Comparative clinical and economic analysis of pozaconazol (Noxafil) for invasive mycoses (IM) prevention in patients with severe neutropenia during treatment of acute myeloid leukemia or myelodysplastic syndrome

Objective: a comparative clinical and economic analysis of posaconazole (Noxafil) for invasive mycoses (IM) prevention in patients with severe neutropenia during treatment of acute myeloid leukemia or myelodysplastic syndrome in Russia.
Materials and methods. A model was constructed that takes into account the use of various mediactions: posaconazole, voriconazole and fluconazole. Cost estimation for IM prevention was carried out considering the direct medical costs of IM prevention, IM therapy, hospital stay, therapeutic and diagnostic procedures and monitoring in case of IM. “Cost–effectiveness” and “budget impact” analyzes were performed.
Results. Based on literature data, high efficacy and safety of posaconazole for IM prevention in patients with severe neutropenia during treatment of acute myeloid leukemia or myelodysplastic syndrome was shown.
Cost analysis of drugs showed the lowest total costs for IM prevention with posaconazole – 185,745.49 rubles, followed by fluconazole – 275,360.26 rubles, and voriconazole – 299,792.76 rubles. At the same time, in the structure of total costs, for posaconazole and voriconazole, the cost of IM prevention prevailed – 155,017.17 rubles and 156,393.92 rubles, respectively, whereas for fluconazole – the costs of IM treatment – 168,390.45 rubles. This is due to the significantly higher incidence of IM cases in fluconazole group compared with posaconazole and voriconazole.
The use of posaconazole also showed the best ratio of cost–effectiveness for one prevented case of infection and for one extended year of the patient’s life (191,490.20 rubles and 34,980.32, respectively). Due to lowest costs and best efficiency of posaconazole, the incremental cost– effectiveness ratio (ICER) was not calculated.
Thus, the use of posaconazole for IM prevention in acute myeloid leukemia patients can reduce the overall cost per patient by 114,047.27 rubles compared with voriconazole and by 89,614.76 rubles compared with fluconazole.
The sensitivity analysis for cost–effectiveness results demonstrated the stability of IM prevention model in acute myeloid leukemia patients to changes in the initial posaconazole price upwards to +61 %.
The model has the highest sensitivity to IM incidence with unsuccessful prevention.
“Budget impact” analysis of IM prevention in acute myeloid leukemia patients older than 13 years in Russia showed that an increase in the posaconazole proportion from 25 to 50 % with a decrease of voriconazole proportion from 25 to 15 % and fluconazole proportion from 50 to 35 % in government procurement will reduce budget costs by 48.1 million rubles.
The sensitivity analysis for “budget impact” results showed the greatest sensitivity to changes in the patient number and to increase of posaconazole proportion in procurement. Results were less sensitive to an increase of voriconazole and fluconazole proportion.
Conclusion. The results of the study showed that the use of posaconazole for the prevention of invasive mycoses in patients with severe neutropenia during treatment of acute myeloid leukemia and myelodysplastic syndrome is clinically effective and economically justified within the system of state preferential drug provision in the Russia.

1. Васильева Н.В., Климко Н.Н., Цинзерлинг В.А. Диагностика и лечение инвазивных микозов: современные рекомендации. Вестник Санкт-Петербургской медицинской академии последипломного образования 2010;2(4):5–18. [Vassilieva N.V., Klimko N.N., Zinserling V.A. Modern recommendations for diagnosis and treatment of invasive myсoses. Vestnik Sankt-Peterburgskoy meditsinskoy akademii poslediplomnogo obrazovaniya = Bulletin of the St. Petersburg Medical Academy of Postgraduate Education 2010;2(4):5–18. (In Russ.)].

2. Walsh T.J., Anaissie E.J., Denning D.W. et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46(3):32–60. DOI: 10.1086/525258. PMID: 18177225.

3. Dignani M.C. Epidemiology of invasive fungal diseases on the basis of autopsy reports. F1000Prime Rep. 2014;6:81. DOI: 10.12703/P6-81. PMID: 25343038.

4. Климко Н.Н., Козлова Я.И., Хостелиди С.Н. и др. Распространенность тяжелых и хронических микотических заболеваний в Российской Федерации по модели LIFE PROGRAM. Проблемы медицинской микологии 2014;6(1):3–8. [Klimko N.N., Kozlova Ya.I., Khostelidi S.N. et al. The prevalence of serious and chronic fungal diseases in Russian Federation on LIFE program model. Problemy meditsinskoy mikologii = Problems in Medical Mycology 2014;16(1):3–8. (In Russ.)].

5. Krueger K.P., Nelson A.C. Economic considerations in the treatment of invasive aspergillosis: a review of voriconazole pharmacoeconomic studies. Clinicoecon Outcomes Res 2009;1:35–43. PMID: 21935305.

6. Cornely O.A., Maertens J., Bresnik M. et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a highloading dose regimen with standard dosing(AmBiLoad trial). Clin Infect Dis 2007;44(10):1289–97. DOI: 10.1086/514341. PMID: 17443465.

7. Nivoix Y., Velten M., Letscher-Bru V. et al. Factors associated with overall and attributable mortality in invasive aspergillosis. Clin Infect Dis 2008;47(9):1176–84. DOI: 10.1086/592255. PMID: 18808352.

8. Freifeld A.G., Bow E.J., Sepkowitz K.A. et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis 2011;52(4):е56–93. DOI: 10.1093/cid/cir073. PMID: 21258094.

9. Диагностика и лечение микозов в отделениях реанимации и интенсивной терапии: Российские рекомендации. 2-е изд., доп. и перераб. Под ред. Н.Н. Климко. М.: Фармтек, 2015. 96 с. [Diagnosis and treatment of mycoses in intensive care units: Russian recommendations. Ed.: Klimko N.N. 2nd edition revised. Moscow: Farmtek, 2015, 96 p. (In Russ.)].

10. Zhao Y.J., Khoo A.L., Tan G. et al. Network meta-analysis and pharmacoeconomic evaluation of fluconazole, itraconazole, posaconazole, and voriconazole in invasive fungal infection prophylaxis. Antimicrob Agents Chemother 2016;60(1):376–86. DOI: 10.1128/AAC.01985-15. PMID: 26525782.

11. Ananda-Rajah M.R., Grigg A., Downey M.T. et al. Comparative clinical effectiveness of prophylactic voriconazole/ posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/ myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period. Haematologica 2012;97(3):459–63. DOI: 10.3324/haematol.2011.051995. PMID: 22058198.

12. Воробьев П.А., Авксекнтьева М.В., Борисенко О.В. и др. Клинико-экономический анализ. 3-е изд., доп., с приложениями. М.: Ньюдиамед, 2008. С. 226–229. [Vorobiev P.A., Avkseknteva M.V., Borisenko O.V. et al. Clinical and economic analysis. 3rd ed., augmented, With attachments. Moscow: N’yudiamed, 2008. Pp. 226–229 (In Russ.)].

13. Крысанов И.С. Введение в фармакоэкономическое моделирование. Фармакоэкономика. Современная фармакоэкономика и фармакоэпидемиология 2008;1(1):7–9. [Krysanov I.S. Introduction to pharmacoeconomic modeling. Pharmacoeconomics. Sovremennaya farmakoekonomika i farmakoepidemiologiya = Modern Pharmacoeconomics and Pharmacoepidemiology 2008;1(1):7–9. (In Russ.)].

14. Фармакоэкономический анализ стоимости инвазивного аспергиллеза у пациентов с нейтропенией на фоне химиотерапии онкогематологических заболеваний. Научно-исследовательский институт клинико-экономической экспертизы и фармакоэкономики. Рук. В.Ю. Ермакова. Исполн.: И.С. Крысанов, Н.Н. Климко. М., 2015. 39 с. [Pharmacoeconomic analysis of the cost of invasive aspergillosis in patients with neutropenia during chemotherapy of oncohematological diseases. Research Report (final). Research Institute of Clinical and Economic Expertise and Pharmacoeconomics. Head: V.Yu. Ermakova Researchers: I.S. Krysanov, N.N. Klimko. Moscow, 2015, 39 p. (In Russ.)].

15. Государственный реестр предельных отпускных цен на ЖНВЛП 2018. Доступно по: http://www.grls.rosminzdrav.ru/Default.aspx. [The State register of limiting prices for vital medications 2018. Available at: http://www.grls.rosminzdrav.ru/Default.aspx. (In Russ.)].

16. Омельяновский В.В., Авксентьева М.В., Сура М.В. и др. Методические рекомендации по оценке влияния на бюджет в рамках реализации программы государственных гарантий бесплатного оказания гражданам медицинской помощи. ФГБУ «ЦЭККМП» Минздрава России. Утверждено приказом ФГБУ «ЦЭККМП» Минздрава России от 23 декабря 2016 г. № 145-од. М., 2016. 28 с. [Omel’yanovskiy V.V., Avksenteva M.V., Sura M.V. et al. Guidelines for assessing the budget impact in the framework of the program of state guarantees of free medical care to citizens. Center of expertise and quality control of medical care (CECCMC) of the Ministry of Health of Russia. Approved by the order of “CECCMC” of the Ministry of Health of Russia dated December 23, 2016 No. 145-од. Moscow, 2016, 28 p. (In Russ.)].

17. Злокачественные новообразования России в 2016 году (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, Г.В. Петровой. М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2018. 250 с. [Malignant tumors in Russia in 2016 (morbidity and mortality). Eds.: А.D. Kaprin, V.V. Starinskiy, G.V. Petrova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMIRTS” Minzdrava Rossii, 2018. 250 p. (In Russ.)].

18. Kim A., Nicolau D.P., Kuti J.L. Hospital costs and outcomes among intravenous antifungal therapies for patients with invasive aspergillosis in the United States. Mycoses 2011;54(5):301–12. DOI: 10.1111/j.1439-0507.2010.01903.x. PMID: 20557463.

19. Rieger C.T., Cornely O.A., Hoppe-Tichy T. et al. Treatment cost of invasive fungal disease(Ifd) in patients with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) in German hospitals. Mycoses 2012;55(6):514–20. DOI: 10.1111/j.1439-0507.2012.02193.x. PMID: 22471310.

20. Rácil Z., Mayer J., Kocmanová I. et al. Invasive aspergillosis in hematooncological patients: advantages and disadvantages of various diagnostic methods, treatment options and financial costs of therapy. Vnitr Lek 2008;54(2):157–68. PMID: 23687707.

21. Cagatay A.A., Cosan F., Karadeniz A. et al. The clinical and pharmacoeconomic analysis of invasive aspergillosis in adult patients with haematological diseases. Mycoses 2008;51(4):328–35. DOI: 10.1111/j.1439-0507.2007.01483.x. PMID: 18331449.

22. Dodds Ashley E., Drew R., Johnson M. et al. Cost of invasive fungal infections in the era of new diagnostics and expanded treatment options. Pharmacotherapy. 2012;32(10):890–901. DOI: 10.1002/j.1875-9114.2012.01124. PMID: 23033228.

23. des Champs-Bro B., Leroy-Cotteau A., Mazingue F. et al. Invasive fungal infections: epidemiology and analysis of antifungal prescriptions in oncohaematology. J Clin Pharm Ther 2011;36(2):152–60. DOI: 10.1111/j.1365-2710.2010.01166.x. PMID: 21366643.

24. Белоусов Ю.Б., Колбин А.С., Королева О.А. и др. Клинико-экономическая целесообразность профилактики инвазивных микозов позаконазолом в сравнении с флуконазолом и итраконазолом у пациентов с выраженной нейтропенией. Клиническая микробиология и антимикробная химиотерапия 2009;1(2):170–82. [Belousov Yu.B., Kolbin A.S., Koroleva O.A. et al. Clinical and economic expediency of posaconazole comparing with fluconazole and itraconazole in primary prophylaxis of systemic mycoses in severe neutropenic patients. Klinicheskaya mikrobiologiya i antimikrobnaya khimioterapiya = Clinical Microbiology and Antimicrobial Chemotherapy 2009;11(2):170–82. (In Russ.)].