Drug Interactions between linezolid and Omnihist II LA

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: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A reduction in anticholinergic dosages may be necessary if excessive adverse effects develop.

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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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MONITOR: The pressor response to phenylephrine may be potentiated by the vagolytic effect of atropine, which inhibits the reflex bradycardia that would normally accompany any increases in blood pressure induced by phenylephrine. Other antimuscarinic agents may also participate in this interaction, although clinical data are lacking. In one report, pseudo-pheochromocytoma (i.e., significant increases in blood pressure and tachycardia) occurred in seven patients who underwent eye surgery and were given phenylephrine 10% ophthalmic solution and systemic atropine, three of whom subsequently developed left ventricular failure and pulmonary edema that required intensive care monitoring. Two patients had preexisting hypertension, while others had no known history of cardiovascular disease. All had received general anesthesia with propofol, phenoperidine, and vecuronium. Since phenylephrine use alone may be associated with cardiovascular toxicities including hypertension, arrhythmia, myocardial infarction and cardiac failure, the extent of involvement by atropine is uncertain. The authors reported no further cardiovascular events following implementation of various measures that reduced phenylephrine dosage and systemic exposure, including: use of a milder strength of phenylephrine ophthalmic solution; swabbing to minimize drainage into the nasolachrymal duct to the nasal mucosa; and use of a cannula to reduce drop size. In a study of six healthy volunteers, diastolic and systolic blood pressure increased by 4 mmHg following administration of phenylephrine (0.42 mcg/kg/min), compared to 17 mmHg when phenylephrine was given after three doses of atropine (0.02, 0.01 and 0.01 mg/kg at 30 minute intervals).

MANAGEMENT: Caution is advised if phenylephrine (systemic or ophthalmic) is used in combination with atropine or other antimuscarinic agents. Cardiovascular status, including blood pressure and heart rate, should be closely monitored. When using ophthalmic formulations, measures to minimize systemic absorption should be employed, such as digital compression of the lacrimal sac or lid closure after instillation. A milder strength (< 10%) is preferable if phenylephrine ophthalmic solution is given.

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