Tumors of female reproductive systemTumors of female reproductive systemОпухоли женской репродуктивной системы1994-40981999-8627Publishing House ABV Press113810.17650/1994-4098-2023-19-3-54-62MAMMOLOGY. REVIEWSМАММОЛОГИЯ. ОБЗОРНЫЕ СТАТЬИNetupitant/palonosetron (NEPA; Akynzeo®) combination in prevention of the nausea and vomiting in patients with breast cancer receiving anthracyclinbased chemotherapyКомбинация нетупитант/палоносетрон (НЕПА; Акинзео®) в профилактике тошноты и рвоты у больных раком молочной железы, получающих антрациклинсодержащую химиотерапиюhttps://orcid.org/0000-0003-1031-9376KedrovaA. G.КедроваА. Г.
Russian Federation

Anna Genrikhovna Kedrova - Department of Oncology CCSMCMT, FBARF; Department of Obstetrics and Gynecology, Academy of Postgraduate Education Federal Research and Clinical Center, FBA.

28 Orekhovyy Bulvar, Moscow 115682; 91 Volokolamskoe Shosse, Moscow 125371

Анна Генриховна Кедрова отделение онкологии ФНКЦ ФМБА России; Кафедра акушерства и гинекологии Академии постдипломного образования ФГБУ ФНКЦ ФМБА России

115682 Москва, Ореховый бульвар, 28; 125371 Москва, Волоколамское шоссе, 91

kedrova.anna@gmail.comBerishviliA. I.БеришвилиА. И.
Russian Federation

Alexander Ilyich Berishvili Department of Obstetrics and Gynecology, Academy of Postgraduate Education.

91 Volokolamskoe Shosse, Moscow 125371

Александр Ильич Беришвили кафедра акушерства и гинекологии Академии постдипломного образования.

125371 Москва, Волоколамское шоссе, 91

aberishvili@yandex.ruFederal Research and Clinical Center for Specialized Medical Care and Medical Technologies, Federal Biomedical Agency of the Russian FederationФГБУ «Федеральный научно-клинический центр специализированных видов медицинской помощи и медицинских технологий Федерального медико-биологического агентства России» (ФНКЦ ФМБА России)Federal Research and Clinical Center, Federal Biomedical AgencyФГБУ ФНКЦ ФМБА России2710202319354622710202327102023https://ojrs.abvpress.ru/ojrs/article/view/1138

Chemotherapy-induced nausea and vomiting is a common problem during cancer treatment, especially in breast cancer patients with anthracycline/cyclophosphamide (ас) chemotherapy. Netupitant/palonosetron (NEPA; Akynzeo®) is a fixed-dose combination of two drugs (netupitant, a neurokinin 1 receptor antagonist; and palonosetron, a serotonin 3 receptor antagonist) which target two diferent signalling pathways involved in the induction of vomiting. Approved for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting in adults, netupitant/palonosetron is given orally or via intravenous infusion as a single dose prior to chemotherapy. In clinical trials, high proportions of patients who received netupitant/palonosetron (used in combination with the corticosteroid dexamethasone) prior to chemotherapy reported no vomiting, no requirement for rescue medication, and no signifcant nausea in the 5 days post chemotherapy. Both the oral and intravenous formulations of the drug combination are well tolerated. Thus, netupitant/palonosetron is a simple, convenient and efective drug combination for the prevention of acute and delayed xhemotherapy-induced nausea and vomiting in patients receiving chemotherapy that has a moderate to high emetogenic potential.

Тошнота и рвота, индуцированные химиотерапией, являются распространенной проблемой во время лечения рака, особенно у больных раком молочной железы, получающих химиотерапию антрациклином и циклофосфамидом (ас). Нетупитант/палоносетрон (НеПа; акинзео®) представляет собой комбинацию 2 препаратов в фиксированных дозах (нетупитант, антагонист рецепторов нейрокинина 1, и палоносетрон, антагонист рецепторов серотонина 3), которые воздействуют на 2 различных сигнальных пути, участвующих в индукции рвоты. Одобренный к применению для профилактики острой и отсроченной тошноты и рвоты, индуцированных химиотерапией, у взрослых, нетупитант/ палоносетрон вводят перорально или путем внутривенной инфузии в виде однократной дозы перед химиотерапией. В клинических испытаниях значительная часть пациентов, получавших нетупитант/палоносетрон (в комбинации с кортикостероидом дексаметазоном) до начала химиотерапии, сообщали об отсутствии рвоты, потребности в экстренных лекарствах и значительной тошноты в течение 5 дней после химиотерапии. Как пероральные, так и внутривенные формы комбинации препаратов хорошо переносятся. Таким образом, нетупитант/палоносетрон – простая, удобная и эффективная комбинация лекарственных средств для профилактики острой и отсроченной тошноты и рвоты у пациентов, получающих химиотерапию, обладающую умеренным или высоким эметогенным потенциалом.

netupitantpalonosetronNEPAAkynzeochemotherapybreast cancervomitingnauseapreventionнетупитантпалоносетронНеПаакинзеохимиотерапиярак молочной железырвотатошнотапрофилактикаThe work was performed without external fundingРабота выполнена без спонсорской поддержки1. Adel N. Overview of chemotherapy-induced nausea and vomiting and evidence-based therapies. Am J Manag Care 2017; 23(14 Suppl):S259–65.Adel N. Overview of chemotherapy-induced nausea and vomiting and evidence-based therapies. Am J Manag Care 2017; 23(14 Suppl):S259–65.2. Botteman M., Nickel K., Corman S. et al. Cost-efectiveness of a fixed combination of netupitant and palonosetron (NEPA) relative to aprepitant plus granisetron (APR+GRAN) for prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a trial-based analysis. Support Care Cancer 2020;28(2):857–66. DOI: 10.1007/s00520-019-04824-yBotteman M., Nickel K., Corman S. et al. Cost-efectiveness of a fixed combination of netupitant and palonosetron (NEPA) relative to aprepitant plus granisetron (APR+GRAN) for prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a trial-based analysis. Support Care Cancer 2020;28(2):857–66. DOI: 10.1007/s00520-019-04824-y3. Hesketh P.J., Kris M.G., Basch E. et al. Antiemetics: ASCO guideline update. J Clin Oncol 2020;38(24):2782–97.Hesketh P.J., Kris M.G., Basch E. et al. Antiemetics: ASCO guideline update. J Clin Oncol 2020;38(24):2782–97.4. National Comprehensive Cancer Network. NCCN Clinical Practice Guildelines in Oncology (NCCN Guidelines®): Antiemesis. Version 1.2021. 2020.National Comprehensive Cancer Network. NCCN Clinical Practice Guildelines in Oncology (NCCN Guidelines®): Antiemesis. Version 1.2021. 2020.5. Roila F., Warr D., Hesketh P.J. et al. 2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following moderately emetogenic chemotherapy. Support Care Cancer 2017;25(1):289–94.Roila F., Warr D., Hesketh P.J. et al. 2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following moderately emetogenic chemotherapy. Support Care Cancer 2017;25(1):289–94.6. US FDA. Akynzeo® (netupitant and palonosetron capsules; fosnetupitant and palonosetron for injection; fosnetupitant and palonosetron injection): US prescribing information. 2020.US FDA. Akynzeo® (netupitant and palonosetron capsules; fosnetupitant and palonosetron for injection; fosnetupitant and palonosetron injection): US prescribing information. 2020.7. European Medicines Agency. Akynzeo: summary of product characteristics. 2021.European Medicines Agency. Akynzeo: summary of product characteristics. 2021.8. Keating G.M. Netupitant/palonosetron: a review in the prevention of chemotherapy-induced nausea and vomiting. Drugs 2015;75(18):2131–41. DOI: 10.1007/s40265-015-0512-9Keating G.M. Netupitant/palonosetron: a review in the prevention of chemotherapy-induced nausea and vomiting. Drugs 2015;75(18):2131–41. DOI: 10.1007/s40265-015-0512-99. European Medicines Agency. Akynzeo: EPAR – public assessment report. 2015.European Medicines Agency. Akynzeo: EPAR – public assessment report. 2015.10. Wong E.H., Clark R., Leung E. et al. The interaction of RS 25259197, a potent and selective antagonist, with 5-HT3 receptors, in vitro. Br J Pharmacol 1995;114(4):851–9. DOI: 10.1111/j.1476-5381.1995.tb13282.xWong E.H., Clark R., Leung E. et al. The interaction of RS 25259197, a potent and selective antagonist, with 5-HT3 receptors, in vitro. Br J Pharmacol 1995;114(4):851–9. DOI: 10.1111/j.1476-5381.1995.tb13282.x11. Yang L.P., Scott L.J. Palonosetron: in the prevention of nausea and vomiting. Drugs 2009;69(16):2257–78.Yang L.P., Scott L.J. Palonosetron: in the prevention of nausea and vomiting. Drugs 2009;69(16):2257–78.12. Rojas C., Stathis M., Thomas A.G. et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg 2008;107(2):469–78. DOI: 10.1213/ane.0b013e318172fa74Rojas C., Stathis M., Thomas A.G. et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg 2008;107(2):469–78. DOI: 10.1213/ane.0b013e318172fa7413. Rojas C., Li Y., Zhang J. et al. The antiemetic 5-HT3 receptor antagonist palonosetron inhibits substance P-mediated responses in vitro and in vivo. J Pharmacol Exp Ther 2010;335(2):362–8.Rojas C., Li Y., Zhang J. et al. The antiemetic 5-HT3 receptor antagonist palonosetron inhibits substance P-mediated responses in vitro and in vivo. J Pharmacol Exp Ther 2010;335(2):362–8.14. Stathis M., Pietra C., Rojas C. et al. Inhibition of substance P-mediated responses in NG108-15 cells by netupitant and palonosetron exhibit synergistic effects. Eur J Pharmacol 2012;689(1–3):25–30.Stathis M., Pietra C., Rojas C. et al. Inhibition of substance P-mediated responses in NG108-15 cells by netupitant and palonosetron exhibit synergistic effects. Eur J Pharmacol 2012;689(1–3):25–30.15. Thomas A.G., Stathis M., Rojas C. et al. Netupitant and palonosetron trigger NK1 receptor internalization in NG108-15 cells. Exp Brain Res 2014;232(8):2637–44.Thomas A.G., Stathis M., Rojas C. et al. Netupitant and palonosetron trigger NK1 receptor internalization in NG108-15 cells. Exp Brain Res 2014;232(8):2637–44.16. Rojas C., Thomas A.G., Alt J. et al. Palonosetron triggers 5-HT3 receptor internalization and causes prolonged inhibition of receptor function. Eur J Pharmacol 2010;626(2–3):193–9.Rojas C., Thomas A.G., Alt J. et al. Palonosetron triggers 5-HT3 receptor internalization and causes prolonged inhibition of receptor function. Eur J Pharmacol 2010;626(2–3):193–9.17. Schwartzberg L., Roeland E., Andric Z. 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(7):1535–40.Schwartzberg L., Roeland E., Andric Z. 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(7):1535–40.18. Aapro M., Rugo H., Rossi G. et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 2014;25(7):1328–33.Aapro M., Rugo H., Rossi G. et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 2014;25(7):1328–33.19. Aapro M., Karthaus M., Schwartzberg L. et al. NEPA, a fixed oral combination of netupitant and palonosetron, improves control of chemotherapy-induced nausea and vomiting (CINV) over multiple cycles of chemotherapy: results of a randomized, doubleblind, phase 3 trial versus oral palonosetron. Support Care Cancer 2017;25(4):1127–35.Aapro M., Karthaus M., Schwartzberg L. et al. NEPA, a fixed oral combination of netupitant and palonosetron, improves control of chemotherapy-induced nausea and vomiting (CINV) over multiple cycles of chemotherapy: results of a randomized, doubleblind, phase 3 trial versus oral palonosetron. Support Care Cancer 2017;25(4):1127–35.20. Gralla R.J., Bosnjak S.M., Hontsa A. et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol 2014;25(7):1333–9.Gralla R.J., Bosnjak S.M., Hontsa A. et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol 2014;25(7):1333–9.21. Yeo W., Lau T., Kwok C. et al. NEPA efficacy and tolerability during (neo)adjuvant breast cancer chemotherapy with cyclophosphamide and doxorubicin. BMJ Support Palliat Care 2022;12:e264–e270.Yeo W., Lau T., Kwok C. et al. NEPA efficacy and tolerability during (neo)adjuvant breast cancer chemotherapy with cyclophosphamide and doxorubicin. BMJ Support Palliat Care 2022;12:e264–e270.22. Yeo W., Mo F.K.F., Suen J.J.S. et al. A randomized study of aprepitant, ondansetron and dexamethasone for chemotherapyinduced nausea and vomiting in Chinese breast cancer patients receiving moderately emetogenic chemotherapy. Breast Cancer Res Treat 2009;113:529–35. DOI: 10.1007/s10549-008-9957-9Yeo W., Mo F.K.F., Suen J.J.S. et al. A randomized study of aprepitant, ondansetron and dexamethasone for chemotherapyinduced nausea and vomiting in Chinese breast cancer patients receiving moderately emetogenic chemotherapy. Breast Cancer Res Treat 2009;113:529–35. DOI: 10.1007/s10549-008-9957-923. Warr D.G., Hesketh P.J., Gralla R.J. et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 2005;23:2822–30.Warr D.G., Hesketh P.J., Gralla R.J. et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 2005;23:2822–30.24. Herrstedt J., Muss H.B., Warr D.G. et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer 2005;104:104:1548–55.Herrstedt J., Muss H.B., Warr D.G. et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer 2005;104:104:1548–55.25. Badalamenti G., Incorvaia L., Messina C. et al. One shot NEPA plus dexamethasone to prevent multiple-day chemotherapy in sarcoma patients. Support Care Cancer 2019;27:3593–7. DOI: 10.1007/s00520-019-4645-3Badalamenti G., Incorvaia L., Messina C. et al. One shot NEPA plus dexamethasone to prevent multiple-day chemotherapy in sarcoma patients. Support Care Cancer 2019;27:3593–7. DOI: 10.1007/s00520-019-4645-326. Hesketh P.J., Bohlke K., Lyman G.H. et al. Antiemetics: American Society of clinical oncology focused guideline update. J Clin Oncol 2016;34:381–6.Hesketh P.J., Bohlke K., Lyman G.H. et al. Antiemetics: American Society of clinical oncology focused guideline update. J Clin Oncol 2016;34:381–6.27. Herrstedt J., Roila F., Warr D. et al. 2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following high emetic risk chemotherapy. Support Care Cancer 2017;25:277–88.Herrstedt J., Roila F., Warr D. et al. 2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following high emetic risk chemotherapy. Support Care Cancer 2017;25:277–88.28. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Antiemesis. Version 1, 2019.National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Antiemesis. Version 1, 2019.29. Schilling J., Kurbacherb Ch., Hanusch C. et al. Quality of life effects of an oral fixed combination of netupitant and palonosetron in chemotherapy-induced nausea and vomiting prevention: realworld evidence in patients with breast cancer receiving anthracycline-cyclophosphamide-based chemotherapy. Breast Care 2022;17:130–6. DOI: 10.1159/000514891Schilling J., Kurbacherb Ch., Hanusch C. et al. Quality of life effects of an oral fixed combination of netupitant and palonosetron in chemotherapy-induced nausea and vomiting prevention: realworld evidence in patients with breast cancer receiving anthracycline-cyclophosphamide-based chemotherapy. Breast Care 2022;17:130–6. DOI: 10.1159/00051489130. Karthaus M., Oskay-Özcelik G., Wülfing P. et al. Realworld evidence of NEPA, netupitant-palonosetron, in chemotherapyinduced nausea and vomiting prevention: effects on quality of life. Future Oncol 2020;16(14):939–53. DOI: 10.2217/fon-2020-0187Karthaus M., Oskay-Özcelik G., Wülfing P. et al. Realworld evidence of NEPA, netupitant-palonosetron, in chemotherapyinduced nausea and vomiting prevention: effects on quality of life. Future Oncol 2020;16(14):939–53. DOI: 10.2217/fon-2020-018731. Schwartzberg L., Navari R., Clark-Snow R. et al. Phase IIIb safety and efficacy of intravenous NEPA for prevention of chemotherapyinduced nausea and vomiting (CINV) in patients with breast cancer receiving initial and repeat cycles of anthracycline and cyclophosphamide (AC) chemotherapy. Oncologist 2020;25(3):e589–97.Schwartzberg L., Navari R., Clark-Snow R. et al. Phase IIIb safety and efficacy of intravenous NEPA for prevention of chemotherapyinduced nausea and vomiting (CINV) in patients with breast cancer receiving initial and repeat cycles of anthracycline and cyclophosphamide (AC) chemotherapy. Oncologist 2020;25(3):e589–97.32. Emend (aprepitant) capsules, for oral use; Emend (aprepitant) for oral suspension: prescribing information. Whitehouse Station: Merck Sharp & Dohme Corp., 2019.Emend (aprepitant) capsules, for oral use; Emend (aprepitant) for oral suspension: prescribing information. Whitehouse Station: Merck Sharp & Dohme Corp., 2019.33. Vidall C., Fernández-Ortega P., Cortinovis D. et al. Impact and management of chemotherapy/radiotherapy-induced nausea and vomiting and the perceptual gap between oncologists/oncology nurses and patients: a cross-sectional multinational survey. Support Care Cancer 2015;23(11):3297–305. DOI: 10.1007/s00520-015-2750-5Vidall C., Fernández-Ortega P., Cortinovis D. et al. Impact and management of chemotherapy/radiotherapy-induced nausea and vomiting and the perceptual gap between oncologists/oncology nurses and patients: a cross-sectional multinational survey. Support Care Cancer 2015;23(11):3297–305. DOI: 10.1007/s00520-015-2750-534. McGowan J.V., Chung R., Maulik A. et al. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther 2017;31(1):63–75.McGowan J.V., Chung R., Maulik A. et al. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther 2017;31(1):63–75.35. Aapro M., Zhang L., Yennu S. et al. Preventing chemotherapyinduced nausea and vomiting with netupitant/palonosetron, the first fixed combination antiemetic: current and future perspective. Future Oncol 2019;15(10):1067–84. DOI: 10.2217/fon-2018-0872Aapro M., Zhang L., Yennu S. et al. Preventing chemotherapyinduced nausea and vomiting with netupitant/palonosetron, the first fixed combination antiemetic: current and future perspective. Future Oncol 2019;15(10):1067–84. DOI: 10.2217/fon-2018-087236. Caputо R., Cazzaniga M., Sbrana A. et al. Netupitant/palonosetron (NEPA) and dexamethasone for prevention of emesis in breast cancer patients receiving adjuvant anthracycline plus cyclophosphamide: a multi-cycle, phase II study. BMC Cancer 2020;20:232–41. DOI: 10.2217/fon-2018-0872Caputо R., Cazzaniga M., Sbrana A. et al. Netupitant/palonosetron (NEPA) and dexamethasone for prevention of emesis in breast cancer patients receiving adjuvant anthracycline plus cyclophosphamide: a multi-cycle, phase II study. BMC Cancer 2020;20:232–41. DOI: 10.2217/fon-2018-087237. Molassiotis A., Aapro M., Dicato M. et al. Evaluation of risk factors predicting chemotherapy-related nausea and vomiting: results from a European prospective observational study. J Pain Symptom Manage 2014;47:839–48.Molassiotis A., Aapro M., Dicato M. et al. Evaluation of risk factors predicting chemotherapy-related nausea and vomiting: results from a European prospective observational study. J Pain Symptom Manage 2014;47:839–48.38. Kubota K., Saito M., Aogi K. et al. Control of nausea with palonosetron versus granisetron, both combined with dexamethasone, in patients receiving cisplatin or anthracycline plus cyclophosphamide-based regimens. Support Care Cancer 2016;24:4025–33. DOI: 10.1007/s00520-016-3203-5Kubota K., Saito M., Aogi K. et al. Control of nausea with palonosetron versus granisetron, both combined with dexamethasone, in patients receiving cisplatin or anthracycline plus cyclophosphamide-based regimens. Support Care Cancer 2016;24:4025–33. DOI: 10.1007/s00520-016-3203-539. De Laurentiis M., Bonfadini C., Lorusso V. et al. Incidence of nausea and vomiting in breast cancer patients treated with anthracycline plus cyclophosphamide-based chemotherapy regimens in Italy: NAVY observational study. Support Care Cancer 2018;26(12):4021–9. DOI: 10.1007/s00520-018-4259-1De Laurentiis M., Bonfadini C., Lorusso V. et al. Incidence of nausea and vomiting in breast cancer patients treated with anthracycline plus cyclophosphamide-based chemotherapy regimens in Italy: NAVY observational study. Support Care Cancer 2018;26(12):4021–9. DOI: 10.1007/s00520-018-4259-140. Spinelli T., Moresino C., Baumann S. et al. Efects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial. Springerplus 2014;3(389):1–11. DOI: 10.1186/2193-1801-3-389Spinelli T., Moresino C., Baumann S. et al. Efects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial. Springerplus 2014;3(389):1–11. DOI: 10.1186/2193-1801-3-389