Rachel Simões Pimenta Riechelmann
Risco de Interações Medicamentosas em Pacientes com Câncer e
Recebendo Cuidados de Suporte Exclusivo
Tese apresentada à Universidade Federal de São Paulo – Escola Paulista de Medicina para obtenção de título de Doutor em Ciências
Rachel Simões Pimenta Riechelmann
Risco de Interações Medicamentosas em Pacientes com Câncer e
Recebendo Cuidados de Suporte Exclusivo
Tese apresentada à Universidade Federal de São Paulo – Escola Paulista de Medicina para obtenção de título de Doutor em Ciências
Área de concentração: Clínica Médica
Orientador: Profo. Dro. Auro Del Giglio
Riechelmann, RSP.
Risco de interações medicamentosas em pacientes com câncer e recebendo cuidados de suporte exclusivo. Rachel Simões Pimenta Riechelmann. São Paulo, 2009.
Palavras-chaves:
1. interações medicamentosas 2. cuidados de suporte 3. câncer 4. varfarina 6. anticonvulsivantes
p.1-79
Tese (Doutorado) - Universidade Federal de São Paulo, Escola Paulista de Medicina. Programa de Pós-Graduação em Clínica Médica.
Título em inglês: Risk of drug interactions among cancer patients who are receiving sopportive care exclusively.
DEDICATÓRIA
Ao meu esposo, Ederson, pelo suporte, cumplicidade e paciência infindáveis nos anos em que este trabalho foi realizado.
Ao meu irmão, Rivaldo, pelo amor e amizade eternos.
Aos meus amigos e mestres Ian Tannock, Monika Krzyzanowska e Camilla Zimmermann: sem seu apoio e ensinamentos, este estudo nunca teria sido possível.
AGRADECIMENTOS
Ao meu amigo e orientador, Auro Del Giglio, por abrir a porta quando precisei e por tornar este doutorado uma realidade. Sem ele, esta tese estaria somente no papel.
À Profa Dra Leny Toma, que possibilitou a realização deste sonho.
A colaboradora Sheray Chin, por me ajudar a coletar os dados num tempo recorde!
As minhas amigas e mestras, Monika Krzyzanowska e Camilla Zimmermann, por todos seus conselhos e supervisão no desenho do estudo.
A estatística Lisa Wang pela essencial colaboração.
A meu mestre e amigo Ian Tannock, pela amizade e suporte neste e tantos outros projetos, que me permitiram realizar minha pós-graduação em pesquisa clínica.
À Universidade de Toronto, pelo apoio financeiro.
Agradeço aos meus amigos “Novartianos”:
Marcos Figueira: pelos artigos solicitados, sempre entregues de forma tão rápida!
Danielly Vicente, Flávia Kiertsman, Débora Barton: por fazerem rir e me encorajar sempre
Trabalho realizado com auxílio financeiro da Universidade de Toronto, Toronto, Ontário, Canadá
APRESENTAÇÃO
RESUMO
1. INTRODUÇÃO
1.1. Conhecimento geral sobre interações medicamentosas 1.2. Interações medicamentosas em oncologia
1.3. Justificativa e hipótese
2. OBJETIVOS
3.REFERÊNCIAS
4. ARTIGOS 1
1-“Drug interactions in oncology: how common are they?”
Annals of Oncology 2009 in press
5.RESUMO DOS ACHADOS DO ARTIGO 1
6.ARTIGO 2
2- “Potential drug interactions in cancer patients receiving supportive care exclusively”
Journal of Pain & Symptom Management 2008; 35 (5): 535-43
7.RESUMO DOS ACHADOS DO ARTIGO 2
8.RESULTADOS EM PERSPECTIVAS
APRESENTAÇÃO
Esta obra inclui uma Introdução que fornece a base científica para compreensão e justificativa dos artigos desenvolvidos sob o mesmo tema geral, finalizando com os Objetivos de cada um. Na seqüência, apresentam-se as Referências do texto
introdutório. Na seqüência, apresentam-se os artigos científicos que compõem esta tese de doutorado na língua e formato nos quais foram submetidos à publicação. O projeto que deu origem aos artigos foi aprovado pelo Comitê de Ética do Hospital Princess Margaret, Universidade de Toronto, Toronto, ON, Canadá. A revisão sistemática foi totalmente realizada no Brasil.
Utiliza-se do capítulo de Resumo dos Achados para consolidar as principais contribuições que os presentes estudos trouxeram ao conhecimento na área.
As Conclusões referem-se ao conjunto da obra.
Este modelo “não-tradicional” de tese de doutorado atende às normas da Pró-Reitoria de Pós-Graduação da Universidade Federal de São Paulo – Escola Paulista de Medicina. O exemplar apresentado à banca examinadora para defesa pública poderá sofrer modificações segundo sugestões da mesma, para ser, então, elaborada sua versão definitiva.
RESUMO
Risco de interações medicamentosas em pacientes com câncer e recebendo cuidados de suporte exclusivo, por Riechelmann, RSP, Tese de doutorado. Universidade Federal de São Paulo, Escola Paulista de Medicina. São Paulo, 2009.
Interações medicamentosas são freqüentes e representam uma causa importante de morbidade e mortalidade em todo o mundo. Um número desconhecido de pacientes com câncer experimenta reações e interações de drogas graves, podendo resultar em hospitalização e até em morte. Particularmente, pacientes portadores de neoplasia maligna comumente recebem um grande número de medicamentos, além de receberem drogas com alto risco de efeitos adversos. Desta forma, dois estudos foram realizados como base para esta tese: uma revisão sistemática e em estudo retrospectivo.
A revisão sistemática da literatura avaliou os estudos publicados sobre a epidemiologia de interações medicamentosas em pacientes com câncer. A busca identificou 8 estudos: 7 artigos publicados no PubMed e um resumo publicado nos proceedings do congresso da sociedade americana de oncologia (ASCO). A maioria dos estudos era retrospectiva e avaliou potenciais interações medicamentosas, com apenas dois estudos publicados sobre reais interações medicamentosas. Aparentemente, um terço dos pacientes oncológico ambulatoriais recebe combinações de drogas com risco de interação. Os principais fatores de risco para interações medicamentosas são: idade avançada, número crescente de medicações, presença de lesões cerebrais (primárias ou secundárias) e pacientes que recebem drogas consideradas de risco como anticonvulsivantes, varfarina e anti-inflamatórios hormonais e não-hormonais.
1. INTRODUÇÃO
1.1. Conhecimento geral sobre interações medicamentosas
Interação medicamentosa se define por interação entre duas drogas, uma droga e um alimento ou ainda, uma droga e fatores físicos, onde o fator que interage com a droga pode alterar o efeito farmacológico desta medicação. No caso das interações medicamentosas entre drogas, esta interação pode causar aumento ou redução do efeito da outra droga, conseqüentemente alterando o efeito biológico desejado de uma determinada medicação. Nesta dissertação, falaremos somente sobre as interações medicamentosas entre drogas.
As interações medicamentosas são classificadas em três tipos: farmacocinéticas, farmacodinâmicas e farmacêuticas.[1] As interações farmacocinéticas são definidas como aquelas em que uma droga altera a absorção, distribuição ou eliminação (metabolização ou excreção) da outra. Estas interações podem ser mensuradas por meio de parâmetros farmacocinéticos, tais como concentrações sérica e urinária, exposição (área sob a curva) e meia vida de eliminação. Dexametasona e fenitoína, por exemplo, interagem desta maneira; uma droga inibe o metabolismo hepático da outra, através de interação com enzimas do complexo do citocromo P450 (CYPs).[2] O cetoconazol, por exemplo, tem sua absorção reduzida no pH gástrico alcalino promovido pelos inibidores da bomba de prótons.[3] Na prática clínica, as principais interações entre medicações são do tipo farmacocinético e envolvem os bem conhecidos indutores e inibidores enzimáticos (drogas que levam a maior e menor atividade de enzimas CYPs, respectivamente).[1] Os indutores enzimáticos mais relevantes na prática clínica são corticosteróides, fenitoína, fenobarbital, carbamazepina e rifampicina, que diminuem os níveis séricos e, conseqüentemente, o efeito e a toxicidade de dicumarínicos, anticoncepcionais orais, cloranfenicol, ciclosporina, metronidazol, verapamil e teofilina, entre outros.[1] Os mais conhecidos inibidores de enzimas CYPs na prática clínica são cimetidina, eritromicina, isoniazida, cloranfenicol, cetoconazol, alopurinol, amiodarona e inibidores da monoamina oxidase.[1] Os inibidores podem bloquear diretamente uma determinada enzima, como por exemplo a cimetidina faz com P450,[1] ou então saturá-la, como fazem por exemplo imipramina e fluoxetina, que são metabolizadas pela mesma via enzimática.
adição/sinergismo ou antagonismo de seus efeitos.[1] A co-administração de naloxona e morfina é um exemplo de antagonismo entre drogas: a naloxona antagoniza os efeitos de depressão respiratória e analgesia da morfina porque ambos bloqueiam os receptores Mu localizados no tronco cerebral. O tipo farmacêutico de interações medicamentosas ocorre fora do corpo humano, geralmente nos recipientes de mistura, como seringas, e diz respeito àquelas drogas que possuem incompatibilidades físico-químicas entre si, levando à inativação de uma das drogas.
O risco de interações entre drogas aumenta com o número de medicações, idade do paciente, presença de comorbidades e fatores genéticos individuais.[4-6] Porém, como é muito difícil predizer quem irá desenvolver uma interação medicamentosa, os médicos terminam por utilizar de forma cautelosas medicamentos com alto potencial de interação, como por exemplo, fenitoína, cetoconazol e digoxina, e, em alguns casos, com monitoramento do seu efeito, como por exemplo, medida da atividade de protrombina durante o uso da varfarina.
Vários estudos em medicina geral avaliaram o risco de interações medicamentosas. Estudos robustos que avaliaram a epidemiologia de potenciais interações medicamentosas entre pacientes internados mostraram que aproximadamente 60% destes pacientes estavam sob risco de interações entre drogas.[7-9] Já estudos conduzidos em departamentos de emergência identificaram freqüências de potenciais interações de 16 a 47%.[10-12] Dentre 103 pacientes ambulatoriais avaliados pelo seu médico de família, quase 70% estavam utilizando combinações de drogas com risco de interação.[13] Um outro estudo epidemiológico rastreou mais de cinco milhões de prescrições do sistema de saúde francês para potenciais interações medicamentosas, encontrando 2% de prescrições com contra-indicação relativa ou total.[14] Desta forma, podemos observar que a frequência de interações medicamentosas varia de acordo com a população e contexto do estudo.
1.2. Interações medicamentosas em oncologia
potenciais interações em pacientes com câncer. O primeiro, estudo piloto retrospectivo e conduzido no Brasil, descreveu a freqüência de potenciais interações medicamentosas em pacientes portadores de tumores sólidos ou cânceres hematológicos que haviam sido internados para tratamento de complicações do câncer ou da terapia antineoplásica e/ou procedimentos invasivos; estes pacientes não estavam recebendo tratamento antineoplásico na época do estudo.[15]
benzodiazepínicos, fenotiazinas, dexametasona, imidazólicos, tiroxina, furosemida, anticonvulsivantes, antiinflamatórios não hormonais (AINH), heparinas de baixo peso molecular (HBPM) e omeprazol. As combinações com potencial interativo mais prescritas foram: opióides e benzodiazepínicos, ISRS e opióides, AINH e HBPM, dexametasona e fenitoína, e omeprazol e benzopiazepínicos. Em análise multivariada, o tempo de internação e número de medicamentos prescritos foram fatores independentes para um risco aumentado de potenciais interações entre drogas.[15]
O segundo estudo foi uma avaliação transversal da epidemiologia de potenciais interações medicamentosas em pacientes canadenses ambulatoriais portadores de tumores sólidos que estavam recebendo terapia antineoplásica.[16] Os pacientes preencheram um questionário sobre os remédios utilizados nas últimas quatro semanas, além de dados demográficos e características do tumor e seu tratamento. Numa amostra de mais de 400 pacientes recrutados num período de 12 meses, 279 potenciais interações medicamentosas foram identificadas, com 27% dos doentes estando expostos a pelo menos uma combinação de drogas com risco de interação.[16] O estudo também avaliou a gravidade e a evidência científica das interações encontradas; o método de rastreamento e classificação das interações foi o programa eletrônico Drug Interaction Facts versão 4.0.[17] Mais de 80% das potenciais interações foram classificadas como graves (risco de vida) ou moderadas (risco de dano a saúde) e quase metade possuía evidência sólida na literatura. A maior parte (87%) das interações identificadas envolveu drogas utilizadas para tratar comorbidades, tais como varfarina, anticonvulsivantes, corticóides e anti-hipertensivos.[16] A análise de regressão logística identificou como fatores associados à utilização de combinações medicamentosas com potencial de interação, o número de drogas que os pacientes utilizaram, presença de tumores cerebrais (primários ou metástases) e uso de drogas para tratamento de doenças concomitantes.[16]
1.3. Justificativa e Hipótese
Interações medicamentosas são freqüentes e representam uma causa importante de morbidade e mortalidade em todo o mundo. Um número indeterminado de pacientes com ou sem câncer experimenta reações e interações de drogas graves, podendo resultar em hospitalização e até em morte. Particularmente, pacientes portadores de neoplasia maligna comumente recebem um grande número de medicamentos. Além de comorbidades, numerosas síndromes coexistem no doente com câncer (dor, náusea, depressão psíquica, hipercalcemia, crises convulsivas etc), o que o leva a receber diversos medicamentos para alívio sintomático. Todo esse arsenal farmacológico pode levar a possíveis interações medicamentosas. Desta forma, a prescrição não criteriosa de drogas com potencial de interação pode provocar sintomas novos, mascarar sintomas antigos e novos, dificultar diagnósticos diferenciais com outras causas ou com a progressão do tumor e até promover risco de vida para o paciente.
Os autores realizaram uma revisão sistemática da literatura sobre a epidemiologia de interações medicamentosas em oncologia (Artigo 1).
2. OBJETIVOS
2. OBJETIVOS
Artigo 1 “drug interactions in oncology: how common are they?”
1. Reportar os estudos sobre a epidemiologia de interações medicamentosas em pacientes com câncer.
2. Descrever a freqüência de potenciais interações medicamentosas em oncologia 3. Descrever a freqüência de reais interações medicamentosas em oncologia 4. Reportar os fatores de risco para interações medicamentosas em oncologia 5. Listar as combinações de drogas mais comumente associadas a interações
medicamentosas que foram reportadas na literatura
Artigo 2 “potential drug interactions in cancer patients receiving supportive care exclusively ”
1. Avaliar a freqüência com que pacientes oncológicos terminais utilizavam medicações com risco de interagirem entre si.
2. Reportar as interações medicamentosas mais comumente encontradas
3. REFERÊNCIAS
1. Scripture CD, Figg WD: Drug interactions in cancer therapy. Nat Rev Cancer 6:546-58, 2006
2. Lackner TE: Interaction of dexamethasone with phenytoin. Pharmacotherapy 11:344-7, 1991
3. Chin TW, Loeb M, Fong IW: Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole. Antimicrob Agents Chemother 39:1671-5, 1995
4. Riechelmann RP, Saad ED: A systematic review on drug interactions in oncology. Cancer Invest 24:704-12, 2006
5. Carbonin P, Pahor M, Bernabei R, et al: Is age an independent risk factor of adverse drug reactions in hospitalized medical patients? J Am Geriatr Soc 39:1093-9, 1991
6. Heininger-Rothbucher D, Bischinger S, Ulmer H, et al: Incidence and risk of potential adverse drug interactions in the emergency room. Resuscitation 49:283-8, 2001
7. Egger SS, Drewe J, Schlienger RG: Potential drug-drug interactions in the medication of medical patients at hospital discharge. Eur J Clin Pharmacol 58:773-8, 2003
8. Geppert U, Beindl W, Hawranek T, et al: [Drug interactions in clinical practice. A pilot project for quality assurance in prescribing]. Hautarzt 54:53-7, 2003
9. Glintborg B, Andersen SE, Dalhoff K: Drug-drug interactions among recently hospitalised patients--frequent but mostly clinically insignificant. Eur J Clin Pharmacol 61:675-81, 2005
10. Karas S: The potential for drug interactions. Ann Emerg Med 10:627-30, 1981
11. Herr RD, Caravati EM, Tyler LS, et al: Prospective evaluation of adverse drug interactions in the emergency department. Ann Emerg Med 21:1331-6, 1992
12. Goldberg RM, Mabee J, Chan L, et al: Drug-drug and drug-disease interactions in the ED: analysis of a high-risk population. Am J Emerg Med 14:447-50, 1996
13. Davidson KW, Kahn A, Price RD: Reduction of adverse drug reactions by computerized drug interaction screening. J Fam Pract 25:371-5, 1987
15. Riechelmann RP, Moreira F, Smaletz O, et al: Potential for drug interactions in hospitalized cancer patients. Cancer Chemother Pharmacol 56:286-90, 2005
16. Riechelmann RP, Tannock IF, Wang L, et al: Potential drug interactions and duplicate prescriptions among cancer patients. J Natl Cancer Inst 99:592-600, 2007
17. Health WK: Drug Interaction Facts, version 4.0, in Comparisons Fa (ed). St Louis, 2006
4. ARTIGO 1
Submetido para publicação em 14 de junho de 2009, ao jornal Annals of Oncology (Anexo 2) e aceito para publicação em 3 de julho de 2009.
“
Drug Interactions in Oncology: how common are they?”
Rachel P. Riechelmann, MD1 and Auro Del Giglio, MD PhD2
1
Federal University of Sao Paulo, Brazil 2
ABC School of Medicine, Brazil
Correspondence to:
Rachel P. Riechelmann, MD Av Vicente Rao 90
Sao Paulo, SP,
Phone: +55 11 99320868 rachelri@terra.com.br
Key Words (MeSH): adverse effects; drug interactions; drug therapy, combination; neoplasms.
Running title: drug interactions in oncology
ABSTRACT
Background: Drug-drug interactions (DDIs) comprise an important problem in medical oncology practice. We systematically reviewed the frequency of DDIs in oncology.
Methods: We searched PubMed for eligible articles and online databases abstracts of major oncology meetings.
Results: Eight studies reported on the frequency of DDIs: six evaluated the frequency of potential DDIs while 2 studies reported on real DDIs, i.e. interactions that had clinical consequences. Studies of potential DDIs found that approximately one third of patients are exposed to dangerous drug doublets, with the most common ones involving warfarin and anticonvulsants. One study of real DDIs found that 2% of hospitalized cancer patients had a DDI as the cause of admission.
INTRODUCTION
A drug-drug interaction (DDI) is defined as an increase or decrease in the clinical effect of a given drug due to interference by another drug;[1] they can occur between drugs and between drugs and food, herbs, formulations excipients/containers or environmental factors (such as tobacco) and are classified into three types: pharmacokinetic, pharmacodynamic, and pharmaceutical.[1] DDI comprise a significant cause of morbidity and mortality worldwide as they may lead to adverse clinical events, result in decrease/inactivation of the therapeutic effect of a drug, may enhance drug toxicity, and indirectly compromise treatment outcomes and adherence.
Studies in general medicine have evaluated the frequency of adverse drug events, including drug interactions, among patients with various medical conditions. They have found frequency of potential drug interactions ranging from a low of 16% among emergency room patients to a high of 70% in a population of ambulatory patients being treated by their family physician.[2, 3] A large population study which analyzed more than five million prescriptions in the French healthcare, identified 2% of outpatients who were prescribed either absolutely or relatively contraindicated drug combinations.[4]
In theory patients with cancer are particularly susceptible to DDIs because they frequently take many medications - to treat their cancer, to treat treatment-induced toxicity and cancer-related syndromes, and drugs to treat other comorbid illnesses.[5] In addition their pharmacokinetic parameters may be distorted because of impaired absorption due to mucositis, increased volume of distribution resulting from edema and malnutrition, and altered excretion secondary to organ dysfunction. However, the exact prevalence of DDIs among cancer patients is unknown. Because of different study designs, screening methods and study populations, the rates of potential drug interactions have varied in the literature.
We have made a systematic review on the epidemiology of drug-drug interactions in oncology.
METHODS
33,000 articles came up, we changed the search to use the title words “drug interactions” AND “oncology” and “drug interactions” AND “cancer”, limiting the search to articles published in English, Portuguese and Spanish. We also sought relevant articles within the reference lists of publications selected for the primary search. We complemented the search with abstracts presented at the American Society of Clinical Oncology (ASCO) meetings from 2005 to 2008; this time span was selected because we considered that studies presented before 2005 were likely to be already published. We used the ASCO website electronic engine to look for eligible studies, utilizing the words “drug interaction” or “drug interactions” listed in the abstracts’ titles. Drug-food, herb and drug-supplement interactions were beyond the scope of this review.
Descriptive statistics were used to describe the results, separated by potential versus real drug-drug interactions.
RESULTS
The primary search retrieved 25 articles (24 full articles from PubMed and one abstract from ASCO) and eight were considered eligible. The results are described separately as (i) Potential drug interactions, i.e. drug combinations with the potential to interact and (ii) Real drug interactions, i.e. drug interactions that resulted in clinical and/or laboratory consequences. A summary of common examples of DDIs reported by the selected studies is listed in Table 3.
Potential drug interactions in oncology
Six articles describing the epidemiology of potential DDIs in oncology were identified. All but one study were performed in a single institution, and most used electronic methods to screen for potential DDIs. The frequency of potential DDI varied from one 12% to 63%, mainly depending on the type of study population. The main findings from these articles are summarized below and in Table 2.
been shown to have an accuracy of more than 95% in detecting previously known drug interactions. [7] The program classifies interactions by pharmacological mechanisms, levels of severity (major, when an interaction could offer risk of death, moderate, when the clinical consequence of an interaction required medical attention, or minor, when minimum clinical effect was expected from the combination of two drugs) and scientific evidence from the literature (rated in a 5-point scale, where level 1 represents a drug interaction supported by clinical trials and level 5 means a theoretical risk for interaction). According to the Drug Interaction Facts classification, interactions were moderate or severe in 75% of the cases and the most common combinations with potential for interaction were opioids with benzodiazepines, selective serotonin reuptake inhibitors (SSRI) with opioids, nonsteroidal anti-inflammatory drugs (NSAID) with low molecular weight heparins (LMWH), dexamethasone with phenytoin, and omeprazole with benzodiazepines.
A cross-sectional multicenter study assessed consecutive 98 colorectal cancer outpatients who were receiving systemic treatment with irinotecan- and/or oxaliplatin-based regimens with the aim of identifying potential DDIs involving such agents.[8] They searched PubMed and EMBASE for known DDIs involving irinotecan and oxaliplatin and examined whether patients were taking those drug combinations with the potential to interact that were selected by the literature search. The authors used the Drug Interaction Facts program and also a panel of oncologists and pharmacists to classify DDIs in terms of clinical significance; the panel scored 12 clinically significant DDI involving these agents. The study found that 71 irinotecan-treated patients were taking at least one drug that could potentially interact with this topoisomerase inhibitor, with the most common ones being loperamide (85% of the 75 patients), dexamethasone (60%) and phenytoin (one patient). No significant potential DDI was identified among oxaliplatin-treated subjects.[8]
anticancer drugs. The potential drug interactions between antineoplastic agents and general medications identified were warfarin associated with either capecitabine, fluorouracil, carboplatin, gemcitabine or paclitaxel (15 cases), hydrochlorothiazide combined with fluorouracil and cyclophosphamide (6 cases), quinolones combined with cyclophosphamide (5 cases), ondasetron and cisplatin (4 cases) and one case each of warfarin given concurrently with tamoxifen, phenytoin and cisplatin, ketoconazol with a protom pump inhibitor, phenytoin with fluorouracil, cimetidine with fluorouracil, and furosemide and cisplatin. Among the 240 potential interactions between ordinary medications, the most common ones were aspirin combined with either a beta-blocker or an angiotensin converting enzyme inhibitor (19 cases), aspirin and a corticosteroid (14 cases), warfarin and a corticosteroid (13 cases) and an angiotensin converting enzyme inhibitor in association with prochlorperazine (9 cases). In adjusted analysis, increasing number of medications (Odds ratio: 1.4; p < 0.0001), the type of medications (Odds ratio: drugs to treat comorbid conditions versus supportive care drugs: 8.6; p < 0.0001; Odds ratio: both types of medications versus supportive care drugs: 2.5; p = 0.018) and cancer type (Odds ratio: brain versus genitor-urinary tumors: 6.7; p = 0.0025) were associated with risk of drug interactions.
A similar study evaluated 100 randomly selected cancer patients older than 70 years and who were on active cancer-directed therapy for potential DDI.[10] The median number of medications was nine per patient and 19% were taking cimetidine, a known CYP3 inhibitor, combined with other drugs such as carboplatin and warfarin. Curiously, no oncologist made any change in patients´ prescriptions despite being alerted about such interactions by the authors. Oncologists claimed that lack of DDI guidelines prevented them from making drug changes or adjustments.
One only study evaluated cancer patient at the end of life. A retrospective study examined the frequency of potential DDIs among patients with advanced cancer who were receiving exclusive supportive care, i.e., they excluded patients who were receiving anticancer treatment. [11] They found that one third (29%; 250 out of 372) of patients were exposed to drug combinations with the potential to interact and that most potential drug interactions involved the same types of medications: aspirin, anticonvulsants and warfarin.
with the potential to interact with other medications.[12] On regression analysis, the authors found that use of p450 inhibitors seemed to be associated with severe non-hematological adverse events, although this result was not statistically significant.
Real drug interactions
Two studies reported on the epidemiology of real DDI (Table 2).
A large retrospective study analyzed all deaths that occurred in a Norwegian hospital during two years in order to evaluate how often deaths resulted from adverse drug reactions. They found that 18% of 732 deaths were directly or indirectly associated with adverse drug events, including drug interactions, and that 4% of the cancer related-deaths were likely to involve a severe drug-related event.[13]
A retrospective study evaluated the charts of all cancer patients admitted to an oncology ward during an 8-month period for reasons of hospitalization.[14] Each hospitalization was independently evaluated by two blinded investigators using a 4-point scale that was developed to classify such reasons by their probability to be associated with either a DDI or an adverse drug reaction (definitely associated, probably associated, possibly associated or unlikely associated).[15] Among 550 hospital admissions, 458 were eligible. Among unplanned admissions (N=298), 33 (11.0%, 95% CI 7.7 – 15.2%) were associated with an adverse drug reaction and 6 (2.0%, 95% CI 0.7 – 4.3%) with a DDI, involving warfarin, captopril and anti-inflammatory agents. The most common adverse drug reaction leading to hospitalization was neutropenic fever post systemic chemotherapy. Most patients were discharged completely recovered but 2 patients with neutropenic fever died. Risk factors for being hospitalized to treat a DDI could not be identified due to the small number of cases of real DDI.[15]
DISCUSSION
Specifically about potential drug interactions, one third of ambulatory cancer patients are apparently exposed to potential DDI.[9, 16] Regardless whether patients were under chemotherapy treatment, the most dangerous combinations involve drugs to treat comorbid conditions such as antihypertensives, warfarin and anticonvulsants. Significant risk factors include presence of brain tumors/metastasis, number of medications taken by patients and use of drugs to treat comorbidities. It is likely that due to the frequent use of anticonvulsants among cancer patients with brain lesions, the tumor is a confounder as anticonvulsants, known to be enzymatic inducers, are drugs known to interact with other agents.[17, 18] The number of medications is an intuitive risk factor and with respect to drugs used for comorbid illnesses, medications such as aspirin, enzyme-converting enzyme inhibitors and warfarin also have potential to interact with other drugs.[19]
The available information about real drug interactions is less clear. The impact of DDI that resulted in clinical events remains to be elucidated. However, it has been shown that real DDIs involved the same medications, warfarin, phenytoin and captopril, considered potentially hazardous by the studies that sought potential DDIs. Therefore it is advisable to pay close attention to cancer patients taking these drugs and if feasible, safer alternatives should be prescribed; for example, low molecular weight heparins do not interact with liver CYP enzymes and could therefore substitute warfarin as an anticoagulant, considering there is not cost issues. In the case a doublet cannot be substituted, as for instance dexamethasone and phenytoin, commonly used by patients with brain lesions, patients taking these drugs should be closely monitored for adverse events and DDIs. It is of note that even though some light has been shed on the subject, the fact that they were single institution studies, were retrospective (not performed in real time of patient admission) might have underpowered the studies to detect clinically important DDIs. Moreover, in the study patients did not have access to new molecular targeted therapy, what makes the results less generalizable to the current practice of oncology.
evaluate the clinical outcomes of drug interactions in a prospective manner without modifying or stopping the medications involved. Recall bias from patients´ part and missed data from retrospective chart reviews are also important drawbacks to consider.
Studies of real drug interactions are also flawed by several confounders such as cancer signs and symptoms, the difficulty to diagnose a drug interaction and also, to prove its causality. Population-based studies have the advantage of large samples and thus, less susceptible to selection bias, when compared to single-institution analyses. Another advantage is to study the prevalence of certain well-known drug interactions, for instance, by quantification of number of hospitalizations resulting from severe hemorrhage that was caused by combining warfarin with capecitabine.[20] Large population studies can even identify risk factors for drug interactions that led to hospital admission. The major disadvantage is that such studies are capable of identifying only drug interactions that led to meaningful adverse events; they cannot assess the real magnitude of drug interactions, i. e., those that led to adverse clinical events that did not bring patients to medical attention. Population studies also need representative and accurate administrative databases.
Another important aspect not covered by these studies is the economic impact of DDIs in medical oncology practice. It is important that not only serious DDIs leading to hospitalization be evaluated for costs but also minor DDIs, which may make the oncologist repeat blood tests, prescribe medications to treat new symptoms, require more visits to the hospital. Population studies could address that issue in collecting information on cost incurred by hospitalizations and invasive proceedings. It is recognizable, though, that the logistics of performing this analysis is far complex as it involves the correct diagnosis of real DDIs.
professionals to identify dangerous drug combinations. The disadvantage of screening all patients is the time spent to do it and the high likelihood to find many non-clinically significant potential drug interactions. A more logical manner is to screen patients at considerable risk for such serious drug interactions as patients taking drugs to treat concurrent illnesses, specially warfarin, anticonvulsants and anti-hypertensives. Other essential attitudes to prevent hazardous drug interactions include the switch of risky drugs to safer alternatives, avoid polypharmacy, and be familiar with potential drug interactions involving medications that are routinely prescribed to one’s patients.
Indirectly, health professionals could decrease the frequency of clinically meaningful drug interactions by increasing awareness about them. Publication of case reports, case discussion at medical rounds, teaching medical students/residents, involving the pharmacy team to discuss patient prescription, and standardized hospital monitoring of adverse drug reactions could increase the recognition and facilitate the prevention of drug interactions.
In conclusion, although it seems that one third of cancer outpatients are at risk of DDI, the proportion of them who actually suffer from DDIs remains unknown. Drugs that should be cautiously prescribed by physicians include warfarin, anticonvulstants and anti-hypertensives. There are still many issues to be investigated about the real impact of DDIs in oncology: how common DDIs involving molecular targeted therapy are and the
Table 1. Characteristics of eligible articles
Characteristic N
All articles 8
Single institution studies 7
Median Number of subjects per study 216 (98 – 732) Design
Prospective/ cross-sectional Retrospective
2 6 Setting
Ambulatory Hospital
5 3 Primary endpoint
Potential drug interaction Real drug interaction
Table 2. Studies of potential drug interactions
Reference patienNo of ts
No of centers per study
Setting/
Population Design Screening method Findings Potential Drug Interactions
Riechelman n et al [6]
100 one Hospital/
Solid and hematologic tumors; patients hospitalized to treat cancer- or anticancer therapy-related complications
retrospecti
ve Drug Interaction Facts software[21]
63% of patients exposed to potential DDIs
Jansman et
al[8] 98 three Ambulatory/ Colorectal patients who were receiving standard
chemotherapy for advance disease
prospectiv
e Drug Interaction Facts software[21]
72% of patients were exposed to at least one potential DDI, mostly either loperamide, dexamethasone or phenytoin combined with irinotecan Riechelman
n et al[9] 405 one Ambulatory/ Solid tumors only; patients on active cancer-directed therapy
Cross
sectional Drug Interaction Facts software[21]
27% of patients exposed to potential DDIs, mostly drugs to treat comorbid illnesses
Sokol et
al[10] 100 one Ambulatory/ Older than 70 years; Solid and hematologic tumors
retrospecti
ve Not reported 19% of patients were taking cimetidine, a known CYP inhibitor; five oncologists were informed about potentially harmful drug combinations but did not make any changes in their patients prescription Riechelman
tumors; patients at the end of life, receiving supportive care exclusively
software[21] mostly drugs to treat comorbid illnesses
Extermann
et al [12] 135 one Ambulatory/ Older than 70 years; Solid and hematologic tumors
retrospecti
ve Not reported Patients were taking a median of 2 drugs that interact with CYP enzymes.
Real Drug Interactions Buadorjet et
al[13] 732 one Hospital/cancer-related deaths retrospective Not reported 4% of cancer-related deaths were deemed to be caused by an adverse drug event.
Del Giglio et
al [15] 298 one Hospital/ Cancer patients hospitalized for any reason
retrospecti
ve Drug Interaction Facts software[21]
Table 3. Common drug interactions identified by the studies.
Drug combination Clinical event Mechanism of interaction Real drug interactions
Phenyoin + Warfarin[22] Deep venous thrombosis
Phenytoin induces warfarin hepatic metabolism with consequent reduction in its anticoagulant effect
Warfarin + Omeprazole[23] Upper digestive hemorrhage
Omeprazole inhibits hepatic metabolism of warfarin, enhancing its anticoagulant effect
Diclofenac +
Enoxaparin[24] Post surgical bleeding Additive anticoagulant effect Potential drug interactions
Phenytoin + corticosteroids[25] Either seizures or phenytoin toxicity Both drugs may increase or decrease each other’s liver metabolism.
Warfarin + corticosteroids[26] thromboembolism Either bleeding or Mechanism unknown.
Phenytoin + acetaminophen[27] Increased liver enzymes
Phenytoin induces acetaminophen’s hepatic metabolism with consequent increased hepatic toxicity.
NSAID + SSRI[28] Bleeding
Increased risk of upper gastrointestinal bleeding. Mechanism unknown, possible additive effects.
Warfarin + acetaminophen[29] Bleeding
Increased vitamin K antagonism by
acetaminophen, with risk of bleeding.
Benzodiazepine + omeprazole[30] Somnolence Inhibition of benzodiazepine’s liver metabolism, with increased sedation Warfarin + fluorouracil/capecitabine/etoposide/ carboplatin/paclitaxel/gemcitabine[31-35] Bleeding Chemotherapy-induced protein displacement and inhibition of warfarin
metabolism with a higher risk of bleeding.
Hydrochlorothiazide +
cyclophosphamide/fluorouracil[36] neutropenia Prolonged
Unknown mechanism. Thiazides may prolong chemotherapy-induced neutropenia
Irinotecan + phenytoin[37] Reduced efficacy of irinotecan Anticonsulsants induce the hepatic metabolism of irinotecan.
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5. RESUMO DO DOS ACHADOS DO ARTIGO 1
“Drug Interactions in Oncology: how common are they?”
1. O estudo de interações medicamentosas em oncologia é muito limitado, onde apenas alguns estudos reportaram até hoje dados sobre a freqüência de potenciais ou verdadeiras interações medicamentosas em pacientes com câncer. Desta forma, esta revisão sistemática vem corroborar com esta afirmação. Esta é a primeira revisão sistemática que descreve sobre a epidemiologia das interações medicamentosas em oncologia.
2. A presente revisão demonstrou que aparentemente um terço de pacientes ambulatoriais com câncer está exposto a pelo menos uma combinação de drogas com risco de interação. Isto porque dois estudos grandes com pacientes ambulatoriais, que estavam recebendo ou não terapia antineoplásica, mostraram que aproximadamente 30% dos pacientes estavam usando drogas que poderiam potencialmente interagir entre si.
3. Um estudo que avaliou interações medicamentosas verdadeiras, isto é, aquelas que resultaram em complicações clínicas, mostrou que apesar de interações medicamentosas serem identificadas como causa de internação hospitalar em numa pequena proporção de doentes oncológicos, as drogas que levaram à hospitalização foram as mesmas medicações identificadas como perigosas nos estudos que avaliaram potenciais interações medicamentosas. Estas drogas incluem anticonvulsivantes, warfarina, anti-inflamatórios hormonais e não hormonais e anti-hipertensivos.
4. Os fatores de risco para interações medicamentosas mais freqüentemente relatados na literatura foram número de medicações por paciente e uso de medicações para tratamento de comorbidades e sintomas.
