Drug Interactions between linezolid and meperidine / promethazine

CONTRAINDICATED: Coadministration of linezolid with serotonergic agents 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. Linezolid is a reversible, nonselective monoamine oxidase inhibitor (MAOI). As such, it can enhance serotonergic effects by inhibiting serotonin metabolism. Rare cases of serotonin syndrome have been reported in association with linezolid use, most often in combination with serotonin reuptake inhibitors. 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: Concomitant use of linezolid and serotonergic agents should be avoided unless no alternatives exist and close monitoring for the development of serotonin syndrome can be provided. In general, most serotonergic psychiatric drugs should be stopped 1 to 2 weeks (i.e., 4 to 5 half-lives) prior to treatment with an MAOI, while others such as fluoxetine may require discontinuation up to 5 weeks in advance due to its prolonged half-life. Treatment with serotonergic medications may be resumed 24 hours after the last dose of linezolid. In emergency situations that may necessitate urgent treatment with linezolid (e.g., vancomycin-resistant Enterococcus faecium (VRE) infections; nosocomial pneumonia and complicated skin and skin structure infections, including cases caused by methicillin-resistant Staphylococcus aureus), the availability of alternative interventions should be considered and the benefit of linezolid treatment should be weighed against the risk of serotonin toxicity. If the decision is made to administer linezolid to a patient receiving a serotonergic drug, the serotonergic drug must be immediately stopped, and the patient closely monitored for emergent symptoms of CNS toxicity for two weeks (five weeks if fluoxetine was taken; three weeks if vortioxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Patients and/or their caregivers should be advised to seek medical attention if potential symptoms of serotonin syndrome develop.

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ADJUST DOSE: The central nervous system and respiratory depressant effects of meperidine may be potentiated by concomitant use of other agents with CNS depressant effects. An increased risk of serious adverse reactions such as respiratory depression, hypotension, profound sedation, syncope, coma, and even death should be considered, particularly in elderly or debilitated patients.

MANAGEMENT: Caution and dosage adjustments are advisable when meperidine is used in combination with other narcotic analgesics, general anesthetics, phenothiazines, sedative-hypnotics, tranquilizers, tricyclic antidepressants, or other CNS depressants such as alcohol. A lower dosage of meperidine should be considered initially, then titrated carefully according to pain level and clinical response. Meperidine dosage reductions of 25% to 50% have been recommended for patients receiving phenothiazines and other tranquilizers. Patients should be advised to avoid rising abruptly from a sitting or recumbent position, and to notify their physician if they experience dizziness, lightheadedness, orthostasis, syncope, tachycardia, or excessive CNS effects that interfere with their normal activities. Patients should also avoid driving or operating hazardous machinery until they know how these medications affect them.

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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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