Drug Interactions between netupitant / palonosetron and Remeron SolTab

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: Coadministration of mirtazapine with drugs that inhibit one or more of its metabolic pathways may result in increased plasma concentrations of mirtazapine. In vitro data from human liver microsomes indicate that CYP450 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite, while CYP450 3A4 is primarily responsible for the formation of the N-desmethyl and N-oxide metabolites. When cimetidine, a weak inhibitor of CYP450 1A2, 2D6 and 3A4, was given at 800 mg twice daily for 14 days to twelve healthy male subjects in combination with mirtazapine 30 mg once daily on days 6 to 12, mean steady-state mirtazapine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 22% and 54%, respectively. Mirtazapine had no effect on the pharmacokinetics of cimetidine. In another study with 24 healthy male Caucasian subjects, administration of the potent CYP450 3A4 inhibitor ketoconazole at 200 mg twice daily for 6.5 days increased Cmax and AUC of a single 30 mg dose of mirtazapine by approximately 40% and 50%, respectively. A case report described increases in serum mirtazapine concentrations of three- to fourfold in two patients following the addition of fluvoxamine, a potent CYP450 1A2 and weak CYP450 2D6/3A4 inhibitor. One patient reported feeling more anxious with the combination.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of mirtazapine should be considered during coadministration of drugs that inhibit CYP450 1A2, 2D6 and/or 3A4. Therapeutic response to mirtazapine should be monitored more closely following initiation, discontinuation, or dosing change of CYP450 inhibitors, and the mirtazapine dosage adjusted as necessary. A prolonged duration of monitoring for adverse effects may be required depending on the elimination half-life of the concomitant drug. For example, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, can increase plasma concentrations and the risk of adverse effects of mirtazapine for at least 28 days after administration of rolapitant.

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