Drug Interactions between Ceron-DM Drops 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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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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GENERALLY AVOID: Coadministration of monoamine oxidase inhibitors (MAOIs) and antihistamines may result in additive central nervous system depressant effects. In addition, limited data suggest that MAOIs may potentiate and prolong the anticholinergic effects of antihistamines due to inhibition of catecholamine degradation, which may lead to overstimulation of the sympathetic nervous system. In one published report, a woman who had been on phenelzine 30 mg/day for six months developed irritability and visual hallucinations two months following the addition of cyproheptadine 2 mg at bedtime to treat phenelzine-induced anorgasmia. The hallucinations cleared over 48 hours following the discontinuation of her medications. In another published report, a patient developed delirium with symptoms of aggression, paranoia, and vivid auditory as well as visual hallucinations after two days of receiving diphenhydramine 300 mg/day and linezolid 600 mg every 12 hours. The patient also had tachycardia, very warm skin, and possibly blurred vision (as evidenced by constant squinting). Central anticholinergic intoxication and dopaminergic hyperactivity were suspected. Symptoms subsided over four days following the discontinuation of diphenhydramine, while linezolid was continued with no subsequent sequelae. In a third report, a patient developed visual hallucinations associated with confusion and disorientation after nine days of linezolid and antihistamine therapy, including dexchlorpheniramine and cetirizine for the first four days and hydroxyzine for the next five. Physical examination did not reveal any focal neurological signs, myoclonus or ataxia, and cerebral CT scan and EEG were within normal limits. Symptoms resolved two days after linezolid was discontinued.

MANAGEMENT: Prescribing antihistamines in combination with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, linezolid, procarbazine) should generally be avoided. If concomitant treatment is unavoidable, 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. It may be appropriate to monitor some patients for increased anticholinergic effects (e.g., constipation, urinary retention, fever, heat intolerance, blurred vision, confusion, hallucinations, dizziness, palpitations, arrhythmias, syncope), since certain populations such as the elderly and those with underlying organic brain disease tend to be more sensitive to these effects and may be susceptible to anticholinergic intoxication. It should be noted that the manufacturers of many of the sedating antihistamines (e.g., chlorpheniramine, dexchlorpheniramine, diphenhydramine, pheniramine, promethazine) consider their use within 14 days of MAOIs to be contraindicated.

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