Netupitant + Palonosetron

Oral
Prophylaxis of chemotherapy-induced nausea and vomiting

Severe or ESRD: Contraindicated.

Severe (Child-Pugh score >9): Contraindicated.

Severe hepatic and renal (including ESRD) impairment. Pregnancy and lactation.

Patient with history of constipation or signs of subacute intestinal obstruction; history of QT prolongation, CHF, bradyarrhythmia, electrolyte abnormalities, and conduction disturbance.

Significant: Hypersensitivity (including anaphylaxis), constipation with faecal impaction.
Blood and lymphatic system disorders: Neutropenia, leucocytosis.
Cardiac disorders: Cardiomyopathy, bundle branch block, atrio-ventricular block, conduction disorder.
Gastrointestinal disorders: Dyspepsia, abdominal distension, abdominal pain, flatulence, nausea, hiccups, diarrhoea.
General disorders and administration site conditions: Fatigue, asthenia.
Investigations: Increased hepatic transaminases, blood alkaline phosphatase, creatine phosphokinase, and creatinine; prolonged QT interval, abnormal ST-T segment.
Metabolism and nutrition disorders: Decreased appetite.
Musculoskeletal and connective tissue disorders: Weakness.
Nervous system disorders: Headache, dizziness, vertigo.
Psychiatric disorders: Somnolence, insomnia.
Skin and subcutaneous tissue disorders: Erythema, alopecia, urticaria.
Vascular disorders: Hypertension.
Potentially Fatal: Serotonin syndrome.

This drug may cause fatigue, dizziness, and somnolence, if affected, do not drive or operate machinery.

Monitor for signs of serotonin syndrome (e.g. mental status and neuromuscular changes, autonomic instability, gastrointestinal symptoms). Obtain liver and renal function. Perform pregnancy test on all pre-menopausal women prior to treatment.

Increased risk of serotonin syndrome with SSRIs and SNRIs.
Netupitant: Plasma concentration is increased by CYP3A4 inhibitors (e.g. ketoconazole) and decreased by CYP3A4 inducers (e.g. rifampicin). Increases exposure to dexamethasone, etoposide, docetaxel, midazolam, erythromycin.

Description:
Mechanism of Action: Netupitant is a selective human substance P/neurokinin (NK₁) receptor antagonist which increases the antiemetic activity of 5-HT₃ receptor antagonists and corticosteroids, thereby inhibiting acute and delayed emesis associated with chemotherapy.
Palonosetron is a selective 5-HT₃ receptor antagonist which blocks serotonin on peripheral vagal nerve terminals in the periphery and centrally in the chemoreceptor trigger zone.
Pharmacokinetics:
Absorption: Netupitant: Time to peak plasma concentration: Approx 5 hours.
Palonosetron: Well absorbed. Absolute bioavailability: Approx 97%.
Distribution: Netupitant: Volume of distribution: 1,982 ± 906 L. Plasma protein binding: >99.5% (netupitant); >97% (major metabolites).
Palonosetron: Volume of distribution: 8.3 ± 2.5 L/kg. Plasma protein binding: Approx 62%.
Metabolism: Netupitant: Extensively metabolised in the liver mainly by CYP3A4, and to a lesser extent by CYP2C9 and CYP2D6, to form active metabolites M1, M2, and M3.
Palonosetron: Metabolised by CYP2D6, CYP3A4, and CYP1A2 to form inactive metabolites N-oxide-palonosetron and 6-S-hydroxy-palonosetron.
Excretion: Netupitant: Mainly via faeces (approx 71%); urine (approx 4%). Elimination half-life: 80 ± 29 hours.
Palonosetron: Mainly via urine (85-93%, 40% as unchanged drug); faeces (5-8%). Elimination half-life: 48 ± 19 hours.

Source: National Center for Biotechnology Information. PubChem Database. Netupitant, CID=6451149, https://pubchem.ncbi.nlm.nih.gov/compound/Netupitant (accessed on Jan. 22, 2020)

Source: National Center for Biotechnology Information. PubChem Database. Palonosetron, CID=6337614, https://pubchem.ncbi.nlm.nih.gov/compound/Palonosetron (accessed on Jan. 22, 2020)

Store between 20-25°C.

Antiemetics

A04AA55 - palonosetron, combinations ; Belongs to the class of serotonin (5HT3) antagonists. Used for the prevention of nausea and vomiting.

Akynzeo Capsule (Eisai Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 30/01/2018.

Anon. Netupitant and Palonosetron. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 30/01/2018.

Buckingham R (ed). Netupitant. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/01/2018.

Buckingham R (ed). Palonosetron Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/01/2018.

Joint Formulary Committee. Palonosetron with Netupitant. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/01/2018.