OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Fosnetupitant – Akynzeo®

DRUG CLASS

Gastrointestinal Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Fosnetupitant	1703748-89-3	C31-H35-F6-N4-O5-P

ANNOTATED BIBLIOGRAPHY

References updated: 28 February 2024

Abbreviations used: 5-HT3, 5-hydroxytryptamine type 3 [serotonin]; iv, intravenous; NEPA, fixed combination of netupitant [or fosnetupitant] and palonosetron; NK-1, neurokinin-1.

• Zimmerman HJ. Antiemetic and prokinetic compounds. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 721.

  (Expert review of hepatotoxicity published in 1999 before the availability of aprepitant, netupitant, and fosnetupitant).
• Sharkey KA, McNaughton WK. Gastrointestinal motility and water flux, emesis, and biliary and pancreatic disease. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 921-44.

  (Textbook of pharmacology and therapeutics).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–2076. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were attributed to an antiemetic agent).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419–1425. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to antiemetics).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata RA, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol. 2014;13:231–239. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most common implicated agents being nimesulide [n=53: 30%], cyproterone [n=18], nitrofurantoin [n=17], antituberculosis drugs [n=13], and flutamide [n=12: 7%]; no antiemetic was listed).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to aprepitant or other antiemetic agents).
• IV aprepitant (Cinvanti) for chemotherapy-induced nausea and vomiting. Med Lett Drugs Ther. 2018;60(1561):e200–e201. [PubMed: 30653479]

  (Concise review of the mechanism of action, clinical efficacy, safety, and costs of aprepitant, the first substance P inhibitor approved for prevention of nausea and vomiting after highly emetogenic chemotherapy, in discussing adverse events does not mention ALT elevations or hepatotoxicity).
• Schwartzberg L, Roeland E, Andric Z, Kowalski D, Radic J, Voisin D, Rizzi G, et al. Phase III safety study of intravenous NEPA: a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy. Ann Oncol. 2018;29:1535–1540. [PubMed: 29722791]

  (Among 404 patients who received fixed doses of netupitant and palonosetron as oral capsules [300 mg, 0.50 mg] vs intravenous [iv] formulations [235 mg/0.25 mg] before 1312 cycles of highly emetogenic chemotherapy regimens, treatment related adverse event rates were similar in the two groups [9.5% vs 8.9%], although ALT elevations were more frequent after oral administration [any elevations 11.9% vs 7.4%; elevations above 5 times ULN 7% vs 1%]).
• Sugawara S, Inui N, Kanehara M, Morise M, Yoshimori K, Kumagai T, Fukui T, et al. Multicenter, placebo-controlled, double-blind, randomized study of fosnetupitant in combination with palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Cancer. 2019;125:4076–4083. [PMC free article: PMC6900104] [PubMed: 31381152]

  (Among 594 Japanese patients treated with fosnetupitant [81 or 235 mg] or placebo combined with palonosetron [0.75 mg] intravenously before highly emetogenic chemotherapy with dexamethasone for 4 days, prevention of nausea and vomiting was 55% for placebo, vs 64% and 77% with fosnetupitant while adverse event rates were similar including ALT elevations in 4.1% vs 5.6% and 5.6%).
• Karthaus M, Voisin D, Rizzi G, Ciuleanu T. Phase 3 study of palonosetron IV infusion vs. iv bolus for chemotherapy-induced nausea and vomiting prophylaxis after highly emetogenic chemotherapy. J Pain Symptom Manage. 2020;60:568–576. [PubMed: 32276098]

  (Among 440 patients who received a single iv infusion or iv bolus of palonosetron [0.25 mg] immediately before highly emetogenic chemotherapy, a similar proportion of each group had no emesis in the next 5 days [76% vs 77%], with similar rates of adverse events [38% vs 36%]; no mention of ALT levels or hepatotoxicity).
• Schwartzberg L, Navari R, Clark-Snow R, Arkania E, Radyukova I, Patel K, Voisin D, et al. Phase IIIb safety and efficacy of intravenous NEPA for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with breast cancer receiving initial and repeat cycles of anthracycline and cyclophosphamide (AC) chemotherapy. Oncologist. 2020;25:e589–e597. [PMC free article: PMC7066686] [PubMed: 32162813]

  (Among 402 patients treated with either oral or intravenous fosnetupitant and palonosetron [NEPA] just before a moderately or highly emetogenic cancer chemotherapy regimen, rates of no emesis over the next 5 days were similar in the two groups [oral 77% vs iv 73%], while treatment related adverse event rates were low and similar [11% vs 8%], there being only one treatment related serious adverse event, and no episodes of hypersensitivity or anaphylaxis; no mention of ALT elevations or hepatotoxicity).
• Aapro M, Navari RM, Roeland E, Zhang L, Schwartzberg L. Efficacy of intravenous NEPA, a fixed NK/5-HT receptor antagonist combination, for the prevention of chemotherapy-induced nausea and vomiting (CINV) during cisplatin- and anthracycline cyclophosphamide (AC)-based chemotherapy: a review of phase 3 studies. Crit Rev Oncol Hematol. 2021;157:103143. [PubMed: 33260048]

  (Analysis of 15 studies of NK-1 receptor inhibitors compared to 5-HT3 receptor inhibitors, including 2077 patients treated with both netupitant and palonosetron [NEPA], 403 orally and 1674 intravenously [iv], the overall complete response with cisplatin regimens was 77% for iv NEPA, which was similar for oral [75-90%], and was higher than that with other NK-1/5-HT3 combinations [66-78%], mentions that NK-1 inhibitors were “safe and well tolerated”; no discussion of ALT elevations or hepatotoxicity).
• Hata A, Okamoto I, Inui N, Okada M, Morise M, Akiyoshi K, Takeda M, et al. Randomized, double-blind, phase III study of fosnetupitant versus fosaprepitant for prevention of highly emetogenic chemotherapy-induced nausea and vomiting: CONSOLE. J Clin Oncol. 2022;40:180–188. [PMC free article: PMC8718175] [PubMed: 34793245]

  (Among 795 patients treated with iv fosnetupitant or fosaprepitant combined with iv palonosetron and 4 days of oral dexamethasone, the complete response rates were 75% vs 71% and treatment related adverse event rates 22% vs 25%, while injection site reactions were less with NEPA [11% vs 21%]).
• Matsuura K, Tsurutani J, Inoue K, Tanabe Y, Taira T, Kubota K, Tamura T, et al. A phase 3 safety study of fosnetupitant as an antiemetic in patients receiving anthracycline and cyclophosphamide: CONSOLE-BC. Cancer. 2022;128:1692–1698. [PMC free article: PMC9306508] [PubMed: 35045185]

  (Among 102 patients treated with iv fosnetupitant or fosaprepitant in combination with palonosetron before receiving cancer chemotherapy, the complete response rate was 46% vs 51% and treatment related adverse event rates were similar [21% vs 22%], although injection site reactions were less frequent with fosnetupitant [6% vs 26%).
• Dranitsaris G, Moezi M, Dobson K, Phelan R, Blau S. A real-world study to evaluate the safety and efficacy of three injectable neurokinin-1 receptor antagonist formulations for the prevention of chemotherapy-induced nausea and vomiting in cancer patients. Support Care Cancer. 2022;30:6649–6658. [PMC free article: PMC9213362] [PubMed: 35499619]

  (Among 294 adults receiving prophylaxis for nausea and vomiting for cancer chemotherapy in 17 community hospitals, those receiving fosaprepitant had slightly lower rates of control of nausea and vomiting and higher rates of infusion reactions compared to those receiving fosnetupitant, while most other adverse event rates were similar; no mention of ALT elevations or hepatotoxicity).