Drug Interactions between Akynzeo and oliceridine

MONITOR CLOSELY: Concomitant use of 5-HT3 receptor antagonists with agents that possess or enhance serotonergic activity such as antidepressants and lithium 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. According to the manufacturers, development of serotonin syndrome has been reported with 5-HT3 receptor antagonists, primarily during concomitant use of serotonergic drugs but also in overdose. Some of the reported cases were fatal. 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.

MONITOR CLOSELY: Treatment with 5-HT3 receptor antagonists has been associated with dose-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval including certain antidepressants and lithium may result in additive effects and increased risk of ventricular arrhythmias such as torsade de pointes and sudden death. Cases of torsade de pointes have been specifically reported with dolasetron and ondansetron during postmarketing use. It is uncertain whether palonosetron also causes significant prolongation of the QT interval. A thorough QT/QTc study in healthy volunteers demonstrated no relevant effect on QT/QTc interval duration or any other ECG interval at doses up to 2.25 mg. However, non-clinical studies have shown that palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarization and to prolong action potential duration. 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). Also, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is advised if 5-HT3 receptor antagonists are prescribed with other agents that affect the serotonergic neurotransmitter system. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is warranted when initiating or increasing the dosages of these agents. In addition, the potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures. Due to the potential for additive effects on the QT interval, ECG monitoring may also be appropriate when 5-HT3 receptor antagonists are used with certain antidepressants or lithium. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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MONITOR CLOSELY: Coadministration with moderate or potent inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations and adverse opioid effects of oliceridine, which is primarily metabolized by both isoenzymes in vitro. In addition, oliceridine concentrations may decrease following discontinuation of a concomitant moderate or potent CYP450 2D6 or 3A4 inhibitor, possibly resulting in decreased opioid efficacy or withdrawal syndrome. The effect of a CYP450 2D6 inhibitor on the pharmacokinetics of oliceridine has not been studied. However, it may be similar to that reported in CYP450 2D6 poor metabolizers, whose plasma clearance of oliceridine is reduced by approximately 50% compared to those who are nonpoor CYP450 2D6 metabolizers. The clearance may be further reduced with the addition of a CYP450 3A4 inhibitor. When a single 0.25 mg dose of oliceridine was given to poor metabolizers of CYP450 2D6 following pretreatment with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily for 5 days), oliceridine systemic exposure (AUC) increased by approximately 80% while peak plasma concentration (Cmax) was not significantly affected. Furthermore, mean oliceridine clearance decreased to approximately 30% of that observed in nonpoor metabolizers of CYP450 2D6. The interaction has not been studied with other, less potent CYP450 3A4 inhibitors.

MANAGEMENT: Caution is recommended if oliceridine is used in combination with moderate or potent inhibitors of CYP450 2D6 or 3A4. If concomitant use is considered necessary, patients may require less frequent dosing of oliceridine and should be closely monitored for respiratory depression, sedation, and QT prolongation. If a moderate or potent CYP450 2D6 or 3A4 inhibitor is discontinued, an increase of the oliceridine dosage may be considered while monitoring for signs of opioid withdrawal until stable drug effects are achieved. Due to the prolonged duration of CYP450 2D6 inhibition by the moderate CYP450 2D6 inhibitor rolapitant, prolonged monitoring for adverse effects of oliceridine for at least 28 days after administration of rolapitant may be required.

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