Riscos sobre a presença de impurezas de n-nitrosaminas e azidas em medicamentos
Palavras-chave:
N-nitrosaminas, Azidas, Sartanas, Contaminação de medicamentos
Resumo
Impurezas de N-nitrosaminas (NA), de conhecido potencial carcinogênico, têm sido motivo de preocupação para a indústria farmacêutica e agências reguladoras em vários países nos últimos anos. NA foram inesperadamente identificadas em medicamentos de controle da hipertensão arterial, as sartanas. Nosso principal objetivo é destacar os riscos da presença dessas impurezas em medicamentos e delinear como autoridades sanitárias, de todo o mundo, realizaram revisões regulatórias onde foram estabelecidas novas resoluções e implementações de novos requisitos rigorosos em relação à análise de risco de formação dessas impurezas no processo de fabricação de insumos e medicamentos. Destacamos que, recentemente, novas impurezas mutagênicas do tipo azida foram identificadas em medicamentos de sartanas; além disso, medicamentos de outras classes terapêuticas também podem apresentar contaminação por NA. Podemos concluir que a realização de programas de monitoramento é mais uma ação para proteger a Saúde Pública e garantir a qualidade, a eficácia e a segurança de medicamentos.Referências
ASSOCIAÇÃO BRASILEIRA DE NORMAS TÉCNICAS. (ABNT) ISO/IEC 17025: Requisitos gerais para a competência de laboratórios de ensaio e calibração. 2017.
BARTSCH, H, O’NEILL, K.I. Ninth International Meeting on N-Nitroso Compounds: Exposures, Mechanisms, and Relevance to Human Cancer. Cancer Res, v. 48, p.4711-4714, 1988.
BARTSH, H.; MONTESANO, R. Relevance of nitrosamines to human cancer. Carcinogeneses, v. 5, p. 1381, 1984.
BRACHER, F., HEISIG, P., LANGGUTH, P., MUTSCHLER, E., RÜCKER, G., SCHIRMEISTER, T., SCRIBA, G.K.E., STAHL-BISKUP, E., TROSCHÜTZ, R. Arzneibuch-Kommentar, 1. Aufl.inkl. 58. Akt.lfg ed., Wissenschaftliche Verlagsgesellschaft Stuttgart, 2018.
BRASIL ANVISA. Agência Nacional de Vigilância Sanitária. Resolução da Diretoria Colegiada - RDC Nº 166, 24/07/2017. Guia para validação de métodos analíticos - Julho, 2017.
BRASIL. Agência Nacional de Vigilância Sanitária- Anvisa. 29 maio 2019. Aprovado regulamento sobre nitrosaminas. Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2019/aprovado-regulamento-sobre-nitrosaminas. Acesso em: 10 jun. 2019.
BRASIL. Agência Nacional de Vigilância Sanitária- Anvisa. Anvisa lança programa de monitoramento de nitrosaminas. 23 maio 2020 Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2020/anvisa-lanca-programa-de-monitoramento-de-nitrosaminas. Acesso em: 10 jun. 2020.
BRASIL. Agência Nacional de Vigilância Sanitária- Anvisa. Programas de monitoramento analítico. Painel: monitoramento pós-mercado de nitrosaminas em medicamentos. Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/laboratorios/programas-de-monitoramento-analitico-1. Acesso em: out. 2021.
BRASIL. Resolução da Diretoria Colegiada - RDC Nº 283, 17/05/2019. Dispõe sobre investigação, controle e eliminação de nitrosaminas potencialmente carcinogênicas em antagonistas de receptor de angiotensina II. Disponível em https://www.in.gov.br/web/dou/-/resolucao-rdc-n-283-de-17-de-maio-de-2019-118357341. Acesso em: out. 2021.
BUSCHMANN, H; HOLZGRABE, U. NDMA in valsartan, Apoth. v. 158 p. 22–26, 2018.
BUSCHMANN, H; HOLZGRABE, U. Noch mehr nitrosamine. DAZ, v. 1-2, pp. 1-2, 2019.
CASTEGNARO, M; PIGNATELLI, B; WALKER, E.A. Analysis of volatile N-nitrosaminesin commercial drugs. Food Cosmet. Toxicol. v. 19, p. 489–491, 1981.
COUNCIL OF EUROPE, 2019. Control of nitrosamine impurities in sartans: revision of five Ph. Eur. Monographs. Disponível em: https://www.edqm.eu/en/news/control-nitrosamine-impurities-sartans-revision-five-ph-eur-monographs. Acesso em: agosto de 2019.
DAWSON, B.A; LAWRENCE, R.C. Analysis of selected drug formulations forvolatile nitrosamines, J. Assoc. Off. Anal. Chem. v. 70, p. 554–556, 1987.
EISENBRAND, G; SPIEGELHALDER, B., KANN, J; KLEIN, R; PREUSSMANN, R. Carcinogenic N-nitrosodimethylamine as a contamination in drugs containing 4-dimethylamino - 2,3 – dimethyl - 1- phenyl – 3 – pyrazolin – 5 – one (amidopyrine, aminophenazone). Arzneimittel-Forschung. v. 29, p. 867–869, 1979.
EUROPEAN MEDICICINES AGENCY, 2019. Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group. Disponível em: https://www.ema.europa.eu/en/medicines/human/referrals/angiotensin-ii-receptor-antagonists-sartans-containing-tetrazole-group. Acesso em: ago 2019.
FOOD AND DRUG ADMNISTRATION, 2018. U.S. FDA Updates on Valsartan Recalls. Disponível em: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan. Acesso em: ago 2019.
FOYE, W.O; SENGUPTA, S.K. Em Principles of Medicinal Chemistry; FOYE, W. O.; LEMKE, T. L; WILLIAMS, D. A., eds.; Williams & Wilkins: Baltimore, p. 747-780, 2013.
French National Agency for Medicines and Health Products Safety Laboratory Controls Devision. Determination of NDMA in Valsartan Active Substances and Finished Products by HPLC/UV, 2018, Disponível em: https://www.edqm.eu/sites/default/files/omcl-method-determination-ndma-valsartan-ansm-september2018.pdf. Acesso em: jul 2019.
HANIGAN, D; FERRER, I; THURMAN, E.M.; HERCKES, P; WESTERHOFF, P. LC/QTOF-MSfragmentation of N-nitrosodimethylamine precursors in drinking watersupplies is predictable and aids their identification. J. Hazard. Mater. 323, p. 18–25, 2017.
HEALTHY CANADIANS. Multiple lots of irbesartan, losartan and valsartan drugs recalled. Disponível em: https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2021/75715a-eng.php. Acesso em: out 2021.
IARC. Monographs on the Evaluation of Carcinogenic Risks to Humans.Vols 1-80. International Agency for Research on Cancer: Lyon, 1972–2004. v. 1 - 80
IARC. Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Some N-nitrosocompounds, IARC: Lyon, 1978.
INTERNATIONAL COUNCIL FOR HARMONISATION - ICH M7(R1). Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. Current Step, 4. version dated, 31 march 2017.
INTERNATIONAL COUNCIL FOR HARMONISATION - ICH M7.. Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. Current Step, 4. version. 2014.
LEAVEY-ROBACK, S.L; KRASNER, S.W.; SUFFET, I.M. Veterinary antibiotics used inanimal agriculture as NDMA precursors. Chemosphere, v. 164, p. 330–338, 2016.
LECLERC, J. Recall of NDMA-contaminated pseudogeneric valsartan; best generics finally no better than others? Can. J. Cardiol., v. 34, p.1370, 2018.
LIU, W.B.; CHEN, C.; LIU, H.L. Dimethylamine as the key intermediate generated in situ from dimethylformamide (DMF) for the synthesis of thioamides. Beilstein J. Org. Chem., v. 11, p. 1721-1726, 2015.
LV, J.; LI, N. Characterization of seven psychoactive pharmaceuticals as N-nitroso dimethylamine precursors during free chlorine and chlorine dioxide chlorination processes. J. Chem. Technol. Biotechnol., 2018.
LV, J.; WANG, L.; LI, Y. Characterization of N-nitrosodimethylamine formation from the ozonation of ranitidine, J. Environ. Sci., China, v. 58, p. 116–126, 2017.
PETO, R., GRAY, R., BRANTOM, P., GRASSO, P. Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20 weeks) and of species (rats, mice or hamsters). IARC Sci Publ, v. 57, p. 627-665, 1984.
PHARMAZEUTISCHE ZEITUNG, 2019. ZL findet NDMA in Tabletten. Disponível em: https://www.pharmazeutische-zeitung.de/ausgabe-302018/zl-findet-ndma-in-tabletten/. Acesso em: 15 ago. 2019.
REYES, F.G.R.; SCANLAN, R.A. N-nitrosaminas: formação e ocorrência em alimentos. Bol. Soc. Bras. Ciênc. Tecnol. Alim., v. 18, p. 299, 1984.
ROCHE, M.O.G.; MELIAN, M.G.; PEREZ, R.C. Centro Panamericano de Ecología Humana y Salud, OPS, OMS, Metepec, Estado do México: México, v. 13, 1994. Série Vigilância, v.13.
SCHERF-CLAVE, O., KINZIG, M., BESA, A., SCHREIBER, A., BIDMON, C., TAWAB, M.A., WOHLFART, J., HOLZGRABE, U. The contamination of valsartan and other sartans, Part 2: untargeted screening reveals contamination with amides additionally to known nitrosamine impurities. Journal of Pharmaceutical and Biomedical Analysis, v. 172, p. 278-284, 2019.
SHEN, R., ANDREWS, S.A. Demonstration of 20 pharmaceuticals and personalcare products (PPCPs) as nitrosamine precursors during chloraminedisinfection. Water Res. v. 45, p. 944–952, 2011
SWAN, P.F. The toxicology of nitrate, nitrite and N- nitroso compounds. J. Sci. Food Agric., v.26, p.1771- 1783, 1975.
SWISS MEDIC. Monitoring of sartan medicines stepped up: traces of a new foreign substance detected. Chemical compound azidomethyl-biphenyl-tetrazole (AZBT) detected in individual sartans. Disponível em: https://www.swissmedic.ch/swissmedic/en/home/news/mitteilungen/intensivierte-ueberwachung-sartan-arzneimittel.html. Acesso em:10 out. 2021.
TAYLOR, P.; BRADDOCK, P.; CARTER, D. The analysis of N-nitrosodimethylamine inantihistamines and cough/cold preparations, IARC Sci. Publ., p. 575–587, 1980.
THERAPEUTIC Goods Administration - TGA. Azide impurity in 'sartan' blood pressure medicines. TGA investigation - low levels of contamination with azidomethyl-biphenyl-tetrazole (AZBT). Disponível em: https://www.tga.gov.au/alert/azide-impurity-sartan-blood-pressure-medicines. Acesso em: 10 out. 2021.
TRICKER, A.R.; PREUSSMANN, R. Carcinogenic N-nitrosamines in diet: occurrence, formation, mechanism and carcinogenic potential. Mutat. Res., Genet. Toxicol., Amsterdam, v.259, p.277- 289, 1991.
WALTERS, C.L. Reactions of nitrate and nitrite in foods with special reference to the determination of N-nitroso compounds. Food Addit. Contam., London, v.9, n.5, p.441-447, 1992.
WANG, X.; YANG, H.; ZHOU, B.; WANG, X.; XIE, Y. Effect of oxidation on amine-based pharmaceutical degradation and N-Nitrosodimethylamineformation, Water Res. v. 87, p. 403–411, 2015.
WHO. World Health Organization. An overview of the evidence on environmental and occupational determinants of cancer.; WHO technical report series, Asturias, Spain, p. 1, 2011.
ZHANG, A., LI, Y., SONG, Y., LV, J., YANG, J. Characterization of pharmaceuticals andpersonal care products as N-nitrosodimethylamine precursors duringdisinfection processes using free chlorine and chlorine dioxide. J. Hazard. Mater. v. 276, p. 499–509, 2014.
BARTSCH, H, O’NEILL, K.I. Ninth International Meeting on N-Nitroso Compounds: Exposures, Mechanisms, and Relevance to Human Cancer. Cancer Res, v. 48, p.4711-4714, 1988.
BARTSH, H.; MONTESANO, R. Relevance of nitrosamines to human cancer. Carcinogeneses, v. 5, p. 1381, 1984.
BRACHER, F., HEISIG, P., LANGGUTH, P., MUTSCHLER, E., RÜCKER, G., SCHIRMEISTER, T., SCRIBA, G.K.E., STAHL-BISKUP, E., TROSCHÜTZ, R. Arzneibuch-Kommentar, 1. Aufl.inkl. 58. Akt.lfg ed., Wissenschaftliche Verlagsgesellschaft Stuttgart, 2018.
BRASIL ANVISA. Agência Nacional de Vigilância Sanitária. Resolução da Diretoria Colegiada - RDC Nº 166, 24/07/2017. Guia para validação de métodos analíticos - Julho, 2017.
BRASIL. Agência Nacional de Vigilância Sanitária- Anvisa. 29 maio 2019. Aprovado regulamento sobre nitrosaminas. Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2019/aprovado-regulamento-sobre-nitrosaminas. Acesso em: 10 jun. 2019.
BRASIL. Agência Nacional de Vigilância Sanitária- Anvisa. Anvisa lança programa de monitoramento de nitrosaminas. 23 maio 2020 Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2020/anvisa-lanca-programa-de-monitoramento-de-nitrosaminas. Acesso em: 10 jun. 2020.
BRASIL. Agência Nacional de Vigilância Sanitária- Anvisa. Programas de monitoramento analítico. Painel: monitoramento pós-mercado de nitrosaminas em medicamentos. Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/laboratorios/programas-de-monitoramento-analitico-1. Acesso em: out. 2021.
BRASIL. Resolução da Diretoria Colegiada - RDC Nº 283, 17/05/2019. Dispõe sobre investigação, controle e eliminação de nitrosaminas potencialmente carcinogênicas em antagonistas de receptor de angiotensina II. Disponível em https://www.in.gov.br/web/dou/-/resolucao-rdc-n-283-de-17-de-maio-de-2019-118357341. Acesso em: out. 2021.
BUSCHMANN, H; HOLZGRABE, U. NDMA in valsartan, Apoth. v. 158 p. 22–26, 2018.
BUSCHMANN, H; HOLZGRABE, U. Noch mehr nitrosamine. DAZ, v. 1-2, pp. 1-2, 2019.
CASTEGNARO, M; PIGNATELLI, B; WALKER, E.A. Analysis of volatile N-nitrosaminesin commercial drugs. Food Cosmet. Toxicol. v. 19, p. 489–491, 1981.
COUNCIL OF EUROPE, 2019. Control of nitrosamine impurities in sartans: revision of five Ph. Eur. Monographs. Disponível em: https://www.edqm.eu/en/news/control-nitrosamine-impurities-sartans-revision-five-ph-eur-monographs. Acesso em: agosto de 2019.
DAWSON, B.A; LAWRENCE, R.C. Analysis of selected drug formulations forvolatile nitrosamines, J. Assoc. Off. Anal. Chem. v. 70, p. 554–556, 1987.
EISENBRAND, G; SPIEGELHALDER, B., KANN, J; KLEIN, R; PREUSSMANN, R. Carcinogenic N-nitrosodimethylamine as a contamination in drugs containing 4-dimethylamino - 2,3 – dimethyl - 1- phenyl – 3 – pyrazolin – 5 – one (amidopyrine, aminophenazone). Arzneimittel-Forschung. v. 29, p. 867–869, 1979.
EUROPEAN MEDICICINES AGENCY, 2019. Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group. Disponível em: https://www.ema.europa.eu/en/medicines/human/referrals/angiotensin-ii-receptor-antagonists-sartans-containing-tetrazole-group. Acesso em: ago 2019.
FOOD AND DRUG ADMNISTRATION, 2018. U.S. FDA Updates on Valsartan Recalls. Disponível em: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan. Acesso em: ago 2019.
FOYE, W.O; SENGUPTA, S.K. Em Principles of Medicinal Chemistry; FOYE, W. O.; LEMKE, T. L; WILLIAMS, D. A., eds.; Williams & Wilkins: Baltimore, p. 747-780, 2013.
French National Agency for Medicines and Health Products Safety Laboratory Controls Devision. Determination of NDMA in Valsartan Active Substances and Finished Products by HPLC/UV, 2018, Disponível em: https://www.edqm.eu/sites/default/files/omcl-method-determination-ndma-valsartan-ansm-september2018.pdf. Acesso em: jul 2019.
HANIGAN, D; FERRER, I; THURMAN, E.M.; HERCKES, P; WESTERHOFF, P. LC/QTOF-MSfragmentation of N-nitrosodimethylamine precursors in drinking watersupplies is predictable and aids their identification. J. Hazard. Mater. 323, p. 18–25, 2017.
HEALTHY CANADIANS. Multiple lots of irbesartan, losartan and valsartan drugs recalled. Disponível em: https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2021/75715a-eng.php. Acesso em: out 2021.
IARC. Monographs on the Evaluation of Carcinogenic Risks to Humans.Vols 1-80. International Agency for Research on Cancer: Lyon, 1972–2004. v. 1 - 80
IARC. Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Some N-nitrosocompounds, IARC: Lyon, 1978.
INTERNATIONAL COUNCIL FOR HARMONISATION - ICH M7(R1). Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. Current Step, 4. version dated, 31 march 2017.
INTERNATIONAL COUNCIL FOR HARMONISATION - ICH M7.. Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. Current Step, 4. version. 2014.
LEAVEY-ROBACK, S.L; KRASNER, S.W.; SUFFET, I.M. Veterinary antibiotics used inanimal agriculture as NDMA precursors. Chemosphere, v. 164, p. 330–338, 2016.
LECLERC, J. Recall of NDMA-contaminated pseudogeneric valsartan; best generics finally no better than others? Can. J. Cardiol., v. 34, p.1370, 2018.
LIU, W.B.; CHEN, C.; LIU, H.L. Dimethylamine as the key intermediate generated in situ from dimethylformamide (DMF) for the synthesis of thioamides. Beilstein J. Org. Chem., v. 11, p. 1721-1726, 2015.
LV, J.; LI, N. Characterization of seven psychoactive pharmaceuticals as N-nitroso dimethylamine precursors during free chlorine and chlorine dioxide chlorination processes. J. Chem. Technol. Biotechnol., 2018.
LV, J.; WANG, L.; LI, Y. Characterization of N-nitrosodimethylamine formation from the ozonation of ranitidine, J. Environ. Sci., China, v. 58, p. 116–126, 2017.
PETO, R., GRAY, R., BRANTOM, P., GRASSO, P. Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20 weeks) and of species (rats, mice or hamsters). IARC Sci Publ, v. 57, p. 627-665, 1984.
PHARMAZEUTISCHE ZEITUNG, 2019. ZL findet NDMA in Tabletten. Disponível em: https://www.pharmazeutische-zeitung.de/ausgabe-302018/zl-findet-ndma-in-tabletten/. Acesso em: 15 ago. 2019.
REYES, F.G.R.; SCANLAN, R.A. N-nitrosaminas: formação e ocorrência em alimentos. Bol. Soc. Bras. Ciênc. Tecnol. Alim., v. 18, p. 299, 1984.
ROCHE, M.O.G.; MELIAN, M.G.; PEREZ, R.C. Centro Panamericano de Ecología Humana y Salud, OPS, OMS, Metepec, Estado do México: México, v. 13, 1994. Série Vigilância, v.13.
SCHERF-CLAVE, O., KINZIG, M., BESA, A., SCHREIBER, A., BIDMON, C., TAWAB, M.A., WOHLFART, J., HOLZGRABE, U. The contamination of valsartan and other sartans, Part 2: untargeted screening reveals contamination with amides additionally to known nitrosamine impurities. Journal of Pharmaceutical and Biomedical Analysis, v. 172, p. 278-284, 2019.
SHEN, R., ANDREWS, S.A. Demonstration of 20 pharmaceuticals and personalcare products (PPCPs) as nitrosamine precursors during chloraminedisinfection. Water Res. v. 45, p. 944–952, 2011
SWAN, P.F. The toxicology of nitrate, nitrite and N- nitroso compounds. J. Sci. Food Agric., v.26, p.1771- 1783, 1975.
SWISS MEDIC. Monitoring of sartan medicines stepped up: traces of a new foreign substance detected. Chemical compound azidomethyl-biphenyl-tetrazole (AZBT) detected in individual sartans. Disponível em: https://www.swissmedic.ch/swissmedic/en/home/news/mitteilungen/intensivierte-ueberwachung-sartan-arzneimittel.html. Acesso em:10 out. 2021.
TAYLOR, P.; BRADDOCK, P.; CARTER, D. The analysis of N-nitrosodimethylamine inantihistamines and cough/cold preparations, IARC Sci. Publ., p. 575–587, 1980.
THERAPEUTIC Goods Administration - TGA. Azide impurity in 'sartan' blood pressure medicines. TGA investigation - low levels of contamination with azidomethyl-biphenyl-tetrazole (AZBT). Disponível em: https://www.tga.gov.au/alert/azide-impurity-sartan-blood-pressure-medicines. Acesso em: 10 out. 2021.
TRICKER, A.R.; PREUSSMANN, R. Carcinogenic N-nitrosamines in diet: occurrence, formation, mechanism and carcinogenic potential. Mutat. Res., Genet. Toxicol., Amsterdam, v.259, p.277- 289, 1991.
WALTERS, C.L. Reactions of nitrate and nitrite in foods with special reference to the determination of N-nitroso compounds. Food Addit. Contam., London, v.9, n.5, p.441-447, 1992.
WANG, X.; YANG, H.; ZHOU, B.; WANG, X.; XIE, Y. Effect of oxidation on amine-based pharmaceutical degradation and N-Nitrosodimethylamineformation, Water Res. v. 87, p. 403–411, 2015.
WHO. World Health Organization. An overview of the evidence on environmental and occupational determinants of cancer.; WHO technical report series, Asturias, Spain, p. 1, 2011.
ZHANG, A., LI, Y., SONG, Y., LV, J., YANG, J. Characterization of pharmaceuticals andpersonal care products as N-nitrosodimethylamine precursors duringdisinfection processes using free chlorine and chlorine dioxide. J. Hazard. Mater. v. 276, p. 499–509, 2014.
Publicado
2022-07-08
Como Citar
OCHS, S.; SANTANA, D.; DE LIMA, P.; NOVOTNY, T.; LIMA, M. E.; DANTAS, A. S.; DE SOUZA, M.; DOS SANTOS, L.; MONTEIRO, M. Riscos sobre a presença de impurezas de n-nitrosaminas e azidas em medicamentos. Revista Científica do UBM, v. 24, n. 47, p. 144-160, 8 jul. 2022.
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