Drug Interactions between amitriptyline / perphenazine and ozanimod

GENERALLY AVOID: Due to the risk of bradycardia and atrioventricular (AV) block, the risk of QT prolongation and torsade de pointes arrhythmia may be increased during initiation of ozanimod treatment in patients receiving drugs that prolong the QT interval. Ozanimod can cause a decrease in heart rate during initiation of therapy, in two studies, following an initial dose of 0.23 mg, the greatest mean decrease from baseline in heart rate of 1.2 bpm occurred at hour 5 on day 1 and returned to near baseline at hour 6. Following continued up-titration, the maximal heart rate effect of ozanimod occurred on day 8. Heart rates below 40 bpm were not observed. Initiation of ozanimod without dose titration may result in greater decreases in heart rate. Initiation of ozanimod treatment has also resulted in transient AV conduction delays. Reportedly, with the administration of ozanimod at doses higher than the recommended dosage and without dose titration, first- and second-degree AV block occurred in healthy subjects. However, in two studies which utilized dose titration, second- or third-degree AV block was not reported in patients receiving ozanimod. 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 increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Ozanimod has not been studied in patients receiving drugs that can prolong the QT interval. Because bradycardia and AV block are recognized risk factors for QT prolongation and torsade de pointes arrhythmia, treatment with ozanimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties. Advice from a cardiologist should be sought if treatment with ozanimod is considered in patients with significant QT prolongation (QTcF greater than 450 msec in males or 470 msec in females), patients on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes or drugs that slow heart rate or AV conduction, or in patients with arrhythmias requiring treatment with Class 1a or Class III antiarrhythmic agents.

MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic 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.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, 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 (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

GENERALLY AVOID: Coadministration of adrenergic agents with drugs that possess monoamine oxidase inhibition (MAOI) activity may precipitate severe hypertensive reactions and hyperpyrexia. Death has occurred in some reported cases. Although the interaction has primarily involved nonselective MAOIs, hypertensive crisis has been reported with selective MAO-B inhibitors. Because an active metabolite of ozanimod inhibits MAO-B in vitro, the interaction may theoretically occur with ozanimod. In a placebo-controlled crossover study involving healthy subjects, coadministration of ozanimod with pseudoephedrine did not potentiate the effects on blood pressure; however, ozanimod did increase the pseudoephedrine-induced heart rate response by approximately 3 beats per minute (bpm). In two clinical studies, ozanimod increased systolic pressure by an average of 1 to 2 mmHg over interferon beta-1a, but had no effect on diastolic pressure. The increase in systolic pressure was first detected after approximately 3 months of treatment and persisted throughout treatment. Hypertension was reported as an adverse reaction in 3.9% of patients treated with ozanimod 0.92 mg, compared to 2.1% of patients treated with interferon beta-1a. Two patients treated with ozanimod and one patient treated with interferon beta-1a in these studies experienced a hypertensive crisis.

GENERALLY AVOID: Coadministration of serotonergic agents with drugs that possess monoamine oxidase inhibition (MAOI) activity 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. Symptoms of the serotonin syndrome 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. Because an active metabolite of ozanimod inhibits MAO-B in vitro, the interaction may theoretically occur with ozanimod. In clinical trials, a small number of patients treated with ozanimod were concomitantly exposed to serotonergic medications; however, this exposure was not adequate to rule out the possibility of an adverse reaction from coadministration.

MANAGEMENT: Until more information is available, concomitant use of ozanimod with agents that possess adrenergic and serotonergic effects should be avoided when possible. Blood pressure and other vitals should be monitored if coadministration is required.