Drug Interactions between meperidine / promethazine and Pavagen

MONITOR CLOSELY: QT interval prolongation and torsade de pointes (TdP) arrhythmia have been associated with intracoronary administration, but not reported following systemic or intracavernosal administration of papaverine. The risk may theoretically increase in patients receiving concomitant medications associated with prolongation of the QT interval. The precise mechanism of papaverine-induced ventricular tachyarrhythmias has not been delineated, but may involve inhibition of potassium currents and prolongation of the action potential duration. The incidence of ventricular tachyarrhythmias has been reported to range between <0.67% and 8.8% following intracoronary administration of papaverine at doses of 6 mg to 20 mg. Female gender, hypokalemia, alkalosis, bradycardia, administration of papaverine into the left coronary artery, and a prior history of drug-induced QT prolongation may be risk factors for papaverine-induced fatal ventricular tachyarrhythmias. Apart from isolated case reports, there are no published data regarding the potential interaction between intracoronary papaverine and its use with other QT-prolonging drugs. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be affected by the drug and dose of that drug, as well as underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia).

MONITOR CLOSELY: Certain phenothiazines, tricyclic antidepressants (TCAs), and antipsychotic (neuroleptic) agents may potentiate the blood pressure lowering capabilities of papaverine due to their peripheral alpha-1 adrenergic blocking activity. Orthostatic hypotension and syncope associated with vasodilation may occur, particularly during initial dosing and/or parenteral administration of the phenothiazine, TCA, or neuroleptic. The severity of this interaction may be affected by the agent's affinity for the alpha-1 adrenoceptor. One in vitro study demonstrated an affinity for the alpha-1 adrenoceptor for some of these medications that was similar to, or greater than, those of alpha blocker medications used to treat hypertension. Examples of drugs evaluated in this study with a high affinity included amitriptyline, clomipramine, chlorpromazine, clozapine, doxepin, flupenthixol, nortriptyline, paliperidone, quetiapine, risperidone, sertindole, and ziprasidone. On the other hand, examples of those with lower affinities included amisulpride, aripiprazole, lofepramine, protriptyline, and sulpiride.

MANAGEMENT: Caution and close clinical monitoring are advised if papaverine is given with certain phenothiazines, TCAs, and/or antipsychotic (neuroleptic) agents. If papaverine is administered via the intracoronary route, additional monitoring of the QT interval is recommended, particularly in patients with other risk factors (described above). All patients should be closely monitored for the development of hypotension, as this adverse effect is possible regardless of how papaverine is administered. A lower starting dosage and slower titration of the phenothiazine, TCA, or antipsychotic may be appropriate, especially in the elderly. It may also be advisable to use a phenothiazine, TCA, or neuroleptic with a lower affinity for the alpha-1 adrenoceptor when possible. Patients should be counseled to avoid rising abruptly from a sitting or recumbent position and to notify their healthcare provider if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. 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.

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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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