Drug Interactions between isocarboxazid and Meprozine

CONTRAINDICATED: Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe and fatal adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases. The exact mechanism of interaction is unknown, but may involve excessive serotonergic activity in the central nervous system (i.e., serotonin syndrome). The interaction is unpredictable and has been reported primarily with meperidine or fentanyl and various MAOIs including phenelzine, tranylcypromine, linezolid, moclobemide, and selegiline. Fatal hyperpyrexia and hypertension have also been observed in animal studies with meperidine and phenelzine or furazolidone. In contrast, symptoms of the depressive reaction probably stem from potentiation of CNS effects by MAOIs and include respiratory depression, cyanosis, hypotension, and coma.

MANAGEMENT: Meperidine and fentanyl should not be used with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, linezolid, methylene blue, procarbazine). Some manufacturers of MAOIs also contraindicate the concomitant use of propoxyphene and methadone due to their possible serotonergic effects. At least 14 days should elapse between discontinuation of MAOI therapy and initiation of treatment with these opioids. Although morphine may also have significant CNS interactions with MAOIs, it is generally considered a safer alternative in patients treated with MAOIs who require a narcotic analgesic. A sensitivity test should be performed in which repeated, small, incremental doses of morphine are administered over the course of several hours while overall clinical status and vital signs are carefully monitored.

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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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