Trintellix (vortioxetine hydrobromide)

Dosage of vortioxetine hydrobromide is expressed in terms of vortioxetine.

Vortioxetine hydrobromide is commercially available as immediate-release tablets, which are administered orally once daily without regard to meals, at approximately the same time each day.

Patients receiving vortioxetine should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments. (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

The manufacturer states that at least 2 weeks must elapse between discontinuance of a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders and initiation of vortioxetine therapy and at least 3 weeks must elapse between discontinuance of vortioxetine and initiation of MAO inhibitor therapy intended to treat psychiatric disorders. (See Contraindications, Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions, and Drug Interactions: Monoamine Oxidase Inhibitors.)

No dosing information is available for this tab.

Vortioxetine is metabolized principally by cytochrome P-450 (CYP) isoenzyme 2D6 with lesser contributions from CYP3A4/5, 2C19, 2C9, 2A6, 2C8, and 2B6. In vitro and in vivo studies have demonstrated that vortioxetine and its metabolites are unlikely to inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5. In an in vitro study, vortioxetine did not induce CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 3A4/5.

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

Serotonergic Agents/Dapoxetine

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

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

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

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

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

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

Serotonergic Agents/Sibutramine

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

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

CLINICAL EFFECTS: Concurrent use of sibutramine and agents which effect serotonin may result in serotonin syndrome, a serious and potentially fatal reaction. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity. (1-5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The Canadian manufacturer of sibutramine formerly stated that concurrent use with antidepressants or serotonergic agents is contraindicated. At least 14 days should elapse between discontinuation of these agents and initiation of sibutramine. Five weeks is required following the discontinuation of fluoxetine.(1) The Australian(2) and UK(3) manufacturers of sibutramine stated that sibutramine is contraindicated within 2 weeks of antidepressant use and should not be used with other serotonergic agents. The US manufacturer of sibutramine stated that in general, sibutramine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors, sumatriptan or dihydroergotamine. However, if concurrent administration is clinically indicated, the patient should be appropriately observed.(4) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. Patients in whom serotonin syndrome is suspected should receive immediate medical attention.

DISCUSSION: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. Sibutramine inhibits serotonin reuptake and serotonin syndrome has been reported during concomitant use of selective serotonin reuptake inhibitors and other selective serotonin reuptake inhibitors, sumatriptan, and dihydroergotamine(1-4)

Serotonin Reuptake Inhibitors; Snris/Selected Maois

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

MECHANISM OF ACTION: Serotonin reuptake inhibitors and MAOIs may act synergistically to increase blood pressure and evoke behavioral excitation.

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

PREDISPOSING FACTORS: None determined.

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

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

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

Agents That Affect Catecholamines/Iobenguane I 123

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Agents That Affect Catecholamines/Iobenguane I 131

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Atomoxetine; Vortioxetine/Strong 2D6 Inhibitors

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

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

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

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

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

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

Clomipramine; Imipramine; Ssris; Snris;/Meperidine

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

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

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

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

PATIENT MANAGEMENT: Use an alternative analgesic whenever possible, particularly in patients with renal impairment. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome, seizure activity. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Case reports describe the interaction between meperidine and serotonin-increasing agents.(3-5) Meperidine has long been associated with the risk for serotonin syndrome, particularly when used with monoamine oxidase inhibitors (MAOIs).(6) In addition to SSRIs and SNRIs, clomipramine, a tricyclic antidepressant(TCA) with strong serotonin effects and imipramine, a TCA with more moderate serotonin effects are also included in this monograph.(7)

Serotonin Reuptake Inhibitors/Linezolid

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

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

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

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

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

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

Ssris; Snris/Selected Anticoagulants (VITAMIN K ANTAGONISTS)

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

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

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

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

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

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

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

Select Serotonergic Agents/Fentanyl

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

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

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

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

PATIENT MANAGEMENT: Most patients tolerate the combination of fentanyl with serotonin-increasing agents. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(1) Monitor patients on multiple serotonergic agents for symptoms of serotonin toxicity. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. Patients in whom serotonin syndrome is suspected should receive immediate medical attention.

DISCUSSION: Health Canada recently reported 5 cases of serotonin syndrome associated with patients receiving fentanyl and at least one other serotonergic agent.(2) Additional cases have been reported in the medical literature.(3-6) Serotonin increasing agents linked to this monograph are: centanafadine, citalopram, clomipramine, desvenlafaxine, duloxetine, fluoxetine, imipramine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone and vortioxetine.

Selected Serotonergic Agents/Dextromethorphan

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

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

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

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

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

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

Selected Ssris; Selected Snris/Clomipramine; Imipramine

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

MECHANISM OF ACTION: The combination of clomipramine or imipramine with the selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors may have additive effects on serotonin levels.

CLINICAL EFFECTS: Some patients may develop an increase in serotonergic activity in the CNS, which could result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

PREDISPOSING FACTORS: Use of multiple drugs which increase serotonin levels.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be observed for signs of increased serotonergic side effects. Counsel patients to report new or worsening muscle twitching, tremors, shivering or stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, decreased coordination, or severe diarrhea.

DISCUSSION: The tricyclic antidepressants clomipramine and imipramine possess significant serotonin reuptake inhibition properties.(2) Concurrent or recent use of other serotoninergic agents can increase the risk of serotonin syndrome.(1,2)

Selected Ssris; Snris/Clopidogrel

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

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

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

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

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

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

Selected Ssris; Snris/Cyclobenzaprine

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

MECHANISM OF ACTION: Cyclobenzaprine and SSRIs or SNRIs may have additive effects on serotonin levels.(1)

CLINICAL EFFECTS: Concurrent administration of cyclobenzaprine with citalopram, duloxetine, escitalopram, levomilnacipran, milnacipran, nefazodone, or vortioxetine may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: Predisposing factors include elderly, hepatic dysfunction and use of multiple agents which increase central serotonin levels. Chronic use of cyclobenzaprine or high doses of citalopram or escitalopram would also be expected to increase the risk for serotonin toxicity.(1)

PATIENT MANAGEMENT: The US manufacturer of cyclobenzaprine recommends limiting use to short term duration, no more than two to three weeks. Use alternative therapy whenever possible, particularly in patients with hepatic impairment.(1) 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.

DISCUSSION: Case reports documenting serotonin syndrome with cyclobenzaprine and other serotonergic agents are described. The risk of serotonin syndrome with cyclobenzaprine and TCAs may also occur based on serotonin activity of both agents.(2,3) A case report of a 70 year old female on phenelzine (non-selective MAOI) 15 mg four times daily for several years developed serotonin syndrome after the third dose of cyclobenzaprine 10 mg three times daily. After discontinuation of both cyclobenzaprine and phenelzine, symptoms resolved within three days. Within the following month, the patient was restarted on phenelzine without any further sequelae.(4) A case report of a 53 year old male on duloxetine (SNRI) 60 mg daily developed symptoms of serotonin syndrome shortly after initiation of cyclobenzaprine 10 mg three times daily. Both cyclobenzaprine and duloxetine were stopped and cyproheptadine was given with resolution of symptoms.(4) A case report of a 27 year old female on escitalopram (SSRI) 10 mg daily presented with serotonin syndrome after an overdose of 5-6 cyclobenzaprine 10 mg tablets. The patient was treated with symptomatic care and cyproheptadine with resolution of symptoms on day two and discharged with instructions to discontinue cyclobenzaprine use.(5)

Selected Ssris; Snris/Tramadol

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, escitalopram, fluvoxamine, levomilnacipran, milnacipran, sertraline, sibutramine, venlafaxine, vilazodone, and vortioxetine.

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)

Serotonergic Agents/Centanafadine

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

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

CLINICAL EFFECTS: Concurrent use of centanafadine with other serotonergic agents may increase the risk of serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,2)

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

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

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

Serotonergic Agents/Dexfenfluramine; Fenfluramine

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. 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, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents.

Serotonergic Agents/Gepirone

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

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

CLINICAL EFFECTS: Concurrent use of gepirone with other serotonergic agents may increase the risk of hypertensive crisis and serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

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

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

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

Serotonergic Agents/Ziprasidone

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

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

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

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

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

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

Ssris; Snris/Amphetamines; Phentermine

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

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

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

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

PATIENT MANAGEMENT: The concurrent use of amphetamines with SSRIs or SNRIs should be approached with appropriate monitoring. Instruct patients receiving concurrent therapy to report any signs or symptoms of serotonin syndrome immediately. Monitor blood pressure during concurrent therapy and adjust dosage or change medication for persistent increases in blood pressure. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a case report, a 13 year-old female experienced tachycardia when amphetamine was added to her sertraline regimen.(2) Increased side effects have also been reported in patients maintained on fluoxetine who ingested illicit amphetamines.(3) In a case report, a 22 year-old female had previously been taking phentermine and oral contraceptive agents. The patient stopped taking phentermine and, after an undetermined length of time, started taking fluoxetine (20 mg daily). The patient discontinued her fluoxetine after three months. Eight days later, she took one dose of phentermine (30 mg). Within several hours, she developed jitteriness, stomach cramps, dry eyes, palpitations, and tremors. The patient received once dose of lorazepam (1.5 mg) and her symptoms resolved over night.(4) In a case report, a 32 year-old male developed agitation, anxiety, shivering, tremors, and diaphoresis two weeks after adding venlafaxine to his dexamphetamine.(5) There have also been reports of safe and effective use of amphetamines with fluoxetine,(6) dextroamphetamine and sertraline,(6) and dextroamphetamine with fluoxetine.(7)

Ssris; Snris/Selected Nsaids; Aspirin

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

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

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

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

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

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

Ssris; Snris/Tapentadol

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

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

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

PREDISPOSING FACTORS: Treatment with multiple medications which increase serotonin levels or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(2)

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

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

Ssris; Vilazodone/Flurbiprofen

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

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

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

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

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

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

Ssris; Vilazodone/Selected Nsaids

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

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

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

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

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

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

Ssris;Snris/Slt Anticoagulants;Antiplatelets;Thrombolytics

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

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

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

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

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

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

Vortioxetine/Carbamazepine; Rifampin

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

MECHANISM OF ACTION: While vortioxetine is primarily metabolized by CYP2D6, many other CYP enzymes also play a role, including CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6.(1) Carbamazepine and rifampin may induce these enzymes.(2-3)

CLINICAL EFFECTS: The concurrent administration of carbamazepine or rifampin may result in decreased levels and effectiveness of vortioxetine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of vortioxetine states that patients receiving strong CYP enzyme inducers for greater than 14 days may require an increase in their dosage of vortioxetine, up to a maximum of three times the original dose.(1) If carbamazepine or rifampin is discontinued in a patient who has been maintained on vortioxetine, the dose of vortioxetine should be reduced to the original level within 14 days.(1)

DISCUSSION: In a study of 14 healthy volunteers, rifampin decreased the area-under-curve (AUC) and maximum concentration (Cmax) of vortioxetine by 72.3% and 50.9%, respectively, compared to vortioxetine when given alone.(4)

Known hypersensitivity to vortioxetine or any ingredients in the formulation. Angioedema has been reported in vortioxetine-treated patients.

Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders. Use of an MAO inhibitor intended to treat psychiatric disorders within 3 weeks of vortioxetine discontinuance. (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Monoamine Oxidase Inhibitors.)

Initiation of vortioxetine therapy in patients receiving MAO inhibitors such as linezolid or IV methylene blue. (See Drug Interactions: Linezolid and also see Drug Interactions: Methylene Blue.)

• Serotonin syndrome

• Angle-closure glaucoma
• Bipolar disorder
• CYp2d6 poor metabolizer
• Risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
• Suicidal ideation
• Upper GI bleed

• Abnormal sexual function
• Hypomania
• Hyponatremia
• Increased risk of bleeding
• Manic disorder
• SIADH syndrome

Adverse effects reported in at least 5% of patients with major depressive disorder receiving vortioxetine and at an incidence of at least twice that reported with placebo in controlled clinical studies include nausea, constipation, and vomiting. Nausea was the most common adverse effect in these studies and it occurred most often during the first week of treatment; the incidence of nausea was dose related and higher in females than in males.

Rare or Very Rare

• Accidental fall
• Acute pancreatitis
• Anaphylaxis
• Angioedema
• Hemorrhage
• Hypersensitivity drug reaction
• Hyponatremia
• Increased risk of bleeding
• Manic disorder
• Secondary angle-closure glaucoma
• Seizure disorder
• Serotonin syndrome
• Suicidal ideation

More Frequent

• Abnormal sexual function
• Constipation
• Nausea
• Vomiting

Less Frequent

• Abnormal hepatic function tests
• Acute abdominal pain
• Anorexia
• Arthralgia
• Cough
• Diarrhea
• Dizziness
• Dream disorder
• Drowsy
• Erectile dysfunction
• Fatigue
• Flatulence
• Insomnia
• Leukopenia
• Libido changes
• Pharyngitis
• Pruritus of skin
• Sedation
• Sinus bradycardia
• Xerostomia

Rare or Very Rare

• Aggressive behavior
• Agitation
• Dysgeusia
• Dyspepsia
• Flushing
• Headache disorder
• Hostility
• Hyperhidrosis
• Hyperprolactinemia
• Hypomania
• Irritability
• Mydriasis
• Orgasm disorder
• Skin rash
• Vertigo
• Weight gain

No enhanced messaging available.

Clinical studies of vortioxetine in pediatric patients have not been conducted; therefore, the safety and effectiveness of the drug in pediatric patients have not been established.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants). However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or ideation. No suicides occurred in these pediatric trials. These findings should be carefully considered when assessing potential benefits and risks of vortioxetine in a child or adolescent for any clinical use. (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Category C. (See Users Guide.)

Some neonates exposed to SSRIs or SNRIs late in the third trimester of pregnancy have developed complications, which have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries. Such complications may arise immediately upon delivery and usually last several days or up to 2-4 weeks. Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features appear to be consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug withdrawal syndrome. In some cases, the clinical picture was consistent with serotonin syndrome (see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions).

For additional information on the management of depression in women prior to conception and during pregnancy, including treatment algorithms, clinicians may consult the joint American Psychiatric Association and American College of Obstetricians and Gynecologists guidelines (at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103063/pdf/nihms293836.pdf).

Vortioxetine is distributed into milk in rats. It is not known whether the drug is distributed into human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

In clinical trials with vortioxetine, 11% of the patients were 65 years of age or older, including in a placebo-controlled study conducted specifically in geriatric patients. No overall differences in safety or effectiveness were observed between geriatric and younger adults in these studies; other reported clinical experience has not identified any differences in response to the drug between geriatric and younger adults.

No dosage adjustment is necessary in geriatric patients. In a single-dose pharmacokinetic study, the pharmacokinetics of vortioxetine generally were similar between geriatric individuals older than 65 years of age and younger individuals (24-45 years of age).

Serotonergic antidepressants, including vortioxetine, have been associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect. (See Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo. (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)