Mirtazapine with Linezolid Interaction Details

Brand Names Associated with Mirtazapine

Brand Names Associated with Linezolid

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 15, 2023

Interaction Effect

Increased risk of serotonin syndrome (hyperthermia, hyperreflexia, myoclonus, mental status changes)

Interaction Summary

Concurrent use of linezolid, an MAOI, and mirtazapine is contraindicated If urgent treatment with linezolid is necessary and alternatives are not available, promptly discontinue mirtazapine and then linezolid may be administered after the risk/benefit has been evaluated. Monitor for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. Mirtazapine can be resumed 24 hours after the last dose of linezolid. Several cases of drug-induced serotonin syndrome have been reported that required drug discontinuation and supportive therapy, some ending in fatality .. In a retrospective cohort study in older adults, serotonin syndrome occurred in less than 0.5% of patients who were taking a concurrent antidepressant and linezolid .

Severity

Contraindicated

Onset

Unspecified

Evidence

Probable

How To Manage Interaction

Concurrent use of linezolid, an MAOI, and mirtazapine is contraindicated. If urgent treatment with linezolid is necessary and alternatives are not available, promptly discontinue mirtazapine and then linezolid may be administered after the risk/benefit has been evaluated. Monitor for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. Mirtazapine can be resumed 24 hours after the last dose of linezolid. Monitoring includes signs and symptoms of neuromuscular abnormalities (including hyperreflexia, tremor, muscle rigidity, clonus, peripheral hypertonicity, and shivering), autonomic hyperactivity (including tachycardia, mydriasis, diaphoresis, the presence of bowel sounds, and diarrhea), and mental status changes (including agitation and delirium). Serotonin syndrome can be life-threatening. If serotonin syndrome develops, discontinue the offending agents and provide supportive care and other therapy as necessary .

Mechanism Of Interaction

Additive serotonergic effects

Literature Reports

A) In a retrospective cohort study in older adults who were prescribed oral linezolid 600 mg twice daily (N=1134), serotonin syndrome occurred in fewer than 6 patients (less than 0.5%) who were taking a concomitant antidepressant (n=215). In the propensity score-matched cohort (n=332), there was no difference in the risk of clinically significant serotonin syndrome in patients taking concomitant antidepressants and linezolid compared with patients taking linezolid without antidepressants (adjusted risk difference, -1.2%; 95% CI, -2.9% to 0.5%). There was also no difference in the rate of altered mental status or confusion, hospitalization, or death from any cause between groups. Patients were aged 66 years or older, and of those taking an antidepressant, 47.9% were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, 3.3% were taking a norepinephrine and dopamine reuptake inhibitor, and none were taking an MAOI .

B) In a review of postmarketing data, 2 cases of serotonin toxicity were reported in the concurrent use of linezolid and mirtazapine. A review was conducted of postmarketing adverse events reported to the US Food and Drug Administration's Adverse Event Reporting System (AERS) database between November 1997 and September 2003 regarding serotonin toxicity with linezolid use. A serotonin toxicity case was defined as having (a) linezolid as the primary suspect drug, (b) concomitant administration of 1 or more secondary suspect drug with CNS serotonergic activity, and (c) serotonin toxicity, as defined by the modified Hunter Serotonin Toxicity Criteria or by the reporter of the adverse event. A total of 29 cases were identified (age range 17 to 83 years), where linezolid was used concomitantly with 1 drug (n=20), with 2 drugs (n=6), and with 3 or more drugs (n=3). While SSRIs were the most common class of drugs received concomitantly with linezolid (n=26), other drug classes included tricyclic antidepressants (n=6) and atypical antidepressants (n=4). Additionally, drugs used concurrently included carbidopa-levodopa (n=2), dextromethorphan (n=1), lithium (n=1), metoclopramide (n=1), risperiDONE (n=1), and traMADol (n=1). Symptoms of serotonin toxicity included tremor, fever, seizure, clonus, sweating, agitation, akathisia, rigors, twitching, and muscle rigidity. Intervention including hospitalization was required in 13 patients, and 3 deaths were reported with concurrent SSRI use. Among the 2 cases identified with concurrent linezolid use, 1 patient received mirtazapine alone and 1 patient received mirtazapine in combination with paroxetine .

C) A retrospective chart review identified one highly probable case of serotonin syndrome in a patient who received concomitant therapy with linezolid and venlafaxine, followed by citalopram. Charts of 72 inpatients who received linezolid and an SSRI or venlafaxine within 14 days of each other were reviewed for a diagnosis of serotonin syndrome (SS) using the Sternbach and the Hunter Serotonin Toxicity criteria. Of these patients, 52 (72%) were treated concomitantly with linezolid and an SSRI or venlafaxine. Four patients met the criteria for having either high or low probability of SS. Of these, one case involved an 81-year-old woman who was diagnosed with a high probability of having SS after receiving concomitant linezolid and venlafaxine followed by citalopram. Linezolid was given for a vancomycin-resistant Enterococcus urinary tract infection. When the patient presented, she refused to eat, was confused as to time and place, and began shouting. Although she appeared to have met 6 of the Sternbach criteria and 4 of the Hunter criteria for SS, a diagnosis of SS was not documented in her chart. Her blood pressure was 180 mmHg with a heart rate of 120 beats/min, and a respiratory rate of 50 breaths/min. The following day, she barely spoke and could not be aroused; additional symptoms included lethargy, extremity twitching and jerking, eyes rolled back in her head, and labored breathing. Linezolid was discontinued, and she was sedated and intubated. Five days following onset of symptoms and 2 days after linezolid was stopped, she was extubated and had returned to baseline mental status with the ability to communicate .

D) In one case report, a 67-year-old man experienced symptoms of serotonin syndrome after concomitant treatment with linezolid and mirtazapine. He was admitted with a history of multiple medical conditions and was stable on existing medications, including linezolid 600 mg twice daily. He was started on mirtazapine, 15 mg/day for increasing depression. His dose was increased a week later to 30 mg/day. Due to excessive sedation, the dose was reduced to 15 mg/day. Gabapentin 300 mg at bedtime was introduced for phantom limb pain. Two weeks into the treatment with gabapentin, the patient became confused and experienced hallucinations. Gabapentin was discontinued and the delirium subsided. No other symptoms indicative of serotonin syndrome were present. Aware of the possible drug interaction between mirtazapine and linezolid, both medications were continued. Three days later, the patient's delirium returned and was resolved when the patient discontinued the mirtazapine. Due to increased depression, the patient then reinstated the mirtazapine without any reoccurring symptoms. Lorazepam was introduced for anxiety and the mirtazapine was discontinued. The patient's depression regressed, requiring hospitalization. He was rechallenged with mirtazapine, 15 mg/day without any evidence of serotonin syndrome. Throughout this time frame, the patient remained on 600 mg twice daily of linezolid .

E) Serotonin syndrome was reported in the case of an 56-year-old woman who was admitted for an allogeneic stem cell transplant. Prior to the transplant, the patient received fludarabine, melphalan, and antithymocyte globulin. She had a medical history of cystic fibrosis, asthma, fungal sinusitis, and depression. Ten days following transplantation, the patient required mechanical ventilation for increasing respiratory distress and was treated empirically with intravenous vancomycin 1 g every 24 hours, IV ceftazidime 2 g every 8 hours, IV acyclovir 300 mg every 8 hours, and oral voriconazole 200 mg twice daily for febrile neutropenia and aspiration pneumonia. Urine culture grew vancomycin-resistant Enterococcus susceptible to linezolid, so vancomycin was discontinued and linezolid 600 mg every 12 hours was initiated. The patient was prescribed oral mirtazapine 30 mg and oral citalopram 40 mg daily along with other medications. After 4 days of concomitant therapy with linezolid, mirtazapine, and citalopram, the patient developed hypertension (160 to 170 mmHg/80 to 100 mmHg), tachycardia (130 to 140 bpm), and fever (100.2 degrees F). She became confused, distressed, lethargic, shaky, and weak. Her diagnostic lab values were lactic dehydrogenase (2931 units/L), aspartate aminotransferase (52 units/mL), troponin I (0.18 nanogram/mL), alkaline phosphatase (160 units/L), total bilirubin (2.8 mg/dL), and creatine kinase-myocardial band (8.9 mcg/L). Final blood culture results reported were negative and linezolid was discontinued. The patient's symptoms diminished within two days of linezolid being discontinued.

Mirtazapine Overview

• Mirtazapine is used to treat depression. Mirtazapine is in a class of medications called antidepressants. It works by increasing certain types of activity in the brain to maintain mental balance.

Linezolid Overview

• Linezolid is used to treat infections, including pneumonia, and infections of the skin . Linezolid is in a class of antibacterials called oxazolidinones. It works by stopping the growth of bacteria.

• Antibiotics such as linezolid will not work for colds, flu, and other viral infections. Using antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.