Drug Interactions between dextromethorphan / promethazine and linezolid

CONTRAINDICATED: Coadministration of dextromethorphan with linezolid may increase the risk of serotonin syndrome, a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Dextromethorphan is a weak serotonin reuptake inhibitor whose serotonergic activity may be enhanced by monoamine oxidase inhibitors (MAOIs). Serious and fatal reactions have been reported, primarily with the antidepressant MAOIs. The risk should be lower with linezolid, a relatively weak, reversible MAOI. When linezolid (600 mg orally every 12 hours for 6 days) and dextromethorphan (20 mg orally twice, 4 hours apart, on days 4 and 6 of linezolid administration) were given to 14 healthy volunteers, no changes in mental status (sedation, performance testing) or autonomic function (blood pressure, heart rate, body temperature) were observed relative to administration of either linezolid or dextromethorphan alone. The conversion of dextromethorphan to its primary metabolite was reduced by linezolid, as evidenced by an approximately 30% decrease in dextrorphan peak plasma concentration (Cmax) and systemic exposure (AUC) during coadministration, but clinical significance is unknown. The investigators concluded that linezolid may be prescribed with dextromethorphan without restrictions. There have been no published reports of serotonin syndrome with the concomitant use of dextromethorphan and linezolid, although known cases have been associated individually with each during coadministration with other serotonergic agents. The British labeling for linezolid describes a postmarketing report of a patient experiencing serotonin syndrome-like effects during concurrent use of dextromethorphan that resolved upon discontinuation of both drugs.

MANAGEMENT: Due to the risk of serotonin syndrome, concomitant use of dextromethorphan with MAOIs is considered contraindicated by manufacturers of dextromethorphan-containing products. If coadministration with linezolid is required, patients should be monitored for the development of serotonin syndrome. Symptoms may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: Coadministration of monoamine oxidase inhibitors (MAOIs) and phenothiazines may result in additive hypotensive effects and central nervous system effects such as dizziness, drowsiness, confusion, disorientation, memory loss, and seizures. MAOIs alone quite commonly produce orthostatic hypotension. This effect may stem from a gradual MAOI-induced accumulation of false neurotransmitters in peripheral adrenergic neurons that have minimal activity at alpha- and beta-adrenergic receptors, resulting in a functional block of sympathetic neurotransmission. Phenothiazines can also cause hypotension (including orthostatic hypotension), reflex tachycardia, increased pulse rate, syncope, and dizziness, particularly during initiation of treatment with parenteral doses. Low-potency agents such as chlorpromazine and thioridazine are more likely to induce these effects, which usually subside within the first couple of hours following administration. Tolerance to the hypotensive effects often develops after a few doses.

MONITOR: An increased incidence of extrapyramidal effects has been reported when some MAOIs and phenothiazines are used concomitantly. Data are limited, and the mechanism of interaction has not been established. There have also been rare reports of suspected neuroleptic malignant syndrome (NMS) in patients treated with irreversible, nonselective MAOIs and certain phenothiazines, although the role of MAOIs is uncertain. Since NMS is thought to be triggered by a sudden decrease of activity at central dopamine receptors, neuroleptics such as phenothiazines alone can cause the syndrome. In one report, a 70-year-old female inpatient of a psychiatric ward developed dyspnea, tachycardia, diffuse muscular rigidity, pyrexia, hypotension, cyanosis, hyperreflexia, coma, and a grand mal seizure while being treated with isocarboxazid and chlorpromazine. Laboratory findings included a mild neutrophil leucocytosis and elevated serum potassium and creatine phosphokinase. The patient improved within 24 hours after discontinuation of psychotropic medications and initiation of supportive measures and anticonvulsants, but she subsequently died from acute renal failure secondary to rhabdomyolysis. Another patient developed symptoms of NMS one week after initiating treatment with a tranylcypromine-trifluoperazine combination, immediately after the dose was doubled. The case was complicated by rhabdomyolysis and disseminated intravascular coagulation, but was treated successfully with dantrolene sodium and generous fluid therapy. In other reports, rare cases of fatal hyperthermia occurred during treatment with methotrimeprazine and pargyline or tranylcypromine. Again, the relationship to MAOIs is unknown, since phenothiazines alone have been associated with hyperpyrexia.

MANAGEMENT: Although often safe and effective, caution is advised during coadministration of MAOIs and phenothiazines, especially during the first few weeks of treatment. Close monitoring for development of hypotension is recommended. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Ambulatory patients should also be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities. Alcohol should be avoided, since it may increase hypotensive and CNS effects.

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