3) Women appear to have a slower flecainide elimination rate than men. PATIENT MANAGEMENT: If predisposing medical conditions exist, avoid the use of sertraline or other CYP2D6 inhibitors. If sertraline is required, use the lowest effective antidepressant dose. Consider plasma level monitoring of flecainide and reduce dose if needed. Many other antidepressants also inhibit CYP2D6 and would not be safer alternatives. Antidepressants which are strong inhibitors of CYP2D6 include bupropion, fluoxetine and paroxetine. Moderate inhibitors include duloxetine and moclobemide (not available in the US). Additional antidepressants associated with weak inhibition of CYP2D6 include desvenlafaxine/venlafaxine and escitalopram/citalopram.(1) Counsel patients to seek medical attention if they experience dizziness, shortness of breath, fainting, weakness, or fast/irregular heartbeat. DISCUSSION: Although sertraline is a weak inhibitor of CYP2D6, higher doses (e.g. 150 mg per day) have been associated with clinically meaningful inhibition of this enzyme. The manufacturer of flecainide states that the majority of patients successfully treated were found to have trough plasma levels between 0.2 and 1 microgram/mL. The probability of adverse effects, especially cardiac, may increase when trough levels exceed 1 microgram/mL.(3)	FLECAINIDE ACETATE
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
Sertraline (Less Than or Equal To 50 mg)/Select Tricyclic Compounds; Trazodone 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. Sertraline, a SSRI, may impair the oxidative hepatic metabolism of tricyclic compounds and trazodone. CLINICAL EFFECTS: Concurrent administration of sertraline, an SSRI, with a tricyclic compound or trazodone may result in an increase in serum levels, toxicities (e.g. torsades de pointes and/or serotonin syndrome), and/or clinical effects of the tricyclic compound or trazodone PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(8) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(8) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants 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.(10) PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds at the initiation of concurrent therapy with sertraline, an SSRI. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If sertraline is discontinued in a patient receiving a tricyclic compound, the dosage of the tricyclic compound may need to be adjusted. 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. Patients receiving concurrent therapy with sertraline and clomipramine, imipramine, and/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. DISCUSSION: Sertraline has been shown to increase the maximum concentration (Cmax) and AUC of desipramine by 31% and 23%, respectively. The affinity of the different SSRIs, SNRIs, and tricyclics for CYP450 may vary.	AMITRIPTYLINE HCL, AMOXAPINE, AMRIX, ANAFRANIL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CLOMIPRAMINE HCL, CYCLOBENZAPRINE HCL, CYCLOBENZAPRINE HCL ER, CYCLOPAK, CYCLOTENS, DESIPRAMINE HCL, DOXEPIN HCL, FEXMID, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, NORPRAMIN, NORTRIPTYLINE HCL, PAMELOR, PERPHENAZINE-AMITRIPTYLINE, PROTRIPTYLINE HCL, PRUDOXIN, RALDESY, SILENOR, TRAZODONE HCL, TRIMIPRAMINE MALEATE, ZONALON
Eliglustat/Weak CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Weak 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 weak 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 is also taking an inhibitor of CYP3A4 and/or has hepatic impairment, 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 weak inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with weak inhibitors of CYP2D6 in extensive CYP2D6 metabolizers with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: 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) Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, clobazam, desvenlafaxine, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, felodipine, gefitinib, hydralazine, hydroxychloroquine, lorcaserin, methadone, panobinostat, propafenone, sertraline, vemurafenib, and venlafaxine.(3,4)	CERDELGA
Thyroid Preparations/Sertraline SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The mechanism by which sertraline lowers serum thyroid hormone concentrations is uncertain. One reported case in which sertraline caused a low serum total thyroxine concentration is believed to be caused by sertraline increasing the clearance of the thyroxine.(1) CLINICAL EFFECTS: The coadministration of thyroid preparations and sertraline may result in decreased levels and clinical effects of thyroid hormones.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients taking thyroid preparations and sertraline should be monitored for changes in thyroid function. The dosage of the thyroid preparation may need to be increased. DISCUSSION: In a case report of 9 levothyroxine treated patients with hypothyroidism, who were treated with sertraline, all were found to have elevated serum thyrotropin concentrations. Elevated thyrotropin levels are indicative of a decrease in the efficacy of levothyroxine. The dose of levothyroxine was increased for all patients. Required dosage adjustments ranged from 11% to 50%.(1) In a study, patients with major depression and hypothyroidism on adequate levothyroxine therapy were treated with either fluoxetine or sertraline. The results of this study showed no change in thyroid levels among hypothyroid patients on levothyroxine therapy who were treated with either fluoxetine or sertraline.(2)	ADTHYZA, ARMOUR THYROID, CYTOMEL, ERMEZA, EUTHYROX, LEVO-T, LEVOTHYROXINE SODIUM, LEVOTHYROXINE SODIUM DILUTION, LEVOXYL, LIOTHYRONINE SODIUM, NIVA THYROID, NP THYROID, PCCA T3 SODIUM DILUTION, PCCA T4 SODIUM DILUTION, RENTHYROID, SYNTHROID, THYQUIDITY, THYROID, TIROSINT, TIROSINT-SOL, UNITHROID
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) PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metoprolol and inhibitors of CYP2D6. The dosage of metoprolol may need to be adjusted.(1,2) Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(3) DISCUSSION: In a study, citalopram (40 mg daily for 22 days) increased plasma concentrations of metoprolol 2-fold.(4) In a study in healthy subjects, duloxetine (60 mg daily), escitalopram (20 mg daily), and sertraline (100 mg daily) increased the AUC of a single dose of metoprolol by 180%, 89%, and 48-67%, respectively.(5) In a study in 7 healthy subjects, ranitidine (150 mg BID) increased the area-under-curve (AUC) of metoprolol by 50% compared to values obtained 10 months earlier in the same subjects with metoprolol alone.(6) In a study in 6 subjects, pretreatment with ranitidine for 1 week increased the maximum concentration (Cmax) of metoprolol. However, in a follow-up study in 12 healthy subjects, ranitidine had no effect on metoprolol pharmacokinetics when administered concurrently for 1 week.(7) In a study in 6 healthy subjects, ranitidine increased the AUC and Cmax of metoprolol by 50%. There were no changes in metoprolol pharmacodynamics.(8) In a study in healthy subjects, ranitidine increased metoprolol Cmax by about 30%.(9) In a study in 12 healthy males, ranitidine had no effect on the pharmacokinetics or pharmacodynamics of metoprolol.(10) In healthy subjects, ranolazine (750 mg twice daily) increased plasma levels of a single dose of metoprolol (100 mg) by 1.8-fold.(11) 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.(3) CYP2D6 inhibitors include: abiraterone, bupropion, celecoxib, cinacalcet, citalopram, dacomitinib, 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
Sertraline (Greater Than 50 mg)/Selected Tricyclic Compounds SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Sertraline may impair the oxidative hepatic metabolism of tricyclic compounds. CLINICAL EFFECTS: Concurrent administration of sertraline with a tricyclic compound may result in an increase in serum levels, toxicities, and/or clinical effects of the tricyclic compound. PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; 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.(8) PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds at the initiation of concurrent therapy with sertraline. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If sertraline is discontinued in a patient receiving a tricyclic compound, the dosage of the tricyclic compound may need to be adjusted. DISCUSSION: Sertraline has been shown to increase the maximum concentration (Cmax) and AUC of desipramine by 31% and 23%, respectively.(5) The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450 may vary.	AMITRIPTYLINE HCL, AMOXAPINE, ANAFRANIL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CLOMIPRAMINE HCL, DESIPRAMINE HCL, DOXEPIN HCL, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, NORPRAMIN, NORTRIPTYLINE HCL, PAMELOR, PERPHENAZINE-AMITRIPTYLINE, PROTRIPTYLINE HCL, SILENOR, TRIMIPRAMINE MALEATE
Selected SSRIs; SNRIs/Cyclobenzaprine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Selected serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs or SNRIs) may impair the oxidative hepatic metabolism of cyclobenzaprine. Cyclobenzaprine is metabolized by CYP1A2, CYP3A4, and to a lesser extent CYP2D6.(4) Fluvoxamine is a strong inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 and CYP2D6. Sertraline and venlafaxine are weak inhibitors of CYP2D6. CLINICAL EFFECTS: Concurrent administration of selected SSRIs or SNRIs with cyclobenzaprine may result in an increase in serum levels, toxicities, and/or clinical effects of cyclobenzaprine, including serotonin syndrome.(4) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity. PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(5) PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of cyclobenzaprine at the initiation of concurrent therapy with selected SSRIs or SNRIs. Plasma concentrations of cyclobenzaprine should be monitored and the dosage adjusted accordingly. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome, and 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. If the SSRI or SNRI is discontinued in a patient receiving cyclobenzaprine, the dosage of the cyclobenzaprine may need to be adjusted. DISCUSSION: There have been case reports of serotonin syndrome with trazodone and amitriptyline with lithium, and cyclobenzaprine with duloxetine.(6) The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450 may vary.	AMRIX, CYCLOBENZAPRINE HCL, CYCLOBENZAPRINE HCL ER, CYCLOPAK, CYCLOTENS, FEXMID
Selected SSRIs; SNRIs/Trazodone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Selected serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs or SNRIs) may impair the oxidative hepatic metabolism of trazodone. Trazodone is metabolized by CYP3A4 and its active metabolite meta-chlorophenylpiperazine (m-CPP) is metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. Desvenlafaxine, fluvoxamine, sertraline, and venlafaxine are weak inhibitors of CYP2D6. Fluvoxamine is also a weak inhibitor of CYP3A4. CLINICAL EFFECTS: Concurrent administration of selected SSRIs or SNRIs with trazodone may result in an increase in serum levels, toxicities (e.g. torsades de pointes), and/or clinical effects of trazodone. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity. PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5) PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of trazodone at the initiation of concurrent therapy with selected SSRIs or SNRIs. Plasma concentrations of trazodone should be monitored and the dosage adjusted accordingly. If the SSRI or SNRI is discontinued in a patient receiving trazodone, the dosage of trazodone may need to be adjusted. 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: There have been case reports of serotonin syndrome with trazodone and amitriptyline with lithium, and cyclobenzaprine (structurally related to the TCAs) with duloxetine.(3) The affinity of the different selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclics for CYP P-450 may vary.	RALDESY, TRAZODONE HCL
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
Tramadol/Selected 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 tramadol 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 tramadol and SSRIs or SNRIs may also lower the seizure threshold.(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) Predisposing factors for a lower seizure threshold include a history of seizures, epilepsy, or a recognized risk for seizures (e.g. head trauma, metabolic disorders, alcohol, drug withdrawal, infections of the central nervous system). A genetic defect in CYP2D6 leading to the slow metabolizer phenotype may increase the risk for serotonin syndrome due to tramadol. PATIENT MANAGEMENT: If concurrent therapy of tramadol with a SSRI or SNRI is warranted, patients should be closely monitored for signs and symptoms of serotonin syndrome and increased seizure activity.(1) DISCUSSION: There are a number of serotonin syndrome case reports following the addition of tramadol to a stable selective serotonin reuptake inhibitor regimen. The syndrome developed between 12 hours to 3 weeks after the initiation of tramadol therapy. Patients recovered after tramadol and/or the SSRI/SNRI was discontinued.(3-14) One patient also developed mania.(3) Another patient developed nightmares and hallucinations after taking concurrent tramadol and paroxetine for 56 days.(15) One author suggests that although the combination of tramadol and SSRIs or SNRIs is associated with a risk for serotonin syndrome, given the high rate of co-prescribing for the combination it is an uncommon outcome.(16) A review of the 124 reports of seizures following tramadol therapy received by the FDA through July 31, 1996 revealed that 20 patients were receiving concurrent therapy with an selective serotonin reuptake inhibitor.(17) The manufacturer of tramadol states that the risk of seizure is increased in patients receiving concurrent therapy with selective serotonin reuptake inhibitors.(1) Selected SSRIs and SNRIs linked to this monograph include: citalopram, desvenlafaxine, fluvoxamine, levomilnacipran, milnacipran, sertraline, sibutramine, venlafaxine, vilazodone, and vortioxetine.	CONZIP, QDOLO, TRAMADOL HCL, TRAMADOL HCL ER, TRAMADOL HCL-ACETAMINOPHEN
Selected SSRIs;SNRIs/Cilostazol; Ticlopidine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets. CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-4) or a serotonin-norepinephrine reuptake inhibitor(5-7) and agents that affect coagulation may result in bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(8) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-4) or serotonin-norepinephrine reuptake inhibitors(5-7) and agents that affect coagulation should be used concurrently with caution. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(9) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(10) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(11) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ration 1.57).(12) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(13)	CILOSTAZOL
Dextromethorphan/Selected Serotonergic Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Dextromethorphan inhibits neuronal reuptake of serotonin. Concurrent administration with one or more serotonergic agents may increase serotonin effects, leading to serotonin toxicity.(1-11) CLINICAL EFFECTS: The concurrent use of dextromethorphan with serotonergic agents may increase the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(3) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(3) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(3) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(3) PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(1-11) PATIENT MANAGEMENT: Monitor patients on multiple serotonergic agents for symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: Dextromethorphan inhibits neuronal reuptake of serotonin and may potentially precipitate dose-dependant serotonin toxicity in conjunction with other serotonergic agents.(4,5) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to duloxetine,(6) escitalopram,(7) fluoxetine,(8,9) paroxetine,(10) and sertraline.(11) Selected serotonergic agents linked to this monograph include: citalopram, clomipramine, duloxetine, escitalopram, fluvoxamine, imipramine, levomilnacipran, milnacipran, sertraline, venlafaxine, vilazodone and vortioxetine.	AUVELITY, BROMFED DM, BROMPHENIRAMINE-PSEUDOEPHED-DM, DEXTROMETHORPHAN HBR, NUEDEXTA, PROMETHAZINE-DM
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 SERTRALINE HCL (sertraline hcl):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*Concomitant use with monoamine oxidase inhibitors (MAOIs) or use within 14 days of stopping MAOIs (including linezolid and IV methylene blue) due to an increased risk of serotonin syndrome. *Concomitant use with pimozide due to the risk of QTc prolongation. *Known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to sertraline or any of the inactive ingredients of the formulation. *Sertraline oral solution only: concomitant use with disulfiram.

There are 1 contraindications. Absolute contraindication.

Contraindication List
Serotonin syndrome

There are 6 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Angle-closure glaucoma
CYp2c19 poor metabolizer
Disease of liver
Risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
Suicidal ideation
Upper GI bleed

There are 8 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Bipolar disorder
Hypomania
Hyponatremia
Increased risk of bleeding
Manic disorder
Seizure disorder
SIADH syndrome
Weight loss

The following adverse reaction information is available for SERTRALINE HCL (sertraline hcl):

Overview
Severe
Less Severe

Adverse reaction overview.

The most common adverse reactions in pooled placebo-controlled clinical trials (incidence of >=5% and twice that observed in the placebo group) were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido.

There are 40 severe adverse reactions.

More Frequent	Less Frequent
None.	None.

Rare/Very Rare
Abnormal hepatic function tests Acute renal failure Agranulocytosis Akathisia Anaphylaxis Angioedema Aplastic anemia Atrioventricular block Bradycardia Cataracts Diabetes mellitus Drug-induced hepatitis Eosinophilic pneumonia Extrapyramidal disease Gastrointestinal hemorrhage Hemorrhage Hepatic failure Hypertension Hyponatremia Jaundice Lupus-like syndrome Manic disorder Microscopic colitis Neuroleptic malignant syndrome Oculogyric crisis Optic neuritis Pancreatitis Prolonged QT interval Rhabdomyolysis Secondary angle-closure glaucoma Seizure disorder Serotonin syndrome Serum sickness SIADH syndrome Spasm of cerebral arteries Stevens-johnson syndrome Suicidal ideation Thrombocytopenic disorder Torsades de pointes Ventricular tachycardia

Rare/Very Rare

Abnormal hepatic function tests
Acute renal failure
Agranulocytosis
Akathisia
Anaphylaxis
Angioedema
Aplastic anemia
Atrioventricular block
Bradycardia
Cataracts
Diabetes mellitus
Drug-induced hepatitis
Eosinophilic pneumonia
Extrapyramidal disease
Gastrointestinal hemorrhage
Hemorrhage
Hepatic failure
Hypertension
Hyponatremia
Jaundice
Lupus-like syndrome
Manic disorder
Microscopic colitis
Neuroleptic malignant syndrome
Oculogyric crisis
Optic neuritis
Pancreatitis
Prolonged QT interval
Rhabdomyolysis
Secondary angle-closure glaucoma
Seizure disorder
Serotonin syndrome
Serum sickness
SIADH syndrome
Spasm of cerebral arteries
Stevens-johnson syndrome
Suicidal ideation
Thrombocytopenic disorder
Torsades de pointes
Ventricular tachycardia

There are 90 less severe adverse reactions.

More Frequent	Less Frequent
Abnormal sexual function Acute abdominal pain Anorexia Diarrhea Disorder of ejaculation Dizziness Drowsy Dyspepsia Erectile dysfunction Fatigue Flatulence Headache disorder Hyperhidrosis Insomnia Libido changes Nausea Tremor Weight loss Xerostomia	Acne vulgaris Agitation Alopecia Back pain Chest pain Concentration difficulty Constipation Hypertonia Increased appetite Irritability Myalgia Pain Palpitations Rhinitis Visual changes Vomiting Weight gain

Rare/Very Rare
Abnormal vaginal bleeding Accidental fall Allergic dermatitis Anticholinergic toxicity Arthralgia Ataxia Blurred vision Bruxism Dental caries Dyschromia Dysphagia Ecchymosis Edema Epistaxis Fever Galactorrhea not associated with childbirth Gynecomastia Hematuria Hostility Hyperglycemia Hyperkinesis Hyperprolactinemia Hypoesthesia Hypomania Hypothyroidism Loss of sense of smell Maculopapular rash Mastalgia Menstrual disorder Muscle spasm Mydriasis Nervousness Nightmares Orgasm disorder Orthostatic hypotension Petechiae Polydipsia Priapism Pruritus of skin Pulmonary hypertension Purpura Skin photosensitivity Skin rash Symptoms of anxiety Syncope Tachycardia Tinnitus Trismus Urinary incontinence Urticaria Vasculitis Vasodilation of blood vessels Vertigo Yawning

Rare/Very Rare

Abnormal vaginal bleeding
Accidental fall
Allergic dermatitis
Anticholinergic toxicity
Arthralgia
Ataxia
Blurred vision
Bruxism
Dental caries
Dyschromia
Dysphagia
Ecchymosis
Edema
Epistaxis
Fever
Galactorrhea not associated with childbirth
Gynecomastia
Hematuria
Hostility
Hyperglycemia
Hyperkinesis
Hyperprolactinemia
Hypoesthesia
Hypomania
Hypothyroidism
Loss of sense of smell
Maculopapular rash
Mastalgia
Menstrual disorder
Muscle spasm
Mydriasis
Nervousness
Nightmares
Orgasm disorder
Orthostatic hypotension
Petechiae
Polydipsia
Priapism
Pruritus of skin
Pulmonary hypertension
Purpura
Skin photosensitivity
Skin rash
Symptoms of anxiety
Syncope
Tachycardia
Tinnitus
Trismus
Urinary incontinence
Urticaria
Vasculitis
Vasodilation of blood vessels
Vertigo
Yawning

The following precautions are available for SERTRALINE HCL (sertraline hcl):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy of sertraline in children with obsessive-compulsive disorder (OCD) younger than 6 years of age have not been established. Safety and efficacy of sertraline in pediatric patients with other disorders (e.g., major depressive disorder, panic disorder, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), social anxiety disorder) have not been established. The overall adverse effect profile of sertraline in 281 pediatric patients who received sertraline in placebo-controlled clinical trials was generally similar to that seen in the adult clinical studies.

As with other SSRIs, decreased appetite and weight loss have been observed in association with sertraline therapy. Monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dosage increases or decreases. Monitor weight and growth in pediatric patients. The oral sertraline solution contains 12% alcohol.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Overall, available published epidemiologic studies of pregnant females exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. Studies that have reported specific major birth defects are inconclusive. Animal studies have not demonstrated teratogenicity; however, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (MRHD) in rats and doses 3.1

times the MRHD in rabbits on a mg/m2 basis in adolescents. When sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first 4 days after birth at the MRHD. Data from observational studies report exposure to SSRIs, particularly in the month before delivery, is associated with a less than a 2-fold increase in the risk of postpartum hemorrhage.

Exposure to SSRIs and SNRIs, including sertraline, in late pregnancy may lead to increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). When treating a pregnant female with sertraline during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates exposed to sertraline in the third trimester of pregnancy for PPHN and drug discontinuation syndrome.

Females who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than females who continue antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to antidepressants during pregnancy.

Advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi stry/antidepressants/. Sertraline oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy.

Available data demonstrate low sertraline levels in human milk (average of 2% of maternal sertraline serum levels; range of 0-15% of maternal sertraline serum levels) with no adverse reactions observed in infants in a pooled analysis of 53 mother-infant pairs. There are no data on the effects of sertraline on milk production. Consider developmental and health benefits of breastfeeding along with the mother's clinical need for sertraline and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

The effect of age on the elimination of sertraline has not been fully elucidated. Plasma clearance of sertraline was approximately 40% lower in a group of 16 geriatric patients (8 males and 8 females) who received 100 mg of the drug for 14 days than that reported in a similar study involving younger individuals (from 25-32 years of age). Based on these results, the manufacturers state that steady-state should be achieved in about 2-3 weeks in older individuals.

In addition, decreased clearance of the sertraline metabolite, N-desmethylsertraline, was noted in older males but not in older females. Of the total number of patients in clinical studies of sertraline for major depressive disorder, OCD, panic disorder, PTSD, social anxiety disorder, and PMDD, 797 (17%) were >=65 years of age and 197 (4%) were >=75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dosage selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In 354 geriatric patients treated with sertraline for major depressive disorder in placebo-controlled trials, the overall profile of adverse effects was generally similar to younger patients, except for tinnitus and arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients. SSRIs, including sertraline, and SNRIs have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction.

The following icd codes are available for SERTRALINE HCL (sertraline hcl)'s list of indications:

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
Obsessive-compulsive disorder
F42	Obsessive-compulsive disorder
F42.2	Mixed obsessional thoughts and acts
F42.3	Hoarding disorder
F42.4	Excoriation (skin-picking) disorder
F42.8	Other obsessive-compulsive disorder
F42.9	Obsessive-compulsive disorder, unspecified
R46.81	Obsessive-compulsive behavior
Panic disorder
F40.01	Agoraphobia with panic disorder
F41.0	Panic disorder [episodic paroxysmal anxiety]
Post traumatic stress disorder
F43.1	Post-traumatic stress disorder (PTSd)
F43.10	Post-traumatic stress disorder, unspecified
F43.11	Post-traumatic stress disorder, acute
F43.12	Post-traumatic stress disorder, chronic
Premenstrual dysphoric disorder
F32.81	Premenstrual dysphoric disorder
Social phobia
F40.1	Social phobias
F40.10	Social phobia, unspecified
F40.11	Social phobia, generalized