Netupitant/Palonosetron (Monograph)

Drug class: 5-HT3 Receptor Antagonists
ATC class: A04AA55
VA class: GA605
Chemical name: N,α,α-Trimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3,5-bis(trifluoromethyl)-benzeneacetamide
Molecular formula: C₃₀H₃₂F₆N₄OC₁₉H₂₄N₂O•HCl
CAS number: 290297-26-6

Netupitant and Palonosetron Hydrochloride is also contained as an ingredient in the following combinations:
Netupitant and Palonosetron Hydrochloride

Medically reviewed by Drugs.com on Feb 23, 2024. Written by ASHP.

Introduction

Antiemetic; fixed combination containing netupitant (a highly selective antagonist at substance P/neurokinin-1 [NK₁] receptors) and palonosetron (a selective, second-generation inhibitor of type 3 serotonergic [5-HT₃] receptors).

Uses for Netupitant/Palonosetron

Cancer Chemotherapy-induced Nausea and Vomiting

Used in fixed combination for 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. Should be used in combination with dexamethasone.

Palonosetron prevents nausea and vomiting during the acute phase after chemotherapy; netupitant prevents nausea and vomiting during both the acute and delayed phase after chemotherapy.

For prevention of nausea and vomiting associated with highly emetogenic chemotherapy regimens (including an anthracycline plus cyclophosphamide), ASCO recommends a 3-drug antiemetic regimen consisting of an NK₁ receptor antagonist (e.g., either oral aprepitant or IV fosaprepitant), a 5-HT₃ receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron), and dexamethasone. ASCO states that fixed-combination netupitant and palonosetron plus dexamethasone is an additional treatment option.

For moderately emetogenic chemotherapy regimens, ASCO recommends a 2-drug antiemetic regimen preferably consisting of palonosetron and dexamethasone. If palonosetron is not available, a first-generation 5-HT₃ receptor antagonist (preferably granisetron or ondansetron) may be substituted. Limited evidence suggests that aprepitant may be added to this regimen; in such cases, use of any 5-HT₃ receptor antagonist is appropriate.

For chemotherapy regimens with a low emetogenic risk, ASCO recommends administration of a single dose of dexamethasone prior to chemotherapy.

For chemotherapy regimens with minimal emetogenic risk, ASCO states that routine antiemetic administration is not necessary.

Related/similar drugs

ondansetron, lorazepam, dexamethasone, Zofran, Ativan, metoclopramide

Netupitant/Palonosetron Dosage and Administration

Administration

Oral Administration

Administer fixed-combination capsules containing netupitant and palonosetron hydrochloride (netupitant/palonosetron; Akynzeo) orally approximately one hour before the start of chemotherapy without regard to meals.

Administer as part of an antiemetic regimen that also includes dexamethasone.

Dosage

Netupitant/palonosetron hydrochloride is a fixed combination; each capsule contains 300 mg of netupitant and 0.5 mg of palonosetron.

The palonosetron component is provided as palonosetron hydrochloride; dosage expressed in terms of palonosetron.

Adults

Cancer Chemotherapy-induced Nausea and Vomiting

Highly Emetogenic Chemotherapy, including Cisplatin-based Chemotherapy

Oral

Administer one capsule (300 mg of netupitant and 0.5 mg of palonosetron) approximately 1 hour prior to start of chemotherapy in conjunction with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1 followed by 8 mg orally once daily on days 2–4 of the treatment regimen.

Anthracycline- and Cyclophosphamide-based Chemotherapy and Chemotherapy Not Considered Highly Emetogenic

Oral

Administer one capsule (300 mg of netupitant and 0.5 mg of palonosetron) approximately 1 hour prior to start of chemotherapy in conjunction with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1 only; administration of dexamethasone on days 2–4 not necessary.

Special Populations

Hepatic Impairment

No dosage adjustments necessary in patients with mild or moderate hepatic impairment (Child-Pugh score 5–9).

Not adequately studied in patients with severe hepatic impairment (Child-Pugh score >9); avoid use in such patients.

Renal Impairment

No dosage adjustments necessary in patients with mild to moderate renal impairment.

Not studied in patients with severe renal impairment or end-stage renal disease; avoid use in such patients.

Geriatric Patients

Dosage adjustments based on age not needed; however, select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant diseases and drug therapy.

Cautions for Netupitant/Palonosetron

Contraindications

None known.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, reported in palonosetron-treated patients with or without known hypersensitivity to other 5-HT₃ receptor antagonists. (See Advice to Patients.)

Serotonin Syndrome

Serotonin syndrome (in some cases fatal) reported in patients receiving 5-HT₃ receptor antagonists. Most cases were associated with concomitant use of other serotonergic drugs (e.g., SSRIs, SNRIs, MAO inhibitors, mirtazapine, fentanyl, lithium, tramadol, IV methylene blue). Serotonin syndrome occurring with overdosage of another 5-HT₃ receptor antagonist alone (ondansetron) also reported. The majority of reports of serotonin syndrome related to 5-HT₃ receptor antagonist use occurred in a post-anesthesia care unit or infusion center.

Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and seizures with or without GI symptoms (e.g., nausea, vomiting, diarrhea).

Monitor patients for emergence of serotonin syndrome, particularly during concomitant use of other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue fixed-combination netupitant and palonosetron and initiate supportive treatment. (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether netupitant or palonosetron distributed into human milk. Discontinue nursing or the fixed combination.

Pediatric Use

Safety and efficacy not established in patients <18 years of age.

Geriatric Use

No substantial differences in safety relative to younger adult cancer patients in clinical studies. (See Geriatric Patients under Dosage and Administration and see Special Populations, under Pharmacokinetics.)

Hepatic Impairment

No dosage adjustment necessary in patients with mild to moderate hepatic impairment (Child-Pugh score 5–9). (See Special Populations, under Pharmacokinetics.)

Limited data in patients with severe hepatic impairment (Child-Pugh score >9); avoid use in such patients.

Renal Impairment

No dosage adjustment necessary in patients with mild or moderate renal impairment.

Avoid use in patients with severe renal impairment or end-stage renal disease. (See Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Headache, asthenia, dyspepsia, fatigue, constipation, erythema.

Drug Interactions

Netupitant metabolism is primarily mediated by CYP3A4 and, to a lesser extent, by CYP2C9 and CYP2D6. Netupitant is a moderate inhibitor of CYP3A4; its M1 metabolite also inhibits CYP3A4.

Clinically important drug interactions via inhibition of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 unlikely.

Netupitant and its principal metabolites (M1, M2, and M3) do not induce CYP isoenzymes 1A2, 2B6, 2C9, 2C19, and 3A4.

Netupitant inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Netupitant is not a substrate for P-gp; however, its M2 metabolite is a P-gp substrate.

Netupitant and its 3 major metabolites unlikely to have clinically important drug interactions with human efflux transporters bile salt export pump (BSEP), multidrug resistance protein (MRP) 2, and human uptake transporters organic anion transport protein (OATP) 1B1 or 1B3, organic anion transporter (OAT) 1 or 3, and organic cation transporter (OCT) 1 or 2.

Palonosetron is metabolized by CYP2D6 and, to a lesser extent, CYP3A4 and CYP1A2. Palonosetron does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2D6, 2E1, and 3A4/5 or induce CYP isoenzymes 1A2, 2D6, or 3A4/5; CYP2C19 not studied.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Substantial increase in systemic exposure to netupitant possible. However, dosage adjustment not necessary for single-dose administration of netupitant/palonosetron.

CYP3A4 substrates: Possible increased plasma concentrations of CYP3A4 substrates; inhibitory effect on CYP3A4 can last for multiple days. Use with caution in patients concomitantly receiving drugs principally metabolized by CYP3A4.

Potent CYP3A inducers: Substantially reduced plasma concentrations of netupitant possible; can decrease efficacy of netupitant/palonosetron. Avoid use in patients chronically receiving a potent CYP3A4 inducer.

Drugs Associated with Serotonin Syndrome

Potentially serious, sometimes fatal, serotonin syndrome, particularly with concomitant use of other serotonergic agents. (See Serotonin Syndrome under Cautions.)

Monitor patients for serotonin syndrome. If serotonin syndrome occurs, immediately discontinue netupitant/palonosetron and initiate supportive treatment.

Netupitant and Palonosetron

Pharmacokinetics of netupitant and palonosetron not substantially affected when netupitant (450 mg) and palonosetron (0.75 mg) are concurrently administered orally.

Specific Drugs

Netupitant/Palonosetron Pharmacokinetics

Absorption

Absorption

Palonosetron: Well absorbed following oral administration, with absolute bioavailability reaching 97%.

Plasma Concentrations

Netupitant: Measurable plasma concentrations achieved within 0.25–3 hours.

Peak plasma concentrations of netupitant and palonosetron attained in approximately 5 hours.

Special Populations

Netupitant: In patients with mild or moderate hepatic impairment, mean exposure was 67 and 86% higher, respectively, than in healthy individuals; mean peak concentration was approximately 40 and 41% higher, respectively, than in healthy individuals.

Palonosetron: In patients with mild or moderate hepatic impairment, mean exposure was 33 and 62% higher, respectively, than in healthy individuals; mean peak concentration was approximately 14% higher and unchanged, respectively, compared with healthy individuals.

Mild and moderate renal impairment: Pharmacokinetics of netupitant not affected.

Severe renal impairment: Pharmacokinetics of netupitant not studied; pharmacokinetics of palonosetron not substantially affected. Pharmacokinetics of netupitant and palonosetron not studied in patients with end-stage renal disease requiring hemodialysis.

In a population pharmacokinetic analysis, age (range: 29–75 years of age) did not affect pharmacokinetics of netupitant or palonosetron in cancer patients receiving the fixed combination. In healthy individuals >65 years of age, mean systemic exposure and peak concentration were 25 and 36% higher for netupitant, respectively, and 37 and 10% higher for palonosetron, respectively, compared with those in healthy younger adults (22–45 years of age).

Distribution

Plasma Protein Binding

Netupitant: >99.5% and >97% for netupitant and its principal metabolites (M1, M2, and M3), respectively.

Palonosetron: Approximately 62%.

Elimination

Metabolism

Netupitant: Extensively metabolized primarily by CYP3A4 and, to a lesser extent, by CYP2C9 and CYP2D6.

Palonosetron: In vitro studies suggest CYP2D6 and, to a lesser extent, CYP3A4 and CYP1A2 involved in metabolism.

Elimination Route

Netupitant: Approximately 50% of a single dose recovered in urine and feces within 120 hours following oral administration. A total of approximately 4 and 71% of a radioactive dose recovered in urine and feces collected over 336 hours, respectively; <1% recovered in urine as unchanged drug.

Palonosetron: 85–93% of palonosetron dose excreted in urine and 5–8% excreted in feces; approximately 40% of the dose recovered in urine as unchanged drug.

Half-life

Netupitant: 80 hours in cancer patients.

Palonosetron: 48 hours in cancer patients.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Actions

• Palonosetron, a second-generation 5-HT₃ receptor antagonist, is pharmacologically related to first-generation 5-HT₃ receptor antagonists (e.g., dolasetron, granisetron, ondansetron), but has a higher potency and higher binding affinity for 5-HT₃ receptors, a longer elimination half-life, and a different molecular interaction with 5-HT₃ receptors than these other 5-HT₃ receptor antagonists and little or no affinity for other receptors.

• Netupitant is a selective antagonist at substance P/NK₁ receptors.

• Netupitant crosses the blood-brain barrier and occupies NK₁ receptors in the brain.

• Antiemetic activity of palonosetron for acute nausea and vomiting appears to be mediated via inhibition of serotonin activity both centrally (in area postrema and chemoreceptor trigger zone) and peripherally (in GI tract).

• Delayed emesis mainly associated with activation of tachykinin family NK₁ receptors, which are widely distributed in the central and peripheral nervous systems, by substance P. Netupitant inhibits substance P-mediated responses in in vitro and in vivo studies. In addition, the combination of palonosetron and netupitant may inhibit the action of substance P synergistically.

Advice to Patients

• Importance of reading the patient information provided by the manufacturer before beginning therapy and rereading it each time netupitant/palonosetron is taken.

• Importance of informing patients to take netupitant/palonosetron with or without food approximately 1 hour before initiation of antineoplastic chemotherapy.

• Importance of informing 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 receiving netupitant/palonosetron fixed combination.

• Importance of informing patients of the possibility of serotonin syndrome, particularly with concomitant use of netupitant/palonosetron and another serotonergic agent (e.g., antidepressants, antimigraine agents). Advise patients to seek immediate medical attention should they experience symptoms of serotonin syndrome, such as alterations in mental status, autonomic instability, or neuromuscular symptoms (with or without GI symptoms).

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other precautionary information. (See Cautions.)

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.

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