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Netupitant and Palonosetron

Class: Antiemetics, Miscellaneous
Chemical Name: 2 - [3,5 - bis(trifluoromethyl)phenyl] - N,2 - dimethyl - N - [4 - (2 - methylphenyl) - 6 - (4 - methylpiperazin - 1 - yl)pyridin - 3 - yl]propanamide
Molecular Formula: C30H32F6N4OC19H24N2O
CAS Number: 290297-26-6
Brands: Akynzeo

Introduction

The fixed combination of netupitant, a neurokinin-1 (NK1) receptor antagonist, and palonosetron, a serotonin-3 (5-HT3) receptor antagonist, is an antiemetic.1

Uses for Netupitant and Palonosetron

Netupitant and palonosetron has the following uses:

Netupitant and palonosetron is a fixed combination of netupitant, a substance P/neurokinin 1 (NK1) receptor antagonist, and palonosetron, a serotonin-3 (5-HT3) receptor antagonist indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Oral palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.1

Netupitant and Palonosetron Dosage and Administration

General

The fixed combination of netupitant and palonosetron is available in the following dosage form(s) and strength(s):

Capsules: 300 mg netupitant/0.5 mg palonosetron.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

One capsule containing 300 mg netupitant/0.5 mg palonosetron administered approximately 1 hour prior to the start of chemotherapy.1

Netupitant and palonosetron can be taken with or without food.1

Cautions for Netupitant and Palonosetron

Contraindications

None.1

Warnings/Precautions

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT3 receptor antagonists. 1

Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors [SSRIs], serotonin and norepinephrine reuptake inhibitors [SNRIs], monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center. 1

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of netupitant and palonosetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue netupitant and palonosetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if netupitant and palonosetron is used concomitantly with other serotonergic drugs.1

Specific Populations

Pregnancy

Pregnancy Category C. 1

Adequate and well-controlled studies with netupitant and palonosetron have not been conducted in pregnant women. Netupitant and palonosetron should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 1

Daily administration of up to 30 mg/kg netupitant in rats (3.7 times the human AUC at the recommended single human dose to be given with each cycle of chemotherapy) during the period of organogenesis produced no effects on embryo-fetal development. However, an increased incidence of external and skeletal abnormalities in rabbit fetuses was observed following daily administration of netupitant in rabbits at 10 mg/kg/day and higher (0.2 times the human AUC at the recommended single human dose to be given with each cycle of chemotherapy) during the period of organogenesis. These abnormalities included positional abnormalities in the limbs and paws, and fused sternebrae. Reduction in fetal rabbit weight occurred at 30 mg/kg/day. Maternal toxicity in rabbits (i.e., loss of bodyweight during the treatment period) was also observed at 30 mg/kg/day. Daily administration of up to 30 mg/kg netupitant (3.7 times the human AUC at the recommended human dose) in rats during organogenesis through lactation produced no adverse effects in the offspring. 1 In animal reproduction studies with palonosetron, no effects on embryo-fetal development were observed in pregnant rats given oral doses up to 60 mg/kg/day (921 times the recommended human oral dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (1841 times the recommended human oral dose based on body surface area) during the period of organogenesis.1

Nursing Mothers

It is not known whether netupitant and palonosetron is present in human milk. Because many drugs are present in human milk and because of the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.1

Pediatric Use

Safety and effectiveness in patients below the age of 18 years have not been established.1

Geriatric Use

Of the 1169 adult cancer patients treated with netupitant and palonosetron in clinical studies, 18% were aged 65 and over, while 2% were aged 75 years and over. The nature and frequency of adverse reactions were similar in elderly and younger patients. Exploratory analyses of the impact of age on efficacy were performed in the two trials that compared netupitant and palonosetron to palonosetron. In Study 1 in patients treated with cisplatin chemotherapy, among the patients less than age 65 years, 115 were treated with netupitant and palonosetron and 116 were treated with palonosetron alone. Among the patients 65 years or older, 20 were treated with netupitant and palonosetron and 20 were treated with palonosetron alone. The difference in Complete Response (CR) rates between netupitant and palonosetron and palonosetron alone was similar between the two age groups in both the acute and delayed phases. In Study 2 in patients treated with anthracyclines plus cyclophosphamide chemotherapy, among the patients less than age 65 years, 608 were treated with netupitant and palonosetron and 602 were treated with palonosetron alone. Among the patients 65 years or older, 116 were treated with netupitant and palonosetron and 123 were treated with palonosetron alone. The difference in CR rates between netupitant and palonosetron and palonosetron alone (4% in <65 years and 2% in >65 years) was similar between the two age groups in the acute phase. In the delayed phase, the difference in CR rates between netupitant and palonosetron and palonosetron alone (9% in <65 years and 1% in ≥ 65 years) was numerically higher in patients <65 years. This difference between age groups in the delayed phase of Study 2 may be explained, in part, by higher CR in the delayed phase associated with palonosetron alone in the older age group (81%) relative to the younger patients treated with palonosetron alone (67%).1

In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy.1

Hepatic Impairment

No dosage adjustment for netupitant and palonosetron is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 8). Limited data are available with netupitant and palonosetron in patients with severe hepatic impairment (Child-Pugh score >9). Avoid use of netupitant and palonosetron in patients with severe hepatic impairment.1

Renal Impairment

No dosage adjustment for netupitant and palonosetron is necessary in patients with mild to moderate renal impairment. The pharmacokinetics and safety of netupitant has not been studied in patients with severe renal impairment, although severe renal impairment did not substantially affect pharmacokinetics of palonosetron. The pharmacokinetics for netupitant and palonosetron was not studied in patients with end-stage renal disease requiring hemodialysis. Avoid use of netupitant and palonosetron in patients with severe renal impairment or end-stage renal disease.1

Common Adverse Effects

Most common adverse reactions (incidence ≥3% and greater than palonosetron) are headache, asthenia, dyspepsia, fatigue, constipation, and erythema. 1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • CYP3A4 Substrates: inhibition of CYP3A4 by netupitant can result in increased plasma concentrations of the concomitant drug that can last at least 4 days and may last longer after single dosage administration of netupitant and palonosetron; use with caution.1

  • CYP3A4 Inducers (e.g., rifampin): decreased plasma concentrations of netupitant; avoid use.1

Actions

Mechanism of Action

Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors. 1

Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. Chemotherapeutic agents produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. The development of acute emesis is known to depend on serotonin and its 5-HT3 receptors have been demonstrated to selectively stimulate the emetic response. 1

Delayed emesis has been largely associated with the activation of tachykinin family neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses. 1

Advice to Patients

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (Patient Information).1

Administration

Advise patients to take netupitant and palonosetron with or without food approximately 1 hour prior to the start of chemotherapy.1

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron. Advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur while taking netupitant and palonosetron.1

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome especially with concomitant use of netupitant and palonosetron and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms, with or without gastrointestinal symptoms. 1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Netupitant and Palonosetron

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsule

300 mg netupitant, 0.5 mg palonosetron

Akynzeo

Eisai Inc.

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: September 16, 2016
Last reviewed: September 16, 2016
Date modified: October 12, 2016

References

1. Eisai Inc. AKYNZEO (Netupitant and Palonosetron) ORAL prescribing information. 2015 Dec.

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