Xadago (safinamide mesylate)

Dosage of safinamide mesylate is expressed in terms of safinamide.

The recommended initial adult dosage of safinamide as an adjunct to levodopa-carbidopa for the management of parkinsonian syndrome is 50 mg once daily. After 2 weeks, dosage may be increased to 100 mg once daily based on individual response and tolerability. Safinamide dosages exceeding 100 mg daily have not been shown to provide additional benefit and may increase the risk of adverse effects, including serious hypertensive reactions. (See Hypertension under Cautions: Warnings/Precautions.)

Because safinamide may cause or exacerbate dyskinesia, dosage reduction of levodopa or other dopaminergic agents may be needed during concomitant therapy to mitigate this effect.

If a dose of safinamide is missed, the dose should be skipped and the next dose should be taken at the usual time the following day.

When discontinuing safinamide therapy in patients receiving a dosage of 100 mg once daily, dosage should be decreased to 50 mg once daily for 1 week prior to discontinuance. (See Neuroleptic Malignant Syndrome under Cautions: Warnings/Precautions.)

Safinamide mesylate is administered orally once daily at the same time each day without regard to meals.

No dosing information is available for this tab.

Safinamide is minimally metabolized by cytochrome P-450 (CYP) 3A4 and other CYP isoenzymes. Safinamide and its major metabolites are neither inhibitors nor inducers of CYP isoenzymes at therapeutic concentrations.

In vitro studies indicate that safinamide and its metabolites are not inhibitors of the efflux transporters P-glycoprotein (P-gp), organic cation transporter 2 (OCT2), organic anion transport proteins (OATP) 1B1 or 1B3, bile salt export pump (BSEP), or organic anion transporter (OAT) 1, OAT3, or OAT4. Safinamide and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP). Safinamide is not a substrate of P-gp.

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

Mao Inhibitors/Bupropion; Solriamfetol

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

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

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

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

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

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

Mao Inhibitors/Selected 5-Ht1d Agonists

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: MAOIs inhibit the metabolism of rizatriptan,(1) sumatriptan,(2-9) and zolmitriptan.(10-11)

CLINICAL EFFECTS: Concurrent use of MAOIs may result in increased levels and effects of rizatriptan, sumatriptan or zolmitriptan.(1-11)

PREDISPOSING FACTORS: Patients with a history of cardiovascular disease, e.g., coronary artery disease (CAD), transient ischemic attack (TIA), stroke, cardiac conduction disorders or poorly controlled hypertension are not considered candidates for 5-HT1D agonist therapy and would be at greater risk for toxicity due to this interaction.

PATIENT MANAGEMENT: Concurrent administration of rizatriptan and a MAOI or administration of rizatriptan within two weeks of the discontinuation of a MAOI is contraindicated according to product labeling for rizatriptan.(1) Concurrent administration of sumatriptan and a MAOI or administration of sumatriptan within two weeks of the discontinuation of a MAOI is contraindicated according to the Australian, Canada, UK, and US product labeling for these agents.(2-9) Concurrent administration of zolmitriptan and a MAO-A inhibitor or the administration of zolmitriptan within two weeks of discontinuation of a MAO-A inhibitor is contraindicated according to US labeling.(10) The UK manufacturer states that a maximum of 7.5 mg of zolmitriptan should be administered within 24 hours of a MAO-A inhibitor.(11) Eletriptan and frovatriptan are not metabolized by MAO-A(12, 13) and may be an alternative in patients who require treatment with an MAO-A inhibitor.

DISCUSSION: Rizatriptan is metabolized by the 'A' subtype of monoamine oxidase. In a study with 12 subjects, the concurrent administration of rizatriptan (10 mg) with moclobemide (450 mg daily, a selective, reversible MAO-A inhibitor) resulted in increases in the rizatriptan area-under-curve (AUC) and maximum concentration (Cmax) by 119% and 41%, respectively. The AUC of the active metabolite, N-monodesmethyl rizatriptan, increased over 400%. Plasma concentrations of rizatriptan may be increased by selective MAO-A inhibitors or by nonselective MAO-A and MAO-B inhibitors, although the interaction is expected to be greater with selective MAO-A inhibitors. The manufacturer also states that no interaction is expected with selective MAO-B inhibitors.(1) Sumatriptan oral bioavailability is approximately 15%, primarily due to presystemic clearance by MAO-A in the gut and liver. A small study found an approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A inhibitor was given prior to a 25 mg oral dose of sumatriptan.(4) In another study, pretreatment with an MAO-A inhibitor prior to administration of injectable sumatriptan resulted in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life.(8) Pretreatment with a MAO-B inhibitor did not produce any significant changes in sumatriptan pharmacokinetics. The effect of a MAOI on nasal sumatriptan systemic absorption is expected to be less than that seen with oral sumatriptan but greater than that seen with injectable sumatriptan.(6) Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold increase in Cmax and AUC for zolmitriptan's active N-desmethyl metabolite.(10,11) Administration of selegiline for one week at a dosage of 10 mg daily had no effect on the pharmacokinetics of zolmitriptan or its metabolite.(10) At daily doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A. Hypertensive reactions to the addition of either tyramine or a sympathomimetic to recommended dosages of selegiline have been reported.(14) Therefore, patients receiving selegiline at dosages of greater than 10 mg daily should be considered to be receiving a MAO-A inhibitor. It would also be prudent to monitor patients receiving selegiline at recommended dosages for this interaction. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(15) Metaxalone is a weak inhibitor of MAO.(17,18) 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.

Mao Inhibitors/Tryptophan

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 use may result in additive effects on serotonin levels. MAOIs may potentiate the effects of tryptophan.(1)

CLINICAL EFFECTS: Concurrent administration of tryptophan with a MAO Inhibitor may result in serotonin syndrome and/or hypertensive crisis.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(15) In addition to these effects, disorientation, delirium, agitation, hypomania, shivering, ocular oscillation, and Babinski signs have been reported with concurrent tryptophan and phenelzine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving MAO Inhibitors should not take agents such as tryptophan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study in nine subjects, the administration of a single intravenous dose of tryptophan with tranylcypromine significantly increased the normal prolactin response to tryptophan. Four of the nine subjects developed a distinctive neuromotor syndrome characterized by hyperreflexia, ankle clonus, nystagmus, incoordination, tremor, myoclonic jerks, and nausea.(2) Another set of authors reported eight cases of delirium, ranging from mild to severe, in patients who received concurrent tranylcypromine and tryptophan. Symptoms developed within two days to 4 weeks of beginning concurrent therapy.(3) In a case report, the addition of tryptophan to a tranylcypromine regimen resulted in hypomania.(4) In another report, a patient developed hyperventilation, shivering, hyperthermia, increased muscle tone, and hyperreflexia when tryptophan was added to tranylcypromine therapy.(5) There are two reports of fatalities following the concurrent administration of tryptophan and tranylcypromine. In the first report, a a patient had been receiving chlorpromazine, lithium, and tryptophan when phenelzine was initiated. Four weeks later, the patient developed neuroleptic malignant syndrome and expired despite resuscitation efforts.(6) In the second report, a patient had been receiving fluoxetine, levothyroxine, propranolol, quinidine, and hydroxyzine. Fluoxetine was discontinued and tranylcypromine, thioridazine, and tryptophan were initiated. The patient developed neuroleptic malignant syndrome two and one-half hours after the first tryptophan dose and expired 24 hours later. (7) In a case report, the addition of tryptophan to a regimen that included phenelzine resulted in an acute behavioral and neurologic syndrome. The patient's symptoms resolved 24 hours after the discontinuation of both agents.(8) In another report, a patient developed hypomania following the addition of tryptophan to phenelzine therapy.(4) Another report describes the development of delirium following the addition of tryptophan to phenelzine.(9) One set of authors reported three cases of myoclonus, hyperreflexia, and diaphoresis following the addition of tryptophan to phenelzine therapy.(10) Some studies have shown that the addition of tryptophan to MAO Inhibitor therapy may have beneficial results, including greater improvement in depression and faster onset of effects.(11,12) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(13,14) Metaxalone is a weak inhibitor of MAO.(16,17)

Maois/Apraclonidine

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: Apraclonidine is an alpha-2-adrenergic agonist used to decrease intraocular pressure. The use of apraclonidine ophthalmic solution leads to systemic absorption.(1) As apraclonidine does not cross the blood brain barrier, peripheral alpha-2-adrenergic effects could potentially result in vasoconstriction.(1)

CLINICAL EFFECTS: Not described.(1)

PREDISPOSING FACTORS: Unknown.

PATIENT MANAGEMENT: The manufacturer of apraclonidine states that concurrent administration of apraclonidine to patients on monoamine oxidase inhibitors (MAOI's) is contraindicated.(1)

DISCUSSION: There is no clinical documentation to support this interaction. The manufacturer of apraclonidine states that concurrent administration of apraclonidine to patients on MAOI's is contraindicated.(1) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Maois/Aspirin With Papaveretum

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: Unknown.

CLINICAL EFFECTS: May result in either CNS depression or excitation.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent therapy with these agents if possible. If concurrent therapy is necessary, monitor patients for signs of CNS depression or excitation.

DISCUSSION: The data sheet for papaverine states that the drug is contraindicated in patients receiving therapy with a MAOI agent. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor MAO-A. Metaxalone is a weak inhibitor of MAO.

Maois/Buspirone

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: Combination of MAOIs, which decrease the breakdown of serotonin, and buspirone, a 5-HT1A and moderate D2 agonist, may cause an increase in endogenous serotonin and dopamine, which in addition to buspirone's agonist effect, could lead to hypertensive crisis.(1-3)

CLINICAL EFFECTS: Concurrent use of buspirone and a MAOI may result in hypertensive crisis.(2,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of buspirone recommends that these drugs not be administered concomitantly. Use of MAOIs to treat depression with buspirone or within 14 days of stopping buspirone is contraindicated. Use of buspirone within 14 days of stopping an MAOI to treat depression is also contraindicated.(2) The US manufacturer of phenelzine states that concurrent use of buspirone is contraindicated. At least 14 days should elapse between the discontinuation of phenelzine and the initiation of buspirone.(3) In emergency situations in patients maintained on buspirone, weigh the availability and safety of alternatives to methylene blue against the risk of hypertensive crisis. If methylene blue therapy is required, the patient's buspirone should be immediately discontinued. Patients should be monitored for hypertensive crisis for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first.(4) In non-emergency situations in patients maintained on buspirone when methylene blue therapy is planned, discontinue the patient's buspirone at least 2 weeks in advance of methylene blue therapy. The patient's buspirone therapy may be resumed 24 hours after the last dose of methylene blue.(4) Do not initiate buspirone therapy in patients receiving methylene blue until 24 hours after the last dose of these agents.(4)

DISCUSSION: Several cases of elevated blood pressure have been reported in patients receiving MAOIs who were given buspirone.(2) No adverse sequelae have been reported in these patients. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(5,6) Metaxalone is a weak inhibitor of MAO.(7,8)

Maois/Centanafadine

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: Combination of MAOIs, which decrease the breakdown of serotonin, and centanafadine, a norepinephrine, dopamine, and serotonin reuptake inhibitor, may cause an increase in endogenous serotonin.(1)

CLINICAL EFFECTS: Concurrent use of centanafadine and MAOIs may result in hypertensive crisis and serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(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: The concurrent use of centanafadine with MAOIs is contraindicated. At least 14 days must elapse between discontinuation of an MAOI and initiation of therapy with centanafadine.(1) Do not initiate centanafadine in a patient being treated with MAOIs such as intravenous methylene blue. If it is necessary to initiate treatment with an MAOI such as intravenous methylene blue in a patient taking centanafadine, discontinue centanafadine before initiating treatment with the MAOI.(1)

DISCUSSION: Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin. Concurrent use with MAOIs can increase heart rate, blood pressure, and the risk of serotonin syndrome.(1) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(3-5) Metaxalone is a weak inhibitor of MAO.(6,7)

Maois/Deutetrabenazine; Tetrabenazine

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: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of deutetrabenazine or tetrabenazine with an MAOI may result in restlessness, disorientation, and confusion.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of deutetrabenazine or tetrabenazine with a MAOI is contraindicated.(1-3) A two-week washout period should elapse between discontinuing a MAOI and the initiation of deutetrabenazine or tetrabenazine.(1-3)

DISCUSSION: Because concurrent use of deutetrabenazine or tetrabenazine with an MAOI may result in restlessness, disorientation, and confusion, tetrabenazine should not be given after a course of any of the MAOI's.(1-3) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(4,5) Metaxalone is a weak inhibitor of MAO.(6,7)

Maois/Dexfenfluramine; Fenfluramine

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 use of serotonergic drugs with MAOIs may result in serotonin syndrome.

CLINICAL EFFECTS: Concurrent therapy may result in serotonin syndrome, which may result in death. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent administration of these agents should be avoided. The manufacturer of dexfenfluramine recommends a two week wash-out period discontinuing a MAOI and initiating therapy with dexfenfluramine and a three week wash-out between discontinuing dexfenfluramine and initiating a MAOI. 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: Although this interaction has not been reported with dexfenfluramine or fenfluramine, the manufacturer 's product information for dexfenfluramine states that concurrent therapy with MAOI's is contraindicated. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Maois/Fentanyl

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: Fentanyl may inhibit neuronal reuptake of serotonin. MAOIs increase neuronal serotonin concentration via inhibition of MAO-A.

CLINICAL EFFECTS: The concurrent use of fentanyl with MAOIs may result in symptoms of serotonin syndrome, including hypertension, hyperpyrexia, sedation, somnolence, and death.(1-4)

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

PATIENT MANAGEMENT: The Australian manufacturers of fentanyl injection(4) and fentanyl lozenges(5) state that concurrent use with or use within 2 weeks of discontinuation of an MAOI is contraindicated. The US manufacturers of fentanyl lozenges(6) and patches(7) state that use in patients who have received an MAOI in the previous 14 days is not recommended. The US manufacturer of fentanyl injection states that use in patients who have received an MAOI in the previous 14 days should be monitored and vasodilators and beta-blockers should be available for the treatment of hypertension.(8)

DISCUSSION: The interaction between another opioid, meperidine, and MAOIs has been well documented.(9,10) There are two reports of potential interactions between MAOIs and dextromethorphan.(1,2) At least one fatality has been reported from the use of fentanyl during surgery in a patient receiving an MAOI.(3) 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.

Maois/Gepirone

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: Combination of MAOIs, which decrease the breakdown of serotonin, and gepirone, a selective 5-HT1A agonist, may cause an increase in endogenous serotonin, which could lead to hypertensive crisis and serotonin syndrome.(1)

CLINICAL EFFECTS: Concurrent use of gepirone and MAOIs may result in hypertensive crisis and 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: The concurrent use of gepirone with MAOIs is contraindicated.(1) At least 14 days must elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with gepirone. Conversely, at least 14 days must be allowed after stopping gepirone before starting an MAOI antidepressant.(1) Do not initiate gepirone in a patient treated with an MAOI such as linezolid or intravenous methylene blue, or until 24 hours after the last dose of linezolid or methylene blue.(1,3) If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking gepirone, discontinue gepirone before initiating the MAOI treatment.(1,3) In emergency situations in patients maintained on gepirone, weigh the availability and safety of alternatives to linezolid or methylene blue against the risk of hypertensive crisis. If linezolid or methylene blue therapy is required, the patient's gepirone should be immediately discontinued. Patients should be monitored for hypertensive crisis for 2 weeks or until 24 hours after the last dose of linezolid or methylene blue, whichever comes first.(3) In non-emergency situations in patients maintained on gepirone when linezolid or methylene blue therapy is planned, discontinue the patient's gepirone at least 2 weeks in advance of linezolid or methylene blue therapy. The patient's gepirone therapy may be resumed 24 hours after the last dose of linezolid or methylene blue.(1)

DISCUSSION: Gepirone and its 3'-OH metabolite act as agonists at 5HT1A receptors. Gepirone is contraindicated in patients taking, or within 14 days of stopping, MAOIs due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome.(1) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(4,5) Metaxalone is a weak inhibitor of MAO.(6,7)

Maois/Guanethidine

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: In patients treated with MAOIs, guanethidine may result in the release of a large quantity of catecholamines.(1,2)

CLINICAL EFFECTS: Use of guanethidine in patients treated with a MAOI may result in hypertensive crisis.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: At least 2 weeks should elapse between the discontinuation of an MAOI and the use of guanethidine.(1,2)

DISCUSSION: In patients treated with MAOIs, guanethidine may result in the release of a large quantity of catecholamines, which may result in hypertensive crisis.(1,2) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(3,4) Metaxalone is a weak inhibitor of MAO.(5,6)

Maois/Indoramin

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: Unknown.

CLINICAL EFFECTS: Concurrent administration may result in hypotension.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent therapy with these agents if possible. If concurrent therapy is necessary, monitor patients for signs of hypotension.

DISCUSSION: The data sheet for indoramin states that the drug is contraindicated in patients receiving therapy with a MAOI agent. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Maois/Linezolid

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: Linezolid is a reversible, nonselective inhibitor of monoamine oxidase (MAO).(1,2)

CLINICAL EFFECTS: Concurrent use of linezolid and other MAO inhibitors may result in additive effects and toxicity.(1,2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and UK manufacturer of linezolid state that it should not be used within 2 weeks of another product which inhibits monoamine oxidase A or B.(1,2) In emergency situations in patients maintained on linezolid, weigh the availability and safety of alternatives to linezolid against the risk of serotonin syndrome. If therapy with linezolid is required, discontinue the MAOI immediately. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first.(3,4) In non-emergency situations in patients maintained on MAOIs when linezolid therapy is planned, discontinue the patient's MAOI at least 2 weeks in advance of linezolid therapy. The patient's MAOI therapy may be resumed 24 hours after the last dose of linezolid.(3) Do not initiate MAOI therapy in patients receiving linezolid until 24 hours after the last dose of the linezolid.(3,4) 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.

DISCUSSION: Linezolid is a reversible, nonselective inhibitor MAO. Concurrent use of linezolid and other MAO inhibitors may result in additive effects and toxicity. The US and UK manufacturer of linezolid state that it should not be used within 2 weeks of another product which inhibits monoamine oxidase A or B.(1,2) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(5,6) Metaxalone is a weak inhibitor of MAO.(7.8) 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. The risk of serotonin syndrome with other psychiatric drugs is unclear.(9,10)

Maois/Methyldopa

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: Monoamine oxidase inhibitors (MAOI's) may inhibit the antihypertensive effects of methyldopa.(1)

CLINICAL EFFECTS: Concurrent use of MAOI's and methyldopa may result in hypertensive crisis(2) and/or hallucinations.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian,(4) UK,(1) and US(5,6) manufacturers of methyldopa state that concurrent use of MAOI's is contraindicated. The US manufacturer of phenelzine states that concurrent use of methyldopa is contraindicated.(2)

DISCUSSION: In a case report, a patient maintained on pargyline developed hallucinations following the increase of her methyldopa from 250 mg daily to 250 mg twice daily.(2) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(7,8) Metaxalone is a weak inhibitor of MAO.(9,10)

Maois/Methylene Blue Injection

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: Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(1,2) Taking multiple MAOIs may result in serotonin syndrome.(3)

CLINICAL EFFECTS: Concurrent use of methylene blue and other MAO inhibitors or use of methylene blue without a sufficient MAOI washout period may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(4) Serotonin syndrome may result in death.(3)

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: In emergency situations in patients maintained on MAOIs, weigh the availability and safety of alternative agents against the risk of serotonin syndrome. If methylene blue therapy is required, the patient's MAOI should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, which ever comes first.(3) In non-emergency situations in patients maintained on MAOIs when methylene blue therapy is planned, discontinue the patient's MAOI at least 2 weeks in advance of methylene blue therapy. The patient's MAOI therapy may be resumed 24 hours after the last dose of methylene blue.(3) Do not initiate MAOI therapy in patients receiving methylene blue until 24 hours after the last dose of methylene blue.(3) 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: Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(1,2) The FDA has received reports of CNS toxicity following the use of injectable methylene blue in patients maintained on psychiatric medications.(3) Metaxalone is a weak inhibitor of MAO.(5,6) 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. The risk of serotonin syndrome with other psychiatric drugs is unclear.(7,8)

Maois/Ozanimod

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: Ozanimod is metabolized by CYP3A4 to RP101075 (a minor active metabolite), which is further metabolized by monoamine oxidase-B (MAO-B) to major active metabolites that make up the predominant circulating active species in the plasma. The major and minor active metabolites have similar activity as ozanimod. Inhibition of MAO-B may alter exposure to ozanimod and its metabolites.(1)

CLINICAL EFFECTS: Concurrent use of ozanimod and MAO inhibitors may result in altered exposure to ozanimod and its active metabolites and may result in decreased efficacy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of ozanimod with MAO inhibitors is contraindicated. At least 14 days should elapse between discontinuation of ozanimod and initiation of MAO inhibitors.(1)

DISCUSSION: The combination of ozanimod with MAO inhibitors has not been studied. The combination of steady state ozanimod 0.92 mg or 1.84 mg with tyramine, an MAO substrate, did not have an effect on tyramine plasma concentrations or tyramine-induced pressor response. However, MAO inhibitors may alter the exposure to ozanimod and its metabolites.(1) Metaxalone is a weak inhibitor of MAO.(2,3)

Maois/Sibutramine

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

MECHANISM OF ACTION: Sibutramine is known to be a potent inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake in vivo.(1,2) Concomitant use of sibutramine with MAOIs, which has serotonin-potentiating effects, may increase the level of serotonin and cause serotonin syndrome.(1)

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of sibutramine and MAOI's is contraindicated by the manufacturer of sibutramine. In addition, at least two weeks should elapse between either discontinuing a MAOI and initiating sibutramine or discontinuing sibutramine and initiating a MAOI.(1) Patients in whom serotonin syndrome is suspected should receive immediate medical attention. 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 is no published documentation to support this interaction. Because sibutramine inhibits serotonin reuptake and serotonin syndrome has been reported during concomitant use of MAOI's and the selective serotonin reuptake inhibitors, the manufacturer of sibutramine states that concurrent use is contraindicated. In addition, at least two weeks should elapse between either discontinuing a MAOI and initiating sibutramine or discontinuing sibutramine and initiating a MAOI.(1) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(4,5) Metaxalone is a weak inhibitor of MAO.(6,7)

Maois/St. John's Wort

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: St. John's wort may inhibit neuronal reuptake of serotonin.(1) MAOIs increase neuronal serotonin concentration via inhibition of MAO-A.

CLINICAL EFFECTS: The concurrent use of St. John's wort with MAOIs may result in symptoms of serotonin syndrome, including hypertension, hyperpyrexia, sedation, somnolence, and death.(2-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: St. John's wort is contraindicated concurrently with and for 14 days after discontinuation of MAO inhibitors.(2-6)

DISCUSSION: Serotonin syndrome has been reported with concurrent St. John's wort and nefazodone,(7) paroxetine,(8) sertraline,(7) and venlafaxine.(9) The use of MAOIs concurrently with St. John's wort is contraindicated. Metaxalone is a weak inhibitor of MAO.(10,11)

Maois/Tramadol

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: Tramadol and MAO inhibitors (MAOIs) may lower the seizure threshold.(1-3) Both tramadol and MAOIs may increase serotonin and norepinephrine. Tramadol inhibits neuronal reuptake of serotonin and norepinephrine, while MAOIs impair metabolism of serotonin and norepinephrine via inhibition of monoamine oxidase(MAO).(1-3)

CLINICAL EFFECTS: Concurrent use of tramadol and an inhibitor of monoamine oxidase may result in seizures or serotonin syndrome.(1-3) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

PREDISPOSING FACTORS: CYP2D6 poor metabolizers, or patients also taking strong CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, terbinafine) will inhibit tramadol metabolism leading higher systemic levels of tramadol. Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(3) The risk of seizure may also be increased in patients receiving more than the upper daily dose limit of tramadol or in patients taking other medications that lower seizure threshold.(1-2)

PATIENT MANAGEMENT: The Australian manufacturers of tramadol state that it is contraindicated in patients who are currently receiving monoamine oxidase inhibitors or who have received them in the previous 14 days.(1,2) The US manufacturer of tramadol states that tramadol should be used with caution in patients taking monoamine oxidase inhibitors and in patients receiving antidepressants.(3)

DISCUSSION: The use of tramadol in patients taking monoamine oxidase inhibitors may increase the risk of seizures, serotonin syndrome, and suicide.(3) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(4,5) Metaxalone is a weak inhibitor of MAO.(7,8) 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.

Maois/Tricyclic; Tetracyclic Compounds

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: Some MAO inhibitors may enhance the effects of tricyclic and tetracyclic compounds indirectly through inhibition of microsomal enzymes.(1) Tricyclic and tetracyclic compounds may sensitize post-synaptic receptors to amines that are accumulating extraneuronally as a result of MAO inhibition.(2) Similarity between cyclobenzaprine and TCAs warrants consideration of TCA interactions for cyclobenzaprine.(6) Mirtazapine, a tetracyclic antidepressant, should also be considered for this interaction.(7)

CLINICAL EFFECTS: Concurrent use may result in a severe reaction including hyperpyrexia, convulsions, excitability, fluctuations in blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma, and death.(1,3-10) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(11)

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

PATIENT MANAGEMENT: The concurrent use of tricyclic antidepressants, cyclobenzaprine or mirtazapine and MAO inhibitors is contraindicated by the manufacturers of tricyclic antidepressants, cyclobenzaprine, mirtazapine, and tranylcypromine.(1,3-10) The manufacturers of tricyclic antidepressants, cyclobenzaprine and mirtazapine recommend at least 14 days between switching therapies.(1,3-9) The manufacturer of tranylcypromine recommends a medication-free interval of at least a week when initiating tranylcypromine in patients who have previously received a tricyclic antidepressant, then initiating tranylcypromine at a reduced dosage of 50% for one week.(10) The US manufacturer of phenelzine states that at least 14 days should elapse between the discontinuation of phenelzine and the initiation of another antidepressant. If phenelzine is used concurrently with or within 10 days of another antidepressant, the patient should be cautioned regarding the possibility of an adverse drug interaction.(8) The US manufacturer of selegiline states that at least 14 days should elapse between the discontinuation of selegiline and the initiation of a tricyclic antidepressant.(9) In emergency situations in patients maintained on tricyclics or tetracyclics, weigh the availability and safety of alternatives to methylene blue against the risk of serotonin syndrome. If methylene blue therapy is required, the patient's tricyclic, cyclobenzaprine or tetracyclic should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first.(12) In non-emergency situations in patients maintained on tricyclics, cyclobenzaprine or tetracyclics when methylene blue therapy is planned, discontinue the patient's tricyclic or tetracyclic at least 2 weeks in advance of methylene blue therapy. The patient's tricyclic or tetracyclic therapy may be resumed 24 hours after the last dose of linezolid or methylene blue.(12) Do not initiate tricyclic, cyclobenzaprine or tetracyclic therapy in patients receiving methylene blue until 24 hours after the last dose of these agents.(12) 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: It should be noted that if this interaction occurs, the consequences will be immediate and severe. Effects may continue to be seen for several days after discontinuing the MAOI. The interaction has been reported with tricyclic antidepressants and selegiline.(9) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(14,15) Metaxalone is a weak inhibitor of MAO.(34,35) The FDA AERS contains reports of serotonin syndrome with concurrent injectable methylene blue and citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. The risk of serotonin syndrome with other psychiatric drugs is unclear.(13) 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.

Maois/Valbenazine

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

MECHANISM OF ACTION: Valbenazine inhibits the vesicular monoamine transporter 2 (VMAT2) that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. Concomitant use with MAOIs may increase the concentration of monoamine neurotransmitters in synapses.

CLINICAL EFFECTS: The concurrent use of valbenazine with MAOIs may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity. Concomitant use of MAOIs with valbenazine may reduce the effectiveness of valbenazine.

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.

PATIENT MANAGEMENT: This combination should be avoided if possible. If concurrent therapy is warranted, patients should be monitored for adverse effects. 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: Concomitant use of valbenazine with MAOIs may increase the concentration of monoamine neurotransmitters in synapses. Metaxalone is a weak inhibitor of MAO.

Maois/Ziprasidone

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: Combination of MAOIs, which decrease the breakdown of serotonin, and ziprasidone, a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor, may cause an increase in endogenous serotonin.(1-2)

CLINICAL EFFECTS: Concurrent use of ziprasidone and MAOIs 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: The concurrent use of ziprasidone with MAOIs is contraindicated. At least 14 days must elapse between discontinuation of an MAOI and initiation of therapy with ziprasidone. Conversely, at least 3 days must be allowed after stopping ziprasidone before starting an MAOI.(1) Do not initiate ziprasidone in a patient being treated with MAOIs such as intravenous methylene blue. If it is necessary to initiate treatment with an MAOI such as intravenous methylene blue in a patient taking ziprasidone, discontinue ziprasidone before initiating treatment with the MAOI.

DISCUSSION: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(7,8) Metaxalone is a weak inhibitor of MAO.(9,10)

Monoamine Oxidase Inhib/Atomoxetine; Reboxetine; Viloxazine

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: Monoamine oxidase Inhibitors (MAOIs) block the enzymes that degrade monoamine neurotransmitters-norepinephrine and serotonin. Atomoxetine, reboxetine, and viloxazine inhibit the pre-synaptic norepinephrine transporter. Concomitant use of atomoxetine, reboxetine, or viloxazine with MAOIs may potentiate the release of norepinephrine and other monoamines from adrenergic nerve endings.(1-3)

CLINICAL EFFECTS: Concurrent use may result in serious and sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of atomoxetine and viloxazine state that the concurrent use of atomoxetine or viloxazine with a monoamine oxidase inhibitor (MAOI) is contraindicated. At least a two-week washout period should occur between switching a patient from a MAOI to atomoxetine or viloxazine, or from atomoxetine to a MAOI.(1,3) The Australian manufacturer of reboxetine states that concurrent use with an MAOI is contraindicated.(2)

DISCUSSION: Because the use of other drugs that affect brain monoamine concentrations with monoamine oxidase inhibitors has resulted in serious and sometimes fatal reactions, the manufacturer of atomoxetine states that the concurrent use of atomoxetine with a MAOI is contraindicated. At least a two-week washout period should occur between switching a patient from a MAOI to atomoxetine or from atomoxetine to a MAOI.(1) The Australian manufacturer of reboxetine and the US manufacturer of viloxazine state that concurrent use with an MAOI is contraindicated.(2-3) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(4-5) Metaxalone is a weak inhibitor of MAO.(8,9) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Monoamine Oxidase Inhibitors/Carbamazepine

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: Carbamazepine is structurally related to the tricyclic antidepressants, which may sensitize adrenergic receptors to amines that can accumulate extra neuronally as a result of MAO inhibition.

CLINICAL EFFECTS: Concurrent use of carbamazepine with a MAOI may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(11) Possible increases in serum carbamazepine levels can be seen predisposing patients to carbamazepine toxicity. This may increase excitation, delirium, tremor, twitching, convulsions, coma, and circulatory collapse. It has also been suggested that the combination of carbamazepine and MAOIs may possibly lead to synergistic hepatotoxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of carbamazepine states that MAOIs should be discontinued at least 14 days prior to initiation of carbamazepine therapy.(2) The US manufacturer of tranylcypromine states that concurrent use of dibenzazepine-related entities (such as carbamazepine) is contraindicated.(3) The US manufacturer of selegiline states that concurrent use of carbamazepine is contraindicated.(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 coordination, or severe diarrhea.

DISCUSSION: Carbamazepine's chemical structure is similar to that of the tricyclic antidepressants (TCAs).(1,2) TCA serum levels have been elevated by coadministration of isoniazid, a monoamine oxidase inhibitor. Because of these similarities, it has been hypothesized that MAOIs could inhibit the metabolism of carbamazepine.(1,4) In a study(4) involving 10 patients, CBZ dosing, and subsequent serum levels, were compared to patients receiving phenelzine verses tranylcypromine. Results showed that the tranylcypromine group required a 2.3 times higher dose than the phenelzine group. In a related study,(1) 10 subjects were given a MAOI, with or without lithium, to examine changes in CBZ pharmacokinetics. Results showed no significant difference in CBZ level or dose when comparing the phenelzine and tranylcypromine group to baseline. There were also no differences in CBZ level or dose when comparing the phenelzine and tranylcypromine group to each other. In one case report,(5) a 52 year old woman on CBZ was started on tranylcypromine. Combination therapy was continued for 2 weeks, at which time the patient's mental state improved and tranylcypromine was discontinued. The patient experienced no adverse events. The same author reports another case(5) involving a 31 year-old woman on CBZ who was started on tranylcypromine. Subsequently, her serum CBZ level decreased 35% over following two weeks. In a related case,(6) a 24 year-old man on CBZ was started on tranylcypromine. CBZ levels were drawn on 15 separate occasions over 52 days, which resulted in no significant change in CBZ serum level from his baseline. This patient also experienced no adverse effects. Because these studies and case reports examined only a small group of patients and their results are conflicting, it is difficult to assess the clinical significance of this interaction. However, the manufacturer of carbamazepine states that MAOIs be discontinued for a minimum of 14 days before beginning carbamazepine therapy.(2) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Safinamide/Levomethadone; Methadone

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: Methadone may inhibit neural reuptake of serotonin. MAOIs increase neuronal serotonin concentrations via inhibition of MAO-A. Levomethadone is an enantiomer of methadone. Safinamide is a selective MAO-B inhibitor at doses </= 100 mg daily. MAO-B selectivity decreases above the recommended dose of 100 mg daily.

CLINICAL EFFECTS: The concurrent use of methadone with safinamide may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

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

PATIENT MANAGEMENT: The US manufacturer of safinamide states the use of methadone is contraindicated during and within 2 two weeks after discontinuation of safinamide. Methadone manufacturer recommendations: The US manufacturer of methadone states that if concurrent use is necessary, a sensitivity test should be performed in which small, incremental doses of methadone are administered over several hours while the patient's condition and vital signs are carefully observed. The Australian manufacturer of methadone states that methadone should not be administered to patients receiving MAOIs. The UK manufacturer of methadone states that concurrent use is contraindicated.

DISCUSSION: FDA performed a search of its adverse event database for cases of serotonin syndrome with selected opiates for the period of January 1, 1969 to June 12, 2013; 5 cases were associated with methadone use during this 43 year period.

Selected Maois/Rasagiline; Oral Selegiline

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: Rasagiline and selegiline are monoamine oxidase (MAO) inhibitors. Rasagiline is a selective, irreversible MAO-B inhibitor. MAO-B selectivity decreases as dose increases.(1) Selegiline has greater affinity for MAO-B at lower doses and inhibits both MAO-A and MOA-B at higher antidepressant doses.(2)

CLINICAL EFFECTS: Concurrent use of rasagiline or selegiline and MAO inhibitors may result in additive MAO inhibition and toxicity, including hypertensive crisis and serotonin syndrome.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of rasagiline with MAO inhibitors is contraindicated. At least 14 days should elapse between discontinuation of rasagiline and initiation of MAO inhibitors.(1) The concurrent use of selegiline with agents that affect MAO is contraindicated. At least 14 days should elapse between discontinuation of selegiline and initiation of any drug that is contraindicated due to risk of hypertensive crisis and serotonin syndrome.(2)

DISCUSSION: Rasagiline and selegiline are MAO inhibitors. Concurrent use with MAO inhibitors may result in a hypertensive crisis and serotonin syndrome.(1,2) Metaxalone is a weak inhibitor of MAO.(3,4)

Selected Maois/Selected Opioids; Dextromethorphan

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

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

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

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

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

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

Selected Maois/Serotonin Reuptake Inhibitors; Snris

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

Maois/Bethanidine

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

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Concurrent administration may result in hypotension.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent therapy with these agents if possible. If concurrent therapy is necessary, monitor patients for signs of hypotension.

DISCUSSION: The data sheet for bethanidine states that the drug is contraindicated in patients receiving therapy with a MAOI agent. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Maois/Droxidopa

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

MECHANISM OF ACTION: MAOIs inhibit the enzyme responsible for degradation of norepinephrine which is formed by droxidopa.

CLINICAL EFFECTS: Concurrent use of MAOIs and droxidopa may result in increased effects of droxidopa, including headache, dizziness, nausea, and hypertensive crisis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of droxidopa recommends concurrent use with non-selective MAOIs should be avoided. Selective MAO-B inhibitors, including rasagiline and selegiline, were used concurrently in clinical trials without an increase in risk of hypertensive crisis. If concurrent therapy is warranted, monitor patient closely for increases in blood pressure.

DISCUSSION: Hypertensive reactions are possible as a result of this interaction. This interaction may be possible for several weeks after the discontinuation of a MAO inhibitor. Furazolidone and linezolid have been shown to inhibit MAO. Metaxalone is a weak inhibitor of MAO.

Maois/Metaxalone

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

MECHANISM OF ACTION: Metaxalone is a weak inhibitor of monoamine oxidase (MAO).(1,2)

CLINICAL EFFECTS: Concurrent use of metaxalone and other MAO inhibitors may result in additive effects and toxicity.(1,2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of metaxalone states serotonin syndrome has resulted from concurrent use with other serotonergic drugs when metaxalone was used as doses within the recommended dosing range. If concurrent use is warranted, monitor the patient closely for signs or symptoms of serotonin syndrome, particularly during initiation or dose adjustment.(1) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In vitro analysis of metaxalone at concentrations ranging from 1.56 to 400 microM resulted in significant dose-related inhibition of MAO-A.(2) Case reports of suspected serotonin syndrome with metaxalone use at both therapeutic doses and in overdose have been reported.(3-5)

Maois/Metoclopramide

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

MECHANISM OF ACTION: In patients treated with MAOIs, metoclopramide may result in the release of a large quantity of catecholamines.(1-3)

CLINICAL EFFECTS: Use of metoclopramide in patients treated with a MAOI may result in hypertensive crisis.(1-3)

PREDISPOSING FACTORS: The risk for hypertensive crisis may be greater in patients with hypertension, pheochromocytoma, or other catecholamine-releasing paragangliomas.

PATIENT MANAGEMENT: The US manufacturer of metoclopramide states avoid the concurrent use of metoclopramide and MAOIs.(1) The Australian manufacturer of metoclopramide states metoclopramide should be used cautiously, it at all, in patients on MAOIs.(2) The Canadian manufacturer of metoclopramide states care should be exercised with concurrent use of metoclopramide and MAOIs.(3) If concurrent use is warranted, monitor blood pressure closely for hypertensive crisis. Consider using the lowest possible dose of both metoclopramide and the MAOI.(1-3) If a rapid rise in blood pressure occurs or hypertensive crisis is suspected, discontinue metoclopramide.(1-3)

DISCUSSION: In patients treated with MAOIs, metoclopramide may result in the release of a large quantity of catecholamines, which may result in hypertensive crisis.(1-3) Metaxalone is a weak inhibitor of MAO.(4,5)

Maois/Trazodone (> 100 MG)

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

MECHANISM OF ACTION: Trazodone is primarily an inhibitor of 5HT2A serotonin receptors, H1 histamine, and alpha-1 receptors.(1) At low doses, inhibition of serotonin reuptake is weak and estimated to be 1/20th of 5HT2A inhibiting activity. At high trazodone doses receptor specificity may be diminished and serotonin reuptake inhibition could be clinically important. In addition, one route of trazodone metabolism leads to formation of an active metabolite, m-chlorophenylpiperazine (mCPP) which is pharmacologically distinct from trazodone in that it is an agonist at a variety of serotonin receptors.(1) MCPP concentrations may be clinically important at antidepressant doses of trazodone. MCPP is converted to an inactive metabolite by CYP2D6.(3) MAO Inhibitors increase serotonin levels via inhibition of its metabolism.

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

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of trazodone, mCPP or more potent MAO inhibitors 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) Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion, cinacalcet, dacomitinib, fluoxetine, paroxetine, quinidine, or systemic terbinafine)(4) may increase mCPP concentration, increasing the risk for serotonin toxicity. Patients who are poor metabolizers at CYP2D6 would be expected to have higher mCPP concentrations compared with extensive metabolizers.

PATIENT MANAGEMENT: Trazodone doses greater than 100 mg should not be prescribed in patients who require treatment with any MAOI and a strong inhibitor of CYP2D6 (e.g. bupropion, cinacalcet, dacomitinib, fluoxetine, paroxetine, quinidine, systemic terbinafine) or any other agent with serotonin-increasing effects (e.g. tramadol, meperidine, most antidepressants). Patients known to be poor metabolizers of CYP2D6 should not receive greater than 100 mg of trazodone per day if they require treatment with a MAOI. To minimize serotonin reuptake inhibition and accumulation of mCPP, limit dosage of trazodone to less than or equal to 100 mg daily in patients receiving MAO inhibitors. If the benefit of higher dose trazodone is judged to be greater than the risk for serotonin toxicities, assure that the patient and health care team are aware of and monitor for signs and symptoms of serotonin syndrome. 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 37 year-old male developed serotonin syndrome following the addition of linezolid to citalopram and trazodone.(5) In a case report, a patient developed serotonin syndrome with concurrent trazodone, isocarboxazid, and methylphenidate.(6) In a case report, a patient developed serotonin syndrome following the abrupt replacement of trazodone with moclobemide.(7) An open study evaluated the efficacy and safety of low dose trazodone for the treatment of MAOI-associated insomnia. Twenty-one patients successfully treated with a MAOI for unipolar or bipolar depression but with persistent insomnia participated in the study. Trazodone 25 to 75 mg was given at bedtime. Patients with a fair or good response to trazodone were monitored for a minimum of 4 months to assess efficacy and safety of treatment. Eleven patients had a resolution of insomnia, 9 had a partial response, and one had no benefit. Side effects noted were nausea in 2 patients, persistent morning grogginess in one patient and memory problems in one patient.(8) A small double-blind placebo controlled study evaluated the efficacy and safety of trazodone 50 mg to treat insomnia due to brofaromine, a MAO-A inhibitor. All seven patients had responded to brofaromine and had been in remission for at least 3 months. Three patients received trazodone on week 1, followed by placebo on week 2, while the other 4 patients received placebo on week 1 and trazodone on week 2. At the end of the trial 4 patients elected to continue trazodone and 3 patients discontinued therapy due to adverse effects (nausea, constipation, vertigo, dry mouth, palpitations, or heartburn). The authors stated no patients had symptoms suggestive of serotonin syndrome.(9) Metaxalone is a weak inhibitor of MAO.(10,11) 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. The risk of serotonin syndrome with linezolid and other psychiatric drugs is unclear.(12,13)

Slt Maois/Mixed & Indirect Sympathomimet; Oral Phenylephrine

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

MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine).

CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Fatalities have occurred with combinations of sympathomimetics and MAO-A inhibitors.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of MAO-A inhibitors and sympathomimetics is contraindicated. The manufacturers of sympathomimetic agents recommend waiting 14 days after discontinuation of MAO inhibitors before initiating the sympathomimetic. Patients receiving indirect acting sympathomimetics should not receive linezolid unless they are monitored for potential increases in blood pressure. Initial dosages of dopamine should be reduced. At recommended dosages, oral selegiline and transdermal selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages they have been shown to lose their selectivity. Patients receiving higher dosages of selegiline should be considered susceptive to this interaction.

DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. Foods containing large amounts of tyramine have also been implicated in this interaction. A significant pressor response was observed in normal subjects receiving linezolid and tyramine doses of more than 100 mg. Administration of linezolid (600 mg BID for 3 days) with pseudoephedrine (60 mg q 4 hours for 2 doses) increased blood pressure by 32 mmHg. Administration of linezolid (600 mg BID for 3 days) with phenylpropanolamine (25 mg q 4 hours for 2 doses) increased blood pressure by 38 mmHg. 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.

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

Maois/Trazodone (<= 100 MG)

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

MECHANISM OF ACTION: Trazodone is primarily an inhibitor of 5HT2A serotonin receptors, H1 histamine, and alpha-1 receptors.(1) Inhibition of serotonin reuptake is weak and estimated to be 1/20th of 5HT2A inhibiting activity. Metabolism of trazodone leads to formation of an active metabolite, m-chlorophenylpiperazine (mCPP) which is an agonist at a variety of serotonin receptors.(1) MCPP is further converted to an inactive metabolite by CYP2D6.(3) MAO Inhibitors increase serotonin levels via inhibition of its metabolism.

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

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of trazodone, mCPP or more potent MAO inhibitors 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) Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion, cinacalcet, dacomitinib, fluoxetine, paroxetine, quinidine, or systemic terbinafine)(4) may increase mCPP concentration, increasing the risk for serotonin toxicity. Patients who are poor metabolizers at CYP2D6 would be expected to have higher mCPP concentrations compared with extensive metabolizers.

PATIENT MANAGEMENT: It would be prudent to seek trazodone alternatives in patients who require treatment with a MAOI and a strong inhibitor of CYP2D6 (e.g. bupropion, cinacalcet, dacomitinib, fluoxetine, paroxetine, quinidine, systemic terbinafine) or another serotonergic agent. Assess patient for additional predisposing risk factors then change/adjust medications or monitor accordingly. To minimize accumulation of mCPP, limit dosage of trazodone to less than or equal to 100 mg daily. Assure careful monitoring for signs and symptoms of serotonin syndrome when the dose of either agent is increased. 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 37 year-old male developed serotonin syndrome following the addition of linezolid to citalopram and trazodone.(5) In a case report, a patient developed serotonin syndrome with concurrent trazodone, isocarboxazid, and methylphenidate.(6) In a case report, a patient developed serotonin syndrome following the abrupt replacement of trazodone with moclobemide.(7) An open study evaluated the efficacy and safety of low dose trazodone for the treatment of MAOI-associated insomnia. Twenty-one patients successfully treated with a MAOI for unipolar or bipolar depression but with persistent insomnia participated in the study. Trazodone 25 to 75 mg was given at bedtime. Patients with a fair or good response to trazodone were monitored for a minimum of 4 months to assess efficacy and safety of treatment. Eleven patients had a resolution of insomnia, 9 had a partial response, and one had no benefit. Side effects noted were nausea in 2 patients, persistent morning grogginess in one patient and memory problems in one patient.(8) A small double-blind placebo controlled study evaluated the efficacy and safety of trazodone 50 mg to treat insomnia due to brofaromine, a MAO-A inhibitor. All seven patients had responded to brofaromine and had been in remission for at least 3 months. Three patients received trazodone on week 1, followed by placebo on week 2, while the other 4 patients received placebo on week 1 and trazodone on week 2. At the end of the trial 4 patients elected to continue trazodone and 3 patients discontinued therapy due to adverse effects (nausea, constipation, vertigo, dry mouth, palpitations, or heartburn). The authors stated no patients had symptoms suggestive of serotonin syndrome.(9) Metaxalone is a weak inhibitor of MAO.(10,11) 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. The risk of serotonin syndrome with other psychiatric drugs is unclear.(12,13)

Safinamide/Glyburide

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

MECHANISM OF ACTION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates such as glyburide.(1) The exact mechanism by which MAO inhibitors such as safinamide affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs.

CLINICAL EFFECTS: Administration of safinamide with glyburide may result in elevated levels of and toxicity from glyburide, including additive hypoglycemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The EMA and UK manufacturer of safinamide recommend monitoring patients who are on concomitant drugs that are substrates of BCRP, including glyburide. Dose adjustment of glyburide should be performed according to the prescribing information for glyburide.(1) Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia.(1)

DISCUSSION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1) In a clinical study, safinamide increased the AUC of rosuvastatin, a BCRP substrate, by 1.25- to 2-fold.(1,3)

Safinamide/Selected Antidiabetics

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

MECHANISM OF ACTION: The exact mechanism by which MAO inhibitors such as safinamide affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs.

CLINICAL EFFECTS: The hypoglycemic response to both insulin and glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylurea may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia.

DISCUSSION: This interaction is likely to occur. The interaction between MAOIs and insulin is well documented. Additional documentation is necessary to confirm the potential interaction of MAOI's with other glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylureas but is expected to occur based on pharmacologic similarity. It may take several weeks for the full hypoglycemic effect of the MAOI to occur. Conversely, it may take several weeks for the effect to dissipate after stopping the MAOI.

Safinamide/Selected Bcrp Substrates

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

MECHANISM OF ACTION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of safinamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The EMA and UK manufacturer of safinamide recommend monitoring patients who are on concomitant drugs that are substrates of BCRP, including diclofenac, methotrexate, rosuvastatin, and topotecan. Dose adjustment of the BCRP substrate should be performed according to the prescribing information for the BCRP substrate.(1) On the other hand, the US manufacturer of safinamide states that rosuvastatin did not have a clinically significant effect on the pharmacokinetics of safinamide.(2)

DISCUSSION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1) In a clinical study, safinamide increased the AUC of rosuvastatin by 1.25- to 2-fold.(1,3) BCRP substrates linked to this monograph include: diclofenac, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, and topotecan.(1,3)

Concomitant use with other drugs that inhibit monoamine oxidase (MAO) (e.g., other MAO inhibitors, linezolid); opiate agonists (e.g., meperidine, methadone, propoxyphene (no longer commercially available in the US), tramadol); serotonin- and norepinephrine-reuptake inhibitors (SNRIs); tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate; amphetamines; St. John's wort (Hypericum perforatum); or dextromethorphan. (See Drug Interactions.)

Known hypersensitivity to safinamide. (See Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.)

Severe hepatic impairment (Child-Pugh class C).

• Child-pugh class C hepatic impairment

• Hallucinations
• Pregnancy
• Psychotic disorder
• Serotonin syndrome

• Dyskinesia
• Hypertension

Adverse effects reported in 2% or more of patients receiving safinamide and occurring more frequently than with placebo include dyskinesia, fall, nausea, insomnia, orthostatic hypotension, anxiety, cough, and dyspepsia.

More Frequent

• Accidental fall

Less Frequent

• Abnormal hepatic function tests
• Hypertension
• Sudden onset of sleep

Rare or Very Rare

• Drug-induced psychosis
• Dyspnea
• Gingivitis
• Hypersensitivity drug reaction
• Serotonin syndrome
• Tongue swelling

More Frequent

• Dyskinesia
• Nausea

Less Frequent

• Dyspepsia
• Insomnia
• Orthostatic hypotension
• Symptoms of anxiety

Rare or Very Rare

• Headache disorder
• Impulse control disorder
• Skin rash

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Safety and efficacy of safinamide have not been established in pediatric patients younger than 18 years of age.

Category C. (See Users Guide.)

There are no adequate and well-controlled studies of safinamide in pregnant women. In animal reproduction studies, safinamide produced developmental toxicity and teratogenic effects (e.g., decreased body weight, cardiac and skeletal malformations, embryofetal death, postnatal death) when the drug was administered to pregnant rats and rabbits at clinically relevant dosages.

Studies in rats indicate that safinamide is distributed into milk; skin discoloration, thought to be caused by hepatobiliary toxicity, was observed in nursing pups exposed to safinamide through milk during the lactation period.

It is not known whether safinamide is distributed into human milk; a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Approximately 38% of patients in clinical studies of safinamide were 65 years of age or older. No overall differences in safety or efficacy relative to younger adults were observed and other clinical experiences have not identified differences in response with regard to age; however, greater sensitivity of some older individuals cannot be ruled out.