ZYVOX (linezolid in dextrose 5 % in water)

There are 9 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Live Typhoid Vaccine/Antimicrobials 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)	VIVOTIF
Apraclonidine/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: 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.	APRACLONIDINE HCL, IOPIDINE
COMT Inhibitors/Selected MAOIs SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: 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)	ENTACAPONE, ONGENTYS, TASMAR, TOLCAPONE
Atomoxetine; Reboxetine; Viloxazine/Monoamine Oxidase Inhib 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.	ATOMOXETINE HCL, QELBREE, STRATTERA
Deutetrabenazine; Tetrabenazine/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: 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)	AUSTEDO, AUSTEDO XR, AUSTEDO XR TITRATION KT(WK1-4), TETRABENAZINE, XENAZINE
Methyldopa/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: 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)	METHYLDOPA, METHYLDOPA-HYDROCHLOROTHIAZIDE, METHYLDOPATE HCL
Guanethidine/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: 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)	GUANETHIDINE HEMISULFATE
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)	AZILECT, EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METAXALONE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, RASAGILINE MESYLATE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE, XADAGO, ZELAPAR
Ozanimod/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: 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)	ZEPOSIA

Drug contraindication overview.

Linezolid is contraindicated in patients with known hypersensitivity to linezolid or any ingredient in the formulation. Linezolid should not be used in patients who are receiving (or have received within the last 2 weeks) drugs that inhibit monoamine oxidase (MAO) A or B, including MAO inhibitor antidepressants (e.g., isocarboxazid, phenelzine). (See Monoamine Oxidase Inhibitors under Drug Interactions.)

Adverse reaction overview.

Adverse effects occurring in 2% or more of adults receiving linezolid include GI effects (diarrhea, nausea, vomiting), headache, anemia, rash, and dizziness. Adverse effects reported in 2% or more of pediatric patients receiving linezolid in clinical studies include GI effects (diarrhea, nausea, vomiting, localized or generalized abdominal pain, loose stools), headache, anemia, and thrombocytopenia.

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 is 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 children of all ages, linezolid clearance varies with age. Excluding neonates younger than 1 week of age, clearance is most rapid in the youngest age groups (i.e., those 7 days to 11 years of age); as children age, the clearance of linezolid decreases and clearance values in adolescents approach those observed in adults. Systemic exposure (mean daily area under the plasma concentration-time curve (AUC)) in pediatric patients younger than 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 in 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 CSF of pediatric patients with ventriculoperitoneal shunts. Inadequate systemic exposure, site and severity of infection, and underlying medical conditions should be considered in children 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.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None