Drug Interactions between acetaminophen / dextromethorphan / doxylamine / pseudoephedrine and Zyvox

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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CONTRAINDICATED: Linezolid may potentiate the pressor response to sympathomimetic agents. Linezolid is a reversible, nonselective monoamine oxidase inhibitor (MAOI) and, as such, may enhance sympathomimetic effect by increasing norepinephrine storage in adrenergic neurons. The interaction may be more likely to occur with indirect- or mixed-acting sympathomimetics such as pseudoephedrine or ephedrine than with direct-acting agents like epinephrine, norepinephrine, and isoproterenol. In healthy normotensive subjects, coadministration of linezolid (600 mg every 12 hours for 3 days) and two doses of pseudoephedrine (60 mg each) or phenylpropanolamine (25 mg each) given 4 hours apart resulted in a mean maximum increase in systolic blood pressure of 32 mmHg and 38 mmHg, respectively, compared to baseline. The mean maximum systolic blood pressure during coadministration was also significantly increased compared to either agent alone. Heart rate was not affected. Maximum blood pressure levels were seen 2 to 3 hours after the second dose of phenylpropanolamine or pseudoephedrine, and returned to baseline 2 to 3 hours after peak.

MANAGEMENT: Unless blood pressure and clinical status can be closely monitored, linezolid should not be administered in combination with direct- or indirect-acting sympathomimetic agents (e.g., pseudoephedrine, phenylpropanolamine), vasopressive agents (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine). If the combination is used, lower initial dosages of adrenergic agents such as dopamine or epinephrine are recommended, with careful titration to the desired response.

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CONTRAINDICATED: Monoamine oxidase inhibitors (MAOIs) may prolong or intensify the anticholinergic and CNS-depressant effects of doxylamine. In addition, concomitant use may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, 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.

MANAGEMENT: The use of doxylamine in combination with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, linezolid, methylene blue, procarbazine) is considered contraindicated. At least 14 days should elapse between discontinuation of MAOI therapy and initiation of treatment with doxylamine.

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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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