Brompheniramine and Linezolid Injection: Interaction Details

a) In a review of post-marketing data, 1 case of serotonin toxicity was reported in the concurrent use of dextromethorphan and linezolid. A review was conducted of post-marketing 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, akathesia, rigors, twitching, and muscle rigidity. Intervention including hospitalization was required in 13 patients, and 3 deaths were reported with concurrent SSRI use ⁵.

b) 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 ².

c) Spontaneous reports of serotonin syndrome including fatal cases associated with the coadministration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported ¹⁶. Symptoms of serotonin syndrome are 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 ³.

d) A case report described serotonin syndrome in a 36-year-old woman following the concomitant use of linezolid and lithium. The patient, who had no history of seizures and whose regimen included lithium, venlafaxine, and imipramine for bipolar disorder, depression, and headaches, respectively, presented to the emergency room (ER) with seizures. Ten days prior to presenting to the ER, the patient received vancomycin for treatment of MRSA empyema. However, therapy was switched to linezolid approximately 36 hours before her ER visit. At presentation, she had a blood pressure (BP) of 234/196 mmHg, a heart rate of 160 beats/min, respiratory rate of 24 breaths/min, and diaphoresis. Her pupils were dilatated with slow reaction to light and she was unresponsive to verbal instructions. The patient was intubated and administered multiple doses of LORazepam, which lessened her tremors and decreased BP to 150/85 mmHg. Her serum lithium level was 1.2 mEq/L and there were no electrolyte abnormalities. Within 3 hours of intubation, mental status and breathing pattern normalized and the patient was extubated. While both imipramine and venlafaxine were withheld, lithium was continued and linezolid was replaced with trimethoprim and sulfamethoxazole. The patient remained alert and oriented over the following days and had reduced anxiety. Three weeks following discharge, the patient reported tremors and anxiety after reinstituting venlafaxine and imipramine. It was postulated that her 3 chronic serotonergic medications led to a baseline hyperserotonergic state, which was acutely aggravated by the addition of linezolid ⁴.