Linezolid (linezolid)

When clinically appropriate, patients treated initially with IV linezolid may be switched to oral linezolid without dosage adjustment.

The manufacturer states that safety and efficacy of >28 days of linezolid treatment have not been evaluated in controlled clinical trials. Linezolid is administered for longer durations when used in multiple-drug regimens for the treatment of multidrug-resistant (MDR) tuberculosis+.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

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

Antibiotics/Fecal Microbiota

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: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

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: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

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 antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Linezolid/Maois

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

MECHANISM OF ACTION: 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/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/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/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/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/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/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.

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.

Selected Maois/Comt Inhibitors

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

MECHANISM OF ACTION: Since MAOI's and COMT are the two major enzymes responsible for the metabolism of catecholamines, the combination of entacapone, tolcapone, or opicapone and a non-selective MAOI may inhibit the majority of catecholamine metabolism pathways.(1-3)

CLINICAL EFFECTS: Concurrent administration of entacapone, tolcapone, or opicapone with a non-selective MAOI may result in elevated levels of catecholamines, which may result in elevated heart rate and blood pressure.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian(4) and UK(1) manufacturers of entacapone state that concomitant use of either a non-selective MAOI or a selective MAO-A inhibitor with a selective MAO-B inhibitor with entacapone is contraindicated. Nonselective MAOI should be discontinued at least 2 weeks prior to initiating entacapone therapy.(4) The UK manufacturer of tolcapone states that tolcapone should not be coadministered with either a non-selective MAOI or a selective MAO-A inhibitor with a selective MAO-B inhibitor. (5) The US manufacturer of tolcapone states that patients should not ordinarily be treated concomitantly with tolcapone and a non-selective MAOI. Tolcapone may be concurrently administered with a selective MAO-B inhibitor.(2) The Middle East and US manufacturers of opicapone state that concomitant use of opicapone with MAO inhibitors other than those for the treatment of Parkinson's disease is contraindicated.(10,11)

DISCUSSION: Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes systems involved in the metabolism of catecholamines. Therefore, theoretically, the combination of either entacapone, tolcapone, or opicapone with a non-selective MAO inhibitor will result in inhibition of the majority of catecholamine metabolism pathways.(1,2) At daily oral doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A.(6) At dosages administered transdermally for the treatment of depression, selegiline is not selective for MAO-B.(7) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(8,9) Metaxalone is a weak inhibitor of MAO.(12,13)

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

Linezolid/Bupropion; Solriamfetol

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

MECHANISM OF ACTION: Bupropion and solriamfetol increase dopamine and norepinephrine concentrations via blockade of the dopamine and norepinephrine reuptake transporters.(1-4) Linezolid is a weak, nonselective monoamine oxidase inhibitor (MAOI) that blocks 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 linezolid may increase the risk for serotonin syndrome and/or severe hypertensive, or other adverse reactions, including mania, psychosis or agitation with bupropion, and headache, nausea, anorexia, or anxiety with solriamfetol.(1-2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: Patients with pre-existing hypertension may be more likely to experience treatment-emergent hypertension.(1) 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.(2)

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.(1,2) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(5) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(6,7) In non-emergency situations in patients maintained on bupropion or solriamfetol when linezolid therapy is planned, discontinue the patient's bupropion or solriamfetol at least 2 weeks in advance of linezolid therapy.(1,6) In emergency situations in patients maintained on bupropion or solriamfetol, weigh the availability and safety of alternatives to linezolid against the risk of acute hypertension. If linezolid 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 linezolid, whichever comes first.(1,6) The patient's bupropion or solriamfetol therapy may be resumed 24 hours after the last dose of linezolid.(1,6) Clinical studies have found a low incidence of serotonin syndrome in patients on concomitant linezolid and serotonergic agents, ranging from 0.24% to 4%, depending on the quality and size of the study. While linezolid-associated serotonin syndrome is potentially serious and fatal, if treated early, it is quickly reversible with discontinuation of offending agents and supportive care. Therefore, some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use of linezolid without a washout is warranted, the patient should be closely monitored.(8-13) 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: The US manufacturers of bupropion and solriamfetol state that concurrent use of bupropion or solriamfetol with a MAOI is contraindicated.(1,2) An FDA alert in July 2011(6) described the risk for serotonin syndrome when bupropion is used concurrently with linezolid. 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.(1,2)

Linezolid/Buspirone; Dexfenfluramine; Fenfluramine

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

MECHANISM OF ACTION: Linezolid is a weak, reversible inhibitor of monoamine oxidase. Buspirone is a 5-HT1A and moderate D2 agonist, while fenfluramine is an agonist of 5HT-2. Combination of these agents may result an increase in endogenous serotonin and dopamine.(1-6)

CLINICAL EFFECTS: Concurrent use of buspirone, dexfenfluramine or fenfluramine with linezolid may result in elevated blood pressure leading to hypertensive crisis.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of buspirone and fenfluramine state that concurrent use of linezolid is contraindicated.(1,2) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(3) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(8,9) In non-emergency situations in patients maintained on buspirone, dexfenfluramine or fenfluramine, when linezolid therapy is planned, discontinue the patient's buspirone, dexfenfluramine or fenfluramine at least 2 weeks in advance of linezolid therapy.(6) In emergency situations in patients maintained on buspirone, dexfenfluramine or fenfluramine, weigh the availability and safety of alternatives to linezolid against the risk of hypertensive crisis. If linezolid therapy is required, the patient's buspirone, dexfenfluramine or fenfluramine should be immediately discontinued. Patients should be monitored for hypertensive crisis for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first.(6) The patient's buspirone, dexfenfluramine or fenfluramine therapy may be resumed 24 hours after the last dose of linezolid.(6) If concurrent therapy is warranted, patients should be monitored closely for hypertensive crisis.

DISCUSSION: Several cases of elevated blood pressure have been reported in patients receiving MAOIs who were given buspirone.(1) No adverse sequelae have been reported in these patients.

Linezolid/Carbidopa-Levodopa-Entacapone

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

MECHANISM OF ACTION: Since monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes responsible for the metabolism of catecholamines, the combination of carbidopa-levodopa-entacapone and a non-selective MAOI may inhibit the majority of catecholamine metabolism pathways.(1-5) Linezolid is a weak, nonselective monoamine oxidase inhibitor (MAOI).(6)

CLINICAL EFFECTS: Concurrent administration of carbidopa-levodopa-entacapone with linezolid may result in elevated levels of catecholamines, which may result in elevated heart rate and blood pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of carbidopa-levodopa-entacapone states that concomitant use with a non-selective MAOI is contraindicated. Nonselective MAOI should be discontinued at least 2 weeks prior to initiating therapy with carbidopa-levodopa-entacapone.(1) The US manufacturer of carbidopa-levodopa states that the concurrent use of nonselective MAO inhibitors is contraindicated. Carbidopa-levodopa may be administered with recommended dosages of selective MAO-B inhibitors.(2) The Canadian(5) and UK(3) manufacturers of entacapone state that concomitant use of either a non-selective MAOI or a selective MAO-A inhibitor with a selective MAO-B inhibitor with entacapone is contraindicated. Nonselective MAOI should be discontinued at least 2 weeks prior to initiating entacapone therapy. The manufacturer of linezolid does not contraindicate the use of adrenergic agents but states that they should not be coadministered unless the patient is closely monitored for potential increases in blood pressure.(6) If concurrent therapy is warranted, patients should be monitored closely for hypertensive crisis. The addition of a decarboxylase inhibitor to the combination of a non-selective MAO inhibitor and levodopa may minimize risk of adverse effects. Phentolamine has been effective in treating hypertension caused by this interaction.

DISCUSSION: Hypertensive reactions, flushing, and palpitations have been reported as a result of the interaction between levodopa and other MAO inhibitors. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes systems involved in the metabolism of catecholamines. Therefore, theoretically, the combination of either entacapone, tolcapone, or opicapone with a non-selective MAO inhibitor will result in inhibition of the majority of catecholamine metabolism pathways.(1-5) In a case report, an 89-year-old female with COPD, sick sinus syndrome, atrial fibrillation, hypertension, history of CVA, ischemic colitis, and Parkinson's disease on many medications including carbidopa-levodopa for 6 years took linezolid for 8 days and developed seizure-like activity. The patient was afebrile and normotensive, but was tachycardic, lethargic, agitated, and exhibited clonus on examination 2 days after linezolid was discontinued.(7)

Linezolid/Centanafadine

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

MECHANISM OF ACTION: Centanafadine is a norepinephrine, dopamine, and serotonin reuptake inhibitor.(1) Linezolid is a weak, nonselective monoamine oxidase inhibitor (MAOI) that blocks the metabolism of norepinephrine and dopamine, also leading to increased neuronal concentrations of norepinephrine and dopamine.(2)

CLINICAL EFFECTS: Concurrent use of centanafadine and linezolid 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.(1-3)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(3) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(3)

PATIENT MANAGEMENT: The US manufacturer of centanafadine states that concurrent use of MAOIs is contraindicated due to the risk for hypertensive crisis and serotonin syndrome.(1) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(2) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(4,5) In non-emergency situations in patients maintained on centanafadine when linezolid therapy is planned, discontinue centanafadine at least 2 weeks in advance of linezolid therapy.(4) In emergency situations in patients maintained on centanafadine, weigh the availability and safety of alternatives to linezolid against the risk of acute hypertension. If linezolid therapy is required, centanafadine should be immediately discontinued. Patients' blood pressure should be closely monitored for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first.(4) Centanafadine therapy may be resumed 24 hours after the last dose of linezolid.(4) Clinical studies have found a low incidence of serotonin syndrome in patients on concomitant linezolid and serotonergic agents, ranging from 0.24% to 4%, depending on the quality and size of the study. While linezolid-associated serotonin syndrome is potentially serious and fatal, if treated early, it is quickly reversible with discontinuation of offending agents and supportive care. Therefore, some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use of linezolid without a washout is warranted, the patient should be closely monitored.(6-11) 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: The US manufacturer of centanafadine states that concurrent use of an MAOI is contraindicated.(1) An FDA alert in July 2011(4) described the risk for serotonin syndrome when serotonergic agents are used concurrently with linezolid. 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.(5)

Linezolid/Fentanyl; Levomethadone; Methadone

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

MECHANISM OF ACTION: Fentanyl, levomethadone, and methadone may inhibit neuronal reuptake of serotonin. Linezolid increases neuronal serotonin concentration via inhibition of monoamine oxidase.

CLINICAL EFFECTS: The concurrent use of fentanyl and methadone with MAOIs has been associated with serotonin syndrome.(1-4) Levomethadone is an enantiomer of methadone.(5) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

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 specific P450 enzyme), or high opioid dosage may increase the risk for a severe interaction.

PATIENT MANAGEMENT: Recommendations regarding concomitant use of MAOIs like linezolid with fentanyl, levomethadone, and methadone vary in different regions. In general, the combination of linezolid with these opioids is not recommended.(1-9) Some regions make stronger recommendations for certain agents. In Australia, fentanyl and methadone are contraindicated with MAOIs.(6-8) In the UK, methadone is contraindicated with MAOIs.(9) In Sweden, levomethadone is contraindicated with MAOIs.(5) The US manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(10) Clinical studies have found a low incidence of serotonin syndrome in patients on concomitant linezolid and serotonergic agents, ranging from 0.24% to 4%, depending on the quality and size of the study. While linezolid-associated serotonin syndrome is potentially serious and fatal, if treated early, it is quickly reversible with discontinuation of offending agents and supportive care. Therefore, some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(11-16) 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: The interaction between another opioid, meperidine, and MAOIs has been well documented.(17,18) There are two reports of potential interactions between MAOIs and dextromethorphan.(19,20) At least one fatality has been reported from the use of fentanyl during surgery in a patient receiving an MAOI.(21) 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; five cases were associated with methadone use during this 43 year period.(22)

Linezolid/Foslevodopa; Levodopa

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

MECHANISM OF ACTION: Linezolid is a weak, nonselective monoamine oxidase inhibitor (MAOI) that blocks the metabolism of dopamine and norepinephrine, which are formed by levodopa. Also, storage and release of dopamine and norepinephrine is increased.(1-2) Foslevodopa is a prodrug of levodopa.

CLINICAL EFFECTS: Concurrent use of linezolid may result in increased effects of levodopa, including tremor, hypertensive crisis, and postural hypotension.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of carbidopa/levodopa states that the concurrent use of nonselective MAO inhibitors is contraindicated.(1) The Canadian manufacturer of foslevodopa/foscarbidopa states that concurrent use of nonselective MAO inhibitors and selective MAO type A inhibitors is contraindicated. MAO inhibitors should be stopped at least 2 weeks prior to initiation of foslevodopa/foscarbidopa therapy.(2) The manufacturer of linezolid does not contraindicate the use of adrenergic agents but states that they should not be coadministered unless the patient is closely monitored for potential increases in blood pressure.(3) If concurrent therapy is warranted, patients should be monitored closely for hypertensive crisis. The addition of a decarboxylase inhibitor to the combination of a non-selective MAO inhibitor and levodopa may minimize risk of adverse effects. Phentolamine has been effective in treating hypertension caused by this interaction.

DISCUSSION: Hypertensive reactions, flushing, and palpitations have been reported as a result of the interaction between levodopa and other MAO inhibitors. In a case report, an 89-year-old female with COPD, sick sinus syndrome, atrial fibrillation, hypertension, history of CVA, ischemic colitis, and Parkinson's disease on many medications including carbidopa-levodopa for 6 years took linezolid for 8 days and developed seizure-like activity. The patient was afebrile and normotensive, but was tachycardic, lethargic, agitated, and exhibited clonus on examination 2 days after linezolid was discontinued.(4)

Linezolid/Milnacipran

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

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.(1,2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3,4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of milnacipran and levomilnacipran state that concurrent administration with a MAOI, including linezolid, is contraindicated. At least 5 days should elapse between discontinuing milnacipran and initiating linezolid,(1) and at least 7 days should elapse between discontinuing levomilnacipran and initiating linezolid.(2) In emergency situations in patients maintained on milnacipran or levomilnacipran, weigh the availability and safety of alternatives to linezolid against the risk of serotonin syndrome. If linezolid therapy is required, the patient's milnacipran or levomilnacipran should be immediately discontinued. Patients should be monitored for serotonin syndrome for 5 days (2 weeks in the case of levomilnacipran) or until 24 hours after the last dose of linezolid, whichever comes first. Do not initiate milnacipran or levomilnacipran therapy in patients receiving linezolid until 24 hours after the last dose of linezolid.

DISCUSSION: Concurrent use or switching between agents without a sufficient washout period may result in serotonin syndrome. Therefore, the US manufacturers of milnacipran and levomilnacipran state that concurrent administration with a MAOI, including linezolid, is contraindicated. At least 5 days should elapse between discontinuing milnacipran and initiating linezolid,(1) and at least 7 days should elapse between discontinuing levomilnacipran and initiating linezolid.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3,4) Many authors state that linezolid is a weak MAOI and rarely causes serotonin toxicity. Cases of serotonin toxicity were rapidly reversible with discontinuation of the offending agent(s) and supportive care. Some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(5-10)

Linezolid/Selected 5-Ht1d Agonists

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

MECHANISM OF ACTION: Monoamine oxidase inhibitors (MAOIs) inhibit the metabolism of rizatriptan,(1) sumatriptan,(2-9) and zolmitriptan.(10) Linezolid is a weak, reversible, nonselective MAOI.(12)

CLINICAL EFFECTS: Concurrent use of linezolid 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 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) The manufacturer of linezolid does not contraindicated the use of 5-HT1D agonists but states that they should not be coadministered unless clinically appropriate and patients are carefully observed for signs and symptoms of serotonin syndrome.(12) Eletriptan and frovatriptan are not metabolized by MAO-A(13,14) and may be an alternative in patients who require treatment with linezolid.

DISCUSSION: The combination of linezolid and 5-HT1D agonists has not been studied. Other MAOIs have been reported to interact with 5-HT1D agonists. 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&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)

Linezolid/Selected Opioids; Dextromethorphan-Quinidine

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

MECHANISM OF ACTION: Selected opioids inhibit neural reuptake of serotonin. Linezolid may increase neuronal serotonin concentrations via inhibition of MAO-A.(23)

CLINICAL EFFECTS: The concurrent use of some opioids with MAOIs has resulted in serotonin syndrome. Severe cases of serotonin syndrome may be fatal. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(23)

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

PATIENT MANAGEMENT: The manufacturer of linezolid states that linezolid should not be used in patients taking serotonergic agents unless clinically appropriate and patients are closely monitored for signs and symptoms of serotonin syndrome.(18) The US manufacturer of Nuedexta (dextromethorphan-quinidine) states Nuedexta is contraindicated within 14 days of MAOI administration.(19) Diamorphine, meperidine, and tapentadol should not be used in patients taking MAOIs, but if concomitant use of serotonergic drugs like linezolid is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment.(20-21) Use alternative agents for cough or pain.

DISCUSSION: The interaction between meperidine and MAOIs has been well documented. There is one case report of serotonin syndrome with concurrent meperidine and linezolid. Many authors state that linezolid is a weak MAOI and rarely causes serotonin toxicity. Cases of serotonin toxicity were rapidly reversible with discontinuation of the offending agent(s) and supportive care. Some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(22-27)

Linezolid/Serotonin Reuptake Inhibitors

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

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

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

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

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

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

Linezolid/Tramadol

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

MECHANISM OF ACTION: Tramadol and linezolid may lower the seizure threshold.(1-3) Both tramadol and linezolid may increase serotonin and norepinephrine. Tramadol inhibits neuronal reuptake of serotonin and norepinephrine, while linezolid impairs metabolism of serotonin and norepinephrine via inhibition of monoamine oxidase(MAO).(1-3)

CLINICAL EFFECTS: Concurrent use of tramadol and linezolid 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.(4)

PREDISPOSING FACTORS: CYP2D6 poor metabolizers,(5) or patients also taking strong CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, terbinafine) will have reduced 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.(1) The risk for seizures may also be increased in patients receiving more than the upper daily dose limit of tramadol, or in patients taking additional medications which lower the seizure threshold.(1)

PATIENT MANAGEMENT: Evaluate the patient for predisposing factors (other drugs, diseases or conditions) which may further increase the risk for serotonin syndrome or seizures. When possible and clinically appropriate, change to an alternative analgesic or antibiotic, particularly when predisposing factors are present. If concomitant therapy is necessary, monitor patient for signs of serotonin toxicity (e.g. tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, muscle rigidity) or seizures, especially after tramadol dose increases. Manufacturer prescribing recommendations: The US manufacturer of tramadol states that tramadol should be used with caution in patients taking monoamine oxidase inhibitors.(1) In contrast, an Australian manufacturer of tramadol states that it is contraindicated in patients who are currently receiving monoamine oxidase inhibitors or who have received them in the previous 14 days.(2) The US manufacturer of linezolid does not have specific recommendations regarding concurrent treatment with tramadol but does state that linezolid should not be used in patients receiving serotonergic drugs (e.g. SSRIs, TCAs, meperidine) unless clinically appropriate and patients are carefully observed for signs and symptoms of serotonin syndrome.(3)

DISCUSSION: Tramadol and its M1 metabolite are pharmacologically active. Tramadol inhibits the reuptake of norepinephrine and serotonin with minimal opioid receptor binding. The active M1 metabolite has 200 times greater binding affinity for the mu-opioid receptor than tramadol and is 6 times more potent in producing analgesia.(1) CYP P-450-2D6 converts tramadol to M1.(1,5) A study in surgery patients included 2D6 EM patients who received concomitant treatment with tramadol and 2D6 inhibitors. Levels of the M1 metabolite were decreased by 80-90% compared with EM patients not taking 2D6 inhibitors. Authors noted some EM patients were converted to the PM phenotype.(6)

Linezolid/Tricyclic; Tetracyclic Agents; Carbamazepine

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

MECHANISM OF ACTION: Linezolid is a weak, reversible inhibitor of monoamine oxidase.(1) Tricyclic and tetracyclic compounds may sensitize post-synaptic receptors to amines that are accumulating extraneuronally as a result of MAO inhibition.(2) Carbamazepine is structurally related to the tricyclic antidepressants.(3) Similarity between cyclobenzaprine and tricyclics warrants consideration of tricyclic interactions for cyclobenzaprine.(4) Mirtazapine, a tetracyclic antidepressant, should also be considered for this interaction.(5)

CLINICAL EFFECTS: Concurrent use with linezolid may result in a severe reaction including hyperpyrexia, convulsions, excitability, fluctuations in blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma, and death.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

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 manufacturers of the tricyclic antidepressants, carbamazepine, cyclobenzaprine and mirtazapine state that coadministration with MAO inhibitors is contraindicated. Concurrent linezolid is specifically contraindicated by the manufacturers of clomipramine, desipramine, mirtazapine, nortriptyline, and trimipramine.(1,3-5,7-12) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(1) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(13,14) In non-emergency situations in patients maintained on tricyclics or tetracyclics when linezolid therapy is planned, discontinue the patient's tricyclic or tetracyclic at least 2 weeks in advance of linezolid therapy. In emergency situations in patients maintained on tricyclics or tetracyclics, weigh the availability and safety of alternatives to linezolid against the risk of serotonin syndrome. If linezolid therapy is required, the patient's tricyclic 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 linezolid, whichever comes first. The patient's tricyclic or tetracyclic therapy may be resumed 24 hours after the last dose of linezolid.(13) Clinical studies have found a low incidence of serotonin syndrome in patients on concomitant linezolid and serotonergic agents, ranging from 0.24% to 4%, depending on the quality and size of the study. While linezolid-associated serotonin syndrome is potentially serious and fatal, if treated early, it is quickly reversible with discontinuation of offending agents and supportive care. Therefore, some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(15-20) 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 linezolid. The FDA FAERS contains reports of serotonin syndrome with the concurrent use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. The risk of serotonin syndrome with other psychiatric drugs is unclear.(14)

Linezolid/Tryptophan

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

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.(2) 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 linezolid should not be administered tryptophan unless they can be closely monitored for 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 patient receiving metoclopramide and a TPN containing tryptophan developed serotonin syndrome following the addition of linezolid to therapy.(3) 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.(4) 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.(5) In a case report, the addition of tryptophan to a tranylcypromine regimen resulted in hypomania.(6) In another report, a patient developed hyperventilation, shivering, hyperthermia, increased muscle tone, and hyperreflexia when tryptophan was added to tranylcypromine therapy.(7) 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.(8) 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. (9) 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.(10) In another report, a patient developed hypomania following the addition of tryptophan to phenelzine therapy.(6) Another report describes the development of delirium following the addition of tryptophan to phenelzine.(11) One set of authors reported three cases of myoclonus, hyperreflexia, and diaphoresis following the addition of tryptophan to phenelzine therapy.(12) 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.(13,14)

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/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/Selected Opioids

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

MECHANISM OF ACTION: Selected opioids inhibit neuronal reuptake of serotonin. Non-selective MAOIs increase neuronal serotonin concentration via inhibition of MAO-A.

CLINICAL EFFECTS: The concurrent use of some opioids with MAOIs has resulted in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

PREDISPOSING FACTORS: Treatment with multiple medications which increase serotonin levels or inhibit the metabolism of serotonin are risk factors for serotonin syndrome. 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 an interaction.

PATIENT MANAGEMENT: Use an alternative analgesic when possible. 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 documentation is lacking for some opioids, the FDA recommends health professionals monitor and advise patients to report symptoms of serotonin syndrome in patients receiving analgesic opioids and serotonergic agents.(2) The interaction between meperidine and MAOIs has been well documented. There are two reports of potential interactions between MAOIs and dextromethorphan.(3,4) In another case report, the concurrent use of propoxyphene and phenylzine resulted in sedation and somnolence. The patient had previously taken both agents alone with no adverse effects.(5) Although some studies have shown that morphine does not interact with MAOIs,(6,7) other data indicates that MAOIs markedly potentiate the effect of morphine.(8) One study indicates that methadone does not interact with MAOIs;(7) however, the UK manufacturer of methadone states that concurrent use is contraindicated.(9) US manufacturers recommend sensitivity tests with small, incremental doses of methadone in patients maintained on MAOIs with careful observation of vital signs.(11) Selected opioids linked to this monograph include: alfentanil, anileridine (not available in US/CA), diphenoxin, meptazinol (not available in US/CA), pentazocine, phenoperidine (not available in US/CA), propoxyphene (not available in US/CA), remifentanil, and sufentanil. Linezolid is known to be a monoamine oxidase inhibitor. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(12,13)

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)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Selected Myelosuppressive Agents/Clozapine

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

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

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

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

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

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

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.

Linezolid/Inhaled Mixed & Direct Acting Sympathomimetics

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

MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics.

CLINICAL EFFECTS: Potentiation of sympathomimetic effect may be observed.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Inhaled sympathomimetics should be used with extreme caution during concurrent therapy with or within 14 days of MAOI use.

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. Linezolid is an antibacterial with monoamine oxidase inhibitor properties.

Linezolid/Rifampin

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

MECHANISM OF ACTION: The exact mechanism is unknown, but may involve induction of linezolid metabolism by CYP2D6(1) or induction of linezolid excretion by P-glycoprotein.(2,3)

CLINICAL EFFECTS: Concurrent or recent use of rifampin may result in decreased levels and effectiveness of linezolid.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor linezolid levels and clinical response in patients who are receiving concurrent rifampin or who have recently discontinued rifampin. The dosage of linezolid may need to be adjusted.

DISCUSSION: In a study in 16 healthy males, pretreatment with oral rifampin (600 mg daily for 8 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single oral dose of linezolid by 21% and 32%, respectively. when compared to the administration of linezolid alone.(1) In a study in 8 healthy males, administration of a single intravenous dose of rifampin (600 mg) decreased the plasma levels of a single intravenous dose of linezolid (600 mg) by 10% at 6 hours post-dose, 20% at 9 hours post-dose, and by 35% at 12 hours post-dose when compared to the administration of linezolid alone.(2) In a case report, low linezolid levels and slow clinical response were noted in a 31 year-old female undergoing concurrent treatment with linezolid and rifampin.(3)

Linezolid/Selected Anticoagulants (Vitamin K Antagonists)

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

MECHANISM OF ACTION: The exact mechanism is unknown. Linezolid may interfere with vitamin K-producing gut flora.

CLINICAL EFFECTS: Concurrent use of linezolid may increase may result in increased anticoagulant effects with possible bleeding.

PREDISPOSING FACTORS: High anticoagulant doses, hepatic or renal impairment, and poor nutrition may increase the risk of bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g., thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., NSAIDs).

PATIENT MANAGEMENT: Consider using an alternative antibiotic. If concurrent therapy is warranted, monitor prothrombin activity and adjust the anticoagulant dosage accordingly. Monitor patients for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g., INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: A retrospective study examined 16 patients with left ventricular assist system for severe heart failure taking warfarin (goal INR 3-4) and started on linezolid. INR increased non-significantly (from 3.74 to 4.06) but warfarin dose decreased (3.23 mg/day to 2.69 mg/day (p=0.001)) and INR/warfarin dose ratio increased significantly. Patients with fever (temperature > 38 degrees C), potentially interacting medications, on liquid diet or TPN or with decreased food intake were excluded.(1) A retrospective study of 6 patients on warfarin and linezolid after cardiovascular surgery found that INR increased from 1.62 to 3 on day 4-5 of concomitant therapy then decreased by day 10 after dose reduction or withdrawal of warfarin. Patients on potentially interacting medications were excluded.(2) In a case series, 4 patients who were 2-5 days post aortic or mitral valve replacement and started on acenocoumarol and linezolid all experienced increased INR ranging from >5 to >10.(3) A case report describes a patient stable on acenocoumarol for a prosthetic aortic valve who developed INR of 5.6 three days after starting linezolid.(4) Another case report describes a patient who experienced INR of 5.2 three days after concomitant therapy with acenocoumarol and linezolid.(5)

Maois/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 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. Furazolidone is known to be a monoamine oxidase inhibitor. 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/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)

*Known hypersensitivity to linezolid or any ingredient in the formulation.

*Current or recent (within the last 2 weeks) treatment with drugs that inhibit MAO A or B (e.g., isocarboxazid, phenelzine).

• Serotonin syndrome

• Carcinoid syndrome
• Clostridioides difficile infection
• Hypertension
• Pheochromocytoma
• Thyrotoxicosis

• Anemia
• Bone marrow depression
• Hyponatremia
• Leukopenia
• Seizure disorder
• SIADH syndrome
• Thrombocytopenic disorder

Adverse effects occurring in >=5% of adults and/or pediatric patients receiving linezolid include diarrhea, nausea, vomiting, headache, and anemia.

More Frequent

• Anemia
• Diarrhea
• Headache disorder
• Vomiting

Less Frequent

• Abnormal hepatic function tests
• Oral candidiasis
• Skin rash
• Thrombocytopenic disorder

Rare or Very Rare

• Anaphylaxis
• Angioedema
• Bone marrow depression
• Bullous dermatitis
• Clostridioides difficile infection
• Eosinophilia
• Fungal infection
• Gastrointestinal hemorrhage
• Heart failure
• Hypersensitivity angiitis
• Hypertension
• Hypoglycemic disorder
• Hypokalemia
• Hyponatremia
• Lactic acidosis
• Leukopenia
• Obstructive hyperbilirubinemia
• Optic neuropathy
• Pancytopenia
• Peripheral neuropathy
• Pure red cell aplasia
• Rhabdomyolysis
• Seizure disorder
• Serotonin syndrome
• SIADH syndrome
• Sideroblastic anemia
• Stevens-johnson syndrome
• Toxic epidermal necrolysis

More Frequent

• Nausea

Less Frequent

• Dizziness
• Dysgeusia
• Loose stools
• Vulvovaginal candidiasis

Rare or Very Rare

• Abdominal pain with cramps
• Acute cognitive impairment
• Anorexia
• Dental discoloration
• Drowsy
• Dyspepsia
• Dyspnea
• Ecchymosis
• Fever
• Flatulence
• Pruritus of skin
• Tongue discoloration
• Vertigo

No enhanced messaging available.

Safety and efficacy of linezolid for the treatment of community-acquired pneumonia (CAP), nosocomial pneumonia, complicated skin and skin structure infections, and vancomycin-resistant Enterococcus faecium infections in pediatric patients are supported by adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, and additional data from a comparator-controlled study of gram-positive infections in neonates and children through 11 years of age. Safety and efficacy of the drug for the treatment of CAP in pediatric patients also are supported by evidence from an uncontrolled study in patients 8 months through 12 years of age.

Safety and efficacy of linezolid for the treatment of uncomplicated skin and skin structure infections in pediatric patients have been established in a comparator-controlled study in pediatric patients 5-17 years of age.

While some pharmacokinetic parameters (i.e., peak plasma concentration, volume of distribution) are similar in pediatric patients of all ages, linezolid clearance varies with age. Excluding neonates <1 week of age, clearance is most rapid in the youngest age groups (i.e., those 7 days to 11 years of age); as pediatric patients age, the clearance of linezolid decreases and clearance values in adolescents approach those observed in adults. Systemic exposure (mean daily AUC) in pediatric patients <12 years of age receiving linezolid every 8 hours generally is similar to that in adults and adolescents receiving the drug every 12 hours. There is wider intraindividual variability in linezolid clearance and systemic drug exposure in all pediatric age groups relative to adults.

The manufacturer states that linezolid is not recommended for empiric treatment of CNS infections in pediatric patients; therapeutic concentrations of the drug were not consistently achieved or maintained in the CSF of pediatric patients with ventriculoperitoneal shunts.

Inadequate systemic exposure, site and severity of infection, and underlying medical conditions should be considered in pediatric patients with a suboptimal response to linezolid, especially those with infections caused by gram-positive bacteria that have minimum inhibitory concentrations (MICs) of 4 mcg/mL.

Available data from published and postmarketing case reports regarding use of linezolid in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In studies in mice, rats, and rabbits, linezolid was not teratogenic; however, embryofetal toxicities were reported. These nonteratogenic effects included increased post-implantational embryo death, decreased fetal body weights, and increased incidence of costal cartilage fusion in mice; decreased fetal body weights, reduced ossification of sternebrae, and decreased survival of pups in rats; and reduced fetal body weight in rabbits.

Linezolid is distributed into human milk. It is not known whether the drug affects the breast-fed infant or milk production. Available data suggest that a breast-fed infant would receive approximately 6-9% of the recommended daily therapeutic infant dose (10 mg/kg every 8 hours).

The benefits of breast-feeding and the importance of linezolid to the woman should be considered along with the potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

If linezolid is used in a nursing woman, the manufacturer recommends that the breast-fed infant be monitored for diarrhea and vomiting since these are the most common adverse reactions reported in infants being treated with linezolid.

Dosage adjustments are not necessary in geriatric patients.

No overall differences in safety, efficacy, or pharmacokinetics have been observed in geriatric patients >=65 years of age compared with younger adults. Other clinical experience has not revealed age-related differences in response, but the possibility of greater sensitivity in some older patients cannot be ruled out.