Prevalence and characteristics of adverse drug events in Brazil

Sousa, Livia Alves Oliveira de; Fonteles, Marta Maria de França; Monteiro, Mirian Parente; Mengue, Sotero Serrate; Bertoldi, Andréa Dâmaso; Pizzol, Tatiane da Silva Dal; Tavares, Noemia Urruth Leão; Oliveira, Maria Auxiliadora; Luiza, Vera Lucia; Ramos, Luiz Roberto; Farias, Mareni Rocha; Arrais, Paulo Sergio Dourado

doi:10.1590/0102-311x00040017

Abstract:

The aim of this study was to describe the prevalence of adverse drug events (ADEs) and associated factors reported by users of medicines in Brazil. This was a cross-sectional population-based study conducted from September 2013 to February 2014 with data from the Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines (PNAUM). The study included all individuals that reported the use of medicines and identified, among them, all those reporting at least one problem with the medicine’s use. A descriptive analysis was performed to estimate ADE prevalence and 95% confidence intervals (95%CI) among the target variables. Crude and adjusted prevalence ratios were calculated using Poisson regression to investigate factors associated with ADEs. Overall ADE prevalence in Brazil was 6.6% (95%CI: 5.89-7.41), and after multivariate analysis, higher prevalence was associated with female gender, residence in the Central and Northeast regions, consumption of more medicines, “bad” self-rated health, and self-medication. The drugs most frequently reported with ADEs were fluoxetine, diclofenac, and amitriptyline. The most frequent ADEs were somnolence, epigastric pain, and nausea. Most reported ADEs were mild, avoidable, and associated with medicines used frequently by the population. The study provided knowledge on the size of the problem with use of medicines in Brazil.

Keywords:
Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Pharmacovigilance; Health Surveys

Introduction

Drugs play an essential role in the care of persons, whether for treatment, prevention, or diagnostic purposes; however, they also have the potential to cause unwanted events ¹1. Departamento de Atenção Básica, Secretaria de Políticas de Saúde, Ministério da Saúde. Política nacional de medicamentos. Brasília: Ministério da Saúde; 2001.. The World Health Organization (WHO) defines adverse drug event (ADE) as “any negative or harmful occurrence that takes place during treatment, that may or may not be associated with a medicine” ²2. Uppsala Monitoring Centre; Organización Mundial de la Salud. Vigilancia de la seguridad de los medicamentos: guía para la instalación y puesta en funcionamiento de un centro de farmacovigilancia. Uppsala: Uppsala Monitoring Centre/Organización Mundial de la Salud; 2002. (p. 26).

ADEs are considered a serious public health problem, since they not only account for increased morbidity and mortality in patients, but also lead to unnecessary expenditures by health systems. They thus have negative clinical, human, and economic impacts ³3. Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.^,⁴4. Scripcaru G, Mateus C, Nunes C. Adverse drug events - analysis of a decade. A Portuguese case-study, from 2004 to 2013 using hospital database. PLoS One 2017; 12:e0178626..

Factors contributing to ADEs in users of medicines include age ³3. Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.^,⁴4. Scripcaru G, Mateus C, Nunes C. Adverse drug events - analysis of a decade. A Portuguese case-study, from 2004 to 2013 using hospital database. PLoS One 2017; 12:e0178626.^,⁵5. Evans RS, Lloyd JF, Stoddard GJ, Nebeker RJ, Samore MH. Risk factors for adverse drug events: a 10 years analysis. Ann Pharmacother 2005; 39:1161-8., female gender ⁴4. Scripcaru G, Mateus C, Nunes C. Adverse drug events - analysis of a decade. A Portuguese case-study, from 2004 to 2013 using hospital database. PLoS One 2017; 12:e0178626.^,⁵5. Evans RS, Lloyd JF, Stoddard GJ, Nebeker RJ, Samore MH. Risk factors for adverse drug events: a 10 years analysis. Ann Pharmacother 2005; 39:1161-8., comorbidities ³3. Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.^,⁵5. Evans RS, Lloyd JF, Stoddard GJ, Nebeker RJ, Samore MH. Risk factors for adverse drug events: a 10 years analysis. Ann Pharmacother 2005; 39:1161-8., previous history of ADEs ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009., polypharmacy ³3. Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.^,⁵5. Evans RS, Lloyd JF, Stoddard GJ, Nebeker RJ, Samore MH. Risk factors for adverse drug events: a 10 years analysis. Ann Pharmacother 2005; 39:1161-8.^,⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009., drug dose ⁵5. Evans RS, Lloyd JF, Stoddard GJ, Nebeker RJ, Samore MH. Risk factors for adverse drug events: a 10 years analysis. Ann Pharmacother 2005; 39:1161-8., nutritional status, environmental factors, and social habits ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.. In addition to patient-related factors and factors inherent to the drug, resulting from its mechanism of action, lack of or insufficient treatment orientation, prescription of inappropriate medicines, lack of treatment adherence, and lack of treatment follow-up can lead to ADEs ⁴4. Scripcaru G, Mateus C, Nunes C. Adverse drug events - analysis of a decade. A Portuguese case-study, from 2004 to 2013 using hospital database. PLoS One 2017; 12:e0178626.^,⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009..

Numerous studies have investigated adverse events in the hospital setting ³3. Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.^,⁴4. Scripcaru G, Mateus C, Nunes C. Adverse drug events - analysis of a decade. A Portuguese case-study, from 2004 to 2013 using hospital database. PLoS One 2017; 12:e0178626.^,⁷7. Cano FG, Rozenfeld S. Adverse drug events in hospitals: a systematic review. Cad Saúde Pública 2009; 25 Suppl 3:S360-72.. Cano & Rosenfeld ⁷7. Cano FG, Rozenfeld S. Adverse drug events in hospitals: a systematic review. Cad Saúde Pública 2009; 25 Suppl 3:S360-72. conducted a systematic review on ADEs in hospital inpatients in 13 countries and found ADE rates ranging from 1.6% to 41.4%.

However, the data are still incipient on ADE prevalence in the community ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.^,⁸8. Alonso Carbonell L, García Milián AJ, López Puig P, Yera Alós I, Blanco Hernández N. Patrón de reacciones adversas a medicamentos referidas por la población mayor de 15 años. Rev Cubana Med Gen Integr 2009; 25:1-13.^,⁹9. Lam CL, Catarivas MG, Munro C, Lauder IJ. Self-medication among Hong Kong Chinese. Soc Sci Med 1994; 39:1641-7.^,¹⁰10. Leone R, Moretti U, D'Incau P, Conforti A, Magro L, Lora R, et al. Effect of pharmacist involvement on patient reporting of adverse drug reactions: first Italian study. Drug Saf 2013; 36:267-76.. A population-based study in Cuba ⁸8. Alonso Carbonell L, García Milián AJ, López Puig P, Yera Alós I, Blanco Hernández N. Patrón de reacciones adversas a medicamentos referidas por la población mayor de 15 años. Rev Cubana Med Gen Integr 2009; 25:1-13. found ADE prevalence of 22.6%. In Hong Kong (China) ⁹9. Lam CL, Catarivas MG, Munro C, Lauder IJ. Self-medication among Hong Kong Chinese. Soc Sci Med 1994; 39:1641-7., ADE prevalence among persons that practiced self-medication was 6.4%, and in Italy, in the regions of Veneto ¹⁰10. Leone R, Moretti U, D'Incau P, Conforti A, Magro L, Lora R, et al. Effect of pharmacist involvement on patient reporting of adverse drug reactions: first Italian study. Drug Saf 2013; 36:267-76. and Campania ¹¹11. Parretta E, Rafaniello C, Magro L, Coggiola Pittoni A, Sportiello L, Ferrajolo C, et al. Improvement of patient adverse drug reaction reporting through a community pharmacist-based intervention in the Campania region of Italy. Expert Opin Drug Saf 2014; 13:21-9., interviews with pharmacists in community pharmacies found ADE prevalence rates of 9.4% and 10.8%, respectively.

A population-based study by Arrais ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009. in Fortaleza, Ceará State, Brazil, found ADE prevalence of 8%. Prevalence was higher in women (9.7%), in the 50-64-year age bracket (14.9%), in individuals with chronic diseases (12%), among persons with lifetime report of ADEs (10%), and among those that rated their health as “bad”, and increased according to the number of medicines used.

According to the Brazilian National Notification System for Sanitary Surveillance (NOTIVISA) of the Brazilian Health Regulatory Agency (Anvisa; http://www.anvisa.gov.br/hotsite/notivisa/relatorios/index.htm, accessed on 20/Mar/2016), 103,887 adverse events were reported in Brazil from 2006 to 2013, of which 38,730 were related to medicines.

ADEs in hospitals and the community compromise patient safety and have thus drawn increasing attention in the literature ¹²12. Reis CT, Martins M, Laguardia J. A segurança do paciente como dimensão da qualidade do cuidado de saúde: um olhar sobre a literatura. Ciênc Saúde Coletiva 2013; 18:2029-36.. However, the shortage of community-based studies on this topic hinders information on the true extent of drug-related morbidity and mortality and the extent to which ADEs affect patient safety in the broad scenario of modern consumer society ³3. Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.. This lack of information hampers planning measures to implement a culture of patient safety among health professionals and to reduce the occurrence of ADEs ¹³13. Clinco SDO. Participação do usuário no seu cuidado: realidade ou ficção? [Tese de Doutorado]. São Paulo: Escola de Administração de Empresas de São Paulo, Fundação Getúlio Vargas; 2013..

In this context, the household survey component of the Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines (PNAUM) ¹⁴14. Mengue SS, Bertoldi AD, Boing AC, Tavares NUL, Dal Pizzol TS, Oliveira MA, et al. Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos (PNAUM): métodos do inquérito domiciliar. Rev Saúde Pública 2016; 50 Suppl 2:4s., by the Brazilian Ministry of Health, allows calculating ADE prevalence and inferring the potential effects, thereby contributing to user safety in the community.

The current study aimed to estimate the prevalence and characteristics of adverse events reported by users of medicines in Brazil, and to identify factors associated with their occurrence, comparing demographic and socioeconomic variables, self-rated health, number of medicines used, and self-medication.

Methods

This cross-sectional, population-based study of data from the PNAUM survey aimed to evaluate access to and rational use of medicines by the Brazilian population.

The PNAUM survey was conducted from September 2013 to February 2014 in a probabilistic sample of the Brazilian population, applying questionnaires. Household interviews were conducted by an outsourced company, trained by the PNAUM team, using tablets for the data collection. In the case of persons under 15 years or with disabilities, the answers were given by their parents or guardians. Further details on the sampling plan and sample size are available in the article on methodological aspects of the PNAUM survey ¹⁴14. Mengue SS, Bertoldi AD, Boing AC, Tavares NUL, Dal Pizzol TS, Oliveira MA, et al. Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos (PNAUM): métodos do inquérito domiciliar. Rev Saúde Pública 2016; 50 Suppl 2:4s..

The questionnaire, consisting of 11 content sections and three forms with details on medicines, was developed and tested by the researchers involved in the PNAUM survey.

The target population for the current study included all persons who reported the use of at least one medicine, including drugs for continuous, occasional, or contraceptive use.

The “dependent” variable was defined as having consumed one or more medicines and having reported ADEs. Identification of users of medicines was based on the following questions:

For continuous-use medicines: “Have you used any medicine for (hypertension, diabetes, heart disease, high cholesterol, stroke, chronic lung disease, arthritis or rheumatism, depression, or another disease lasting more than six months)?” (yes, no). If yes, “Are you currently taking any of these medicines?” (yes, no);
For medicines with occasional use: in addition to the above-mentioned medicines, “Have you used any other medicine in the last 15 days, for (infection, problems sleeping or for nerves, stomach or intestinal problems, fever, pain, flu, cold, allergic rhinitis, nausea, or vomiting)?” (yes, no);
For contraceptive use: “Are you using any contraceptive pill to avoid becoming pregnant?” (yes, no). “Do you use some injection to avoid becoming pregnant?” (yes, no).
Presence of ADEs among users of medicines was investigated with the following questions:
Does this medicine bother you or cause any problem? (yes, no). If yes, why? (This same question was used for continuous and occasional-use medicines);
Does the contraceptive cause any health problem for you? If yes, what problem(s)?
All persons who reported at least one health problem with the use of these medicines were classified as having suffered an ADE.

The “independent” variables were demographic, socioeconomic, self-rated health, number of medicines, and self-medication, analyzed as follows:

(a) Demographic: sex (female, male); age (0-9 years, 10-19 years, 20-39 years, 40-59 years, ≥ 60); region (North, Northeast, Central, South, and Southeast).

(b) Socioeconomic: schooling (0-8 years, 9-11 years, and ≥ 12); ABEP Economic Classification (A/B, C, D/E), according to the Brazilian Economic Classification Criterion of the Brazilian Association of Market Research Companies (ABEP; http://www.abep.org/).

(c) Health indicators: self-rated health status (very good, good, regular, bad, and very bad).

(d) Consumption of medicines: medicine(s) used; number of medicines (1, 2, 3-4, and 5 or more); form of consumption: self-medication (yes, no). Self-medication is defined here as the selection and use of medicines without supervision by a physician and/or dentist ¹⁵15. Arrais PSD, Fernandes MEP, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, et al. Prevalence of self-medication in Brazil and associated factors. Rev Saúde Pública 2016; 50 Suppl 2:13s..

Medicines were listed and classified according to the Anatomical Therapeutic Chemical Classification System (ATC classification) ¹⁶16. WHO Collaborating Centre for Drug Statistics Methodology; Norwegian Institute of Public Health. Guidelines for ATC classification and DDD assignment. 16th Ed. Oslo: World Health Organization; 2013.. Description of the medicines used the following ATC levels: first (organ or system where the medicine acts), second (therapeutic subgroup), and fifth (drug).

ADE was defined by the WHO criterion ²2. Uppsala Monitoring Centre; Organización Mundial de la Salud. Vigilancia de la seguridad de los medicamentos: guía para la instalación y puesta en funcionamiento de un centro de farmacovigilancia. Uppsala: Uppsala Monitoring Centre/Organización Mundial de la Salud; 2002.. ADEs were classified according to the Adverse Reaction Terminology¹⁷17. Uppsala Monitoring Centre. Adverse reaction terminology. Uppsala: Uppsala Monitoring Centre/Organización Mundial de la Salud; 1995..

Statistical data analysis estimated the overall prevalence of ADEs in the study population and respective 95% confidence intervals (95%CI), according to the independent variables. The association between ADEs and target variables was investigated with the Pearson chi-square test, with significance set at 5% (p < 0.05). Poisson regression was used to estimate crude and adjusted prevalence ratios (PR) and 95%CI. Variables with p < 0.20 in the test of association were included in the multivariate model, with significance set at 5% for maintaining variables in the model, using backward selection of variables. The schooling variable entered the first stage of the multivariate adjustment (together with the other variables with p < 20% in the crude analysis). From that point on, as determined by the backward selection method, the non- significant variables were removed. The variables that were removed include schooling, which at some moment failed to show significance at 5% to remain in the final model. The analyses used a set of appropriate svy commands for analysis of complex samples, which guaranteed the necessary weighting of the sampling design.

For the medicines, ADE frequencies were estimated according to organ or system (first ATC level), therapeutic subgroup (second ATC level), and drug (fifth ATC level), plus the respective 95%CI.

All the analyses used Stata, version 13.0 (StataCorp LP, College Station, USA).

The PNAUM research project was approved by the Brazilian National Commission on Research Ethics (case review n. 18947013.6.0000.0008) and by the Institutional Review Board of the Federal University of Rio Grande do Sul (UFRGS), where the survey is coordinated, under case review n. 19997.

Results

Of the 41,433 participants in the PNAUM survey, 50.7% reported consuming medicines.

ADE prevalence was 6.6% overall, and was higher in females (7.8%), in the 20-39-year age bracket (8.2%), in the Central region (8.4%), with “bad” self-rated health (14.8%), with consumption of 5 or more medicines (14.7%), and with self-medication (7.8%) (Table 1).

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Table 1
Prevalence of adverse drug events (ADEs) according to demographic and socioeconomic variables, self-rated health, use of medicines, and self-medication. Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines (PNAUM), Brazil, 2014.

Bivariate analysis showed a positive and statistically significant association between ADEs and the following variables: female sex; age; Northeast, Southeast, and Central regions; “fair”, “bad”, and “very bad” self-rated health; use of 2 or more medicines; and self-medication. There was no significant association between ADE prevalence and socioeconomic status (ABEP) or schooling (Table 2).

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Table 2
Distribution of crude and adjusted prevalence ratios (PR) (Poisson regression) for adverse drug events (ADEs) and respective 95% confidence intervals (95%CI) according to study variables. Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines (PNAUM), Brazil, 2014.

However, the multivariate analysis showed that only female sex (PR = 1.34; 95%CI: 1.05-1.72); the Central (PR = 1.54; 95%CI: 1.16-2.02) and Northeast regions (PR = 1.36; 95%CI: 1.04-1.79); “bad” self-rated health (PR = 1.90; 95%CI: 1.22-2.98); use of 2 (PR = 2.15; 95%CI: 1.59-2.91), 3-4 (PR = 3.57; 95%CI: 2.54-5.01), and 5 or more medicines (PR = 6.30; 95%CI: 4.64-8.55); and self-medication (PR = 1.21; 95%CI: 1.02-1.44) continued to show a positive and statistically significant association with ADEs (Table 2).

Of the 57,424 medicines consumed by the interviewees, 2,447 (4.2%) were related to the reported ADEs. Table 3 shows the therapeutic groups and subgroups most related to ADEs.

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Table 3
Frequency of adverse drug events (ADEs) and respective 95% confidence intervals (95%CI) according to the organ or system and therapeutic subgroup related to the drug reported as causing the problem. Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines (PNAUM), Brazil, 2014.

The groups or systems with the highest frequencies of ADEs were related to antineoplastic and immune-modulating agents (19.2%), followed by medicines for the genitourinary system and sex hormones (8.6%), and systemic-use anti-infectious agents (8%). The therapeutic subgroups with the highest frequencies of ADEs were sex hormones and modulators of the genital system (8.2%), followed by antiepileptics (7.9%) and anti-inflammatory and antirheumatic drugs (7.3%). The drugs with the highest frequencies of ADEs were fluoxetine (9.3%), diclofenac (9%), and amitriptyline (8.5%) (Table 4).

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Table 4
Frequency of adverse drug events (ADEs) and respective 95% confidence intervals (95%CI), according to drug reported as cause of problem. Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines (PNAUM), Brazil, 2014.

The organs or systems affected by ADEs involved mainly the gastrointestinal system (36.9%), followed by psychiatric disorders (18.7%), general health status (13.1%), and the central and peripheral nervous systems (9%), with somnolence (12.5%), epigastric pain (10.5%), and nausea (6.8%) as the most frequently reported ADEs (Table 5).

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Table 5
Characteristics of adverse drug events (ADEs) according to organ/system affected and reported events among interviewees that consumed medicines. Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines (PNAUM), Brazil, 2014.

Discussion

ADE prevalence in the overall Brazilian population was lower than in Cuba ⁸8. Alonso Carbonell L, García Milián AJ, López Puig P, Yera Alós I, Blanco Hernández N. Patrón de reacciones adversas a medicamentos referidas por la población mayor de 15 años. Rev Cubana Med Gen Integr 2009; 25:1-13., Veneto ¹⁰10. Leone R, Moretti U, D'Incau P, Conforti A, Magro L, Lora R, et al. Effect of pharmacist involvement on patient reporting of adverse drug reactions: first Italian study. Drug Saf 2013; 36:267-76. and Campania ¹¹11. Parretta E, Rafaniello C, Magro L, Coggiola Pittoni A, Sportiello L, Ferrajolo C, et al. Improvement of patient adverse drug reaction reporting through a community pharmacist-based intervention in the Campania region of Italy. Expert Opin Drug Saf 2014; 13:21-9. in Italy, and Fortaleza ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009. in Brazil, and was higher than in persons that practiced self-medication in Hong Kong ⁹9. Lam CL, Catarivas MG, Munro C, Lauder IJ. Self-medication among Hong Kong Chinese. Soc Sci Med 1994; 39:1641-7..

Nationwide studies to identify ADEs reported by the population are quite incipient in the international literature, which hinders comparison between countries. The Cuban study ⁸8. Alonso Carbonell L, García Milián AJ, López Puig P, Yera Alós I, Blanco Hernández N. Patrón de reacciones adversas a medicamentos referidas por la población mayor de 15 años. Rev Cubana Med Gen Integr 2009; 25:1-13. found an ADE prevalence rate approximately four times greater than in the current study (22.6%). This result is probably influenced by the fact that subjects in Cuba reported events any time in life.

In general, and considering that every adverse drug reaction is an adverse drug event, most studies have been conducted in the hospital setting, related to admission for ADEs in the emergency department or their occurrence during hospital stay ⁷7. Cano FG, Rozenfeld S. Adverse drug events in hospitals: a systematic review. Cad Saúde Pública 2009; 25 Suppl 3:S360-72.^,¹⁸18. Gandhi TK, Weingart SN, Borus J, Seger AC, Peterson J, Burdick E, et al. Adverse drug events in ambulatory care. N Engl J Med 2003; 348:1556-64.^,¹⁹19. Mastroianni PDC, Varallo FR, Barg MS, Noto AR, Galduróz JCF. Contribuição do uso de medicamentos para a admissão hospitalar. Braz J Pharm Sci 2009; 45:163-70.. In the case of ADEs that occur during hospital stay, studies are limited to the drugs used in this setting. In the community, however, the consumption of medicines reflects the products’ wide availability on the pharmaceutical market, with countless pharmaceutical specialties, some of which have less than optimal intrinsic values and are even unnecessary or hazardous, which (associated with the pharmaceutical industry’s marketing) can result in induction or encouragement for inadequate use of medicines ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.^,²⁰20. Negreiros RL. Agravos provocados por medicamentos em crianças até 12 anos de idade, no Estado do Rio de Janeiro, entre os anos 2000 e 2001 [Dissertação de Mestrado]. Rio de Janeiro: Universidade Federal Fluminense; 2006..

As for ADE prevalence in females, the same was found by Alonso Carbonell et al. ⁸8. Alonso Carbonell L, García Milián AJ, López Puig P, Yera Alós I, Blanco Hernández N. Patrón de reacciones adversas a medicamentos referidas por la población mayor de 15 años. Rev Cubana Med Gen Integr 2009; 25:1-13. in Cuba and by Arrais ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009. in Fortaleza. The factors that may explain this phenomenon include pharmacokinetic, pharmacodynamic, and body-weight when compared to men, besides hormonal factors ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.^,²¹21. Francelino EV. Centro de Farmacovigilância do Ceará: análise do perfil de reação adversa a medicamento e queixa técnica [Dissertação de Mestrado]. Fortaleza: Universidade Federal do Ceará; 2007.. Women present more health problems, which are less serious on average, but they use health services more, have more appointments and tests, obtain more diagnoses and medical prescriptions, and thus consume more medicines, prescribed or not ¹⁵15. Arrais PSD, Fernandes MEP, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, et al. Prevalence of self-medication in Brazil and associated factors. Rev Saúde Pública 2016; 50 Suppl 2:13s.^,²²22. Bertoldi AD, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, Tavares NUL, et al. Sociodemographic profile of medicines users in Brazil: results from the 2014 PNAUM survey. Rev Saúde Pública 2016; 50 Suppl 2:5s.^,²³23. Bertoldi AD, Arrais PSD, Tavares NUL, Ramos LR, Luiza VL, Mengue SS et al. Utilização de medicamentos genéricos na população brasileira: uma avaliação da PNAUM 2014. Rev Saúde Pública 2016; 50 Suppl 2:11s.. Another factor that may have contributed to this gender difference was the fact that ADEs were also reported by users of contraceptives in the study.

As for age bracket, we expected to find higher ADE prevalence at the extremes of age (children and elderly), since according to the literature these are the groups most predisposed to ADEs ²⁴24. Menon SZ, Lima AC, Chorilli M, Franco YO. Reações adversas a medicamentos (RAMs). Saúde Rev 2005; 7:71-9.. However, we observed the highest ADE prevalence in young people and young adults. This result may be explained in part by the ADEs reported by contraceptive users, or by difficulties by patients and/or caregivers in identifying ADEs; aggravated by lack of information, this may have influenced the result and contributed to minimizing ADE prevalence in children and the elderly ²¹21. Francelino EV. Centro de Farmacovigilância do Ceará: análise do perfil de reação adversa a medicamento e queixa técnica [Dissertação de Mestrado]. Fortaleza: Universidade Federal do Ceará; 2007.^,²⁵25. Marin MJS, Cecílio LCDO, Perez AEWUF, Santella F, Silva CBA, Gonçalves Filho JR, et al. Caracterização do uso de medicamentos entre idosos de uma unidade do Programa Saúde da Família. Cad Saúde Pública 2008; 24:1545-55..

As for the higher association between consumption of medicines and ADEs in residents of the Northeast and Central regions of Brazil, the lack of similar studies prevents a more detailed explanation. However, this result may be influenced by difficulties in access to health services and the need to relieve minor symptoms with self-medication ¹⁵15. Arrais PSD, Fernandes MEP, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, et al. Prevalence of self-medication in Brazil and associated factors. Rev Saúde Pública 2016; 50 Suppl 2:13s.^,²²22. Bertoldi AD, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, Tavares NUL, et al. Sociodemographic profile of medicines users in Brazil: results from the 2014 PNAUM survey. Rev Saúde Pública 2016; 50 Suppl 2:5s.^,²⁶26. Domingues PHF, Galvão TF, Andrade KRCD, Sá PTTD, Silva MT, Pereira MG. Prevalence of self-medication in the adult population of Brazil: a systematic review. Rev Saúde Pública 2015; 49:36., which involves some of the most widely used medicines in this study ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.^,¹⁵15. Arrais PSD, Fernandes MEP, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, et al. Prevalence of self-medication in Brazil and associated factors. Rev Saúde Pública 2016; 50 Suppl 2:13s.^,²³23. Bertoldi AD, Arrais PSD, Tavares NUL, Ramos LR, Luiza VL, Mengue SS et al. Utilização de medicamentos genéricos na população brasileira: uma avaliação da PNAUM 2014. Rev Saúde Pública 2016; 50 Suppl 2:11s.^,²⁷27. Carvalho MF, Pascom ARP, Souza-Júnior PRB, Damacena GN, Szwarcwald CL. Utilization of medicines by the Brazilian population, 2003. Cad Saúde Pública 2005; 21 Suppl:S100-8.. Self-medication is practiced in all regions of Brazil. Self-medication rates in the North (17.8%), Northeast (23.5%), and Central (19.2%) were higher than the national rate (16.1%) ¹⁵15. Arrais PSD, Fernandes MEP, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, et al. Prevalence of self-medication in Brazil and associated factors. Rev Saúde Pública 2016; 50 Suppl 2:13s..

Polypharmacy was significantly associated with ADEs, corroborating findings in the literature ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.^,²⁴24. Menon SZ, Lima AC, Chorilli M, Franco YO. Reações adversas a medicamentos (RAMs). Saúde Rev 2005; 7:71-9.. ADEs increase significantly with the number of drugs used by the patient and the treatment complexity, since polypharmacy appears as a potential risk factor for drug-drug interactions, medication errors, and inadequate use of medicines, potentially resulting in hospitalization, and in severe cases, death ²⁸28. Secoli SR, Lebrão ML. Risco de eventos adversos e uso de medicamentos potencialmente interativos. Saúde Colet (Barueri) 2009; 6:113-8.^,²⁹29. Varallo FR, Costa MA, Mastroianni PC. Potenciais interações medicamentosas responsáveis por internações hospitalares. Rev Ciênc Farm Básica Apl 2013; 34:79-85.. This risk can be minimized by greater control of polypharmacy by health professionals, adequate prescription, patient-adjusted doses, and effective pharmacotherapeutic follow-up ³⁰30. Lobo LB. Polifarmácia entre os idosos de Dourados, Mato Grosso do Sul: um estudo de base populacional [Dissertação de Mestrado]. Cuiabá: Faculdade de Ciências da Saúde, Universidade Federal da Grande Dourados; 2015..

As for self-rated health status, patients with “bad” self-rated health reported the most ADEs, similar to the study by Arrais ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.. This generally occurs because these patients are more likely to seek medical care and consume more medicines, prescribed or not, in the attempt to solve their health problems ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.^,³¹31. Bertoldi AD, Barros AJD, Hallal PC, Lima RC. Utilização de medicamentos em adultos: prevalência e determinantes individuais. Rev Saúde Pública 2004; 38:228-38..

Patients in this study that self-medicated showed higher ADE prevalence, corroborating the studies by Lam et al. ⁹9. Lam CL, Catarivas MG, Munro C, Lauder IJ. Self-medication among Hong Kong Chinese. Soc Sci Med 1994; 39:1641-7. in Hong Kong, Arrais ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009. in Fortaleza, and Yu et al. ³²32. Yu YM, Shin WG, Lee JY, Choi SA, Jo YH, Youn SJ, et al. Patterns of adverse drug reactions in different age groups: analysis of spontaneous reports by community pharmacists. PLoS One 2015; 10:e0132916. in Korea Republic.

Self-medication is common not only in Brazil ¹⁵15. Arrais PSD, Fernandes MEP, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, et al. Prevalence of self-medication in Brazil and associated factors. Rev Saúde Pública 2016; 50 Suppl 2:13s., but worldwide, and it involves economic, political, and cultural factors ²⁶26. Domingues PHF, Galvão TF, Andrade KRCD, Sá PTTD, Silva MT, Pereira MG. Prevalence of self-medication in the adult population of Brazil: a systematic review. Rev Saúde Pública 2015; 49:36.. Self-medication may or may not benefit the individual: when used rationally, it can mean a savings for the patient due to ease in acquiring the medicine and possible resolution of the health problem, and for health services, due to the reduction in demand for care and hospital expenses. But if used irrationally, self-medication can delay the correct diagnosis of a disease, mask symptoms, increase antimicrobial resistance, and harm the individual’s health through the appearance of ADEs such as medication errors, adverse reactions, and intoxication ³³33. Asseray N, Ballereau F, Trombert-Paviot B, Bouget J, Foucher N, Renaud B, et al. Frequency and severity of adverse drug reactions due to self-medication: a cross-sectional multicentre survey in emergency departments. Drug Saf 2013; 36:1159-68..

Education and awareness-raising for health professionals and the general population are thus necessary, focusing on the rational use of medicines, the development of public policies fostering improved access to health services, more intense regulation of abusive advertising and irregular sales of over-the-counter drugs ³⁴34. Musial DC, Dutra JS, Becker TC. A automedicação entre os brasileiros. SaBios (Campo Mourão) 2007; 2:5-8., and especially effective action by pharmacists in community pharmacies to minimize harm to the population’s health due to self-medication ³⁵35. Rêgo ARA, Peixoto MC. Uso racional de medicamentos versus automedicação: possíveis contribuições do profissional farmacêutico no contexto multiprofissional. Acta Científica 2012; 4:95-103..

ADEs were proportionally more frequent with less consumed drugs, but with greater potential for adverse reactions or drug-drug interactions, as with fluoxetine and amitriptyline, which should thus be used under strict supervision ³⁶36. Wannmacher L. Uso racional de antidepressivos. In: Secretaria de Ciência e Tecnologia e Insumos Estratégicos, Ministério da Saúde, organizador. Uso racional de medicamentos: temas selecionados. Brasília: Editora MS; 2012. p. 83-9.. But ADEs also appeared with drugs that are frequently used in Brazil, with or without prescriptions, such as diclofenac, fixed-dose caffeine + carisoprodol + diclofenac + paracetamol, prednisone, and nimesulide ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.^,¹⁵15. Arrais PSD, Fernandes MEP, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, et al. Prevalence of self-medication in Brazil and associated factors. Rev Saúde Pública 2016; 50 Suppl 2:13s.^,²³23. Bertoldi AD, Arrais PSD, Tavares NUL, Ramos LR, Luiza VL, Mengue SS et al. Utilização de medicamentos genéricos na população brasileira: uma avaliação da PNAUM 2014. Rev Saúde Pública 2016; 50 Suppl 2:11s.^,²⁷27. Carvalho MF, Pascom ARP, Souza-Júnior PRB, Damacena GN, Szwarcwald CL. Utilization of medicines by the Brazilian population, 2003. Cad Saúde Pública 2005; 21 Suppl:S100-8..

In the case of non-steroidal anti-inflammatory drugs (NSAIDs), there are important restrictions on use in the elderly, with the possibility of gastrointestinal, renal, and cardiovascular risks and interaction with other drugs frequently used in primary care (paracetamol, some anti-hypertensives, antidepressants, and selective serotonin reuptake inhibitors) ³⁷37. Pinheiro RM, Wannmacher L. Uso racional de anti-inflamatórios não esteroides. In: Secretaria de Ciência e Tecnologia e Insumos Estratégicos, Ministério da Saúde, organizador. Uso racional de medicamentos: temas selecionados. Brasília: Editora MS; 2012. p. 41-50..

Adverse events associated with oral contraceptives featured levonorgestrel associated with ethinylestradiol, and ciproterone+ethinylestradiol, the most widely consumed oral contraceptives on the Brazilian pharmaceutical market ³⁸38. Farias MR, Leite SN, Tavares NUL, Oliveira MA, Arrais PSD, Bertoldi AD, et al. Use of and access to oral and injectable contraceptives in Brazil. Rev Saúde Pública 2016; 50 Suppl 2:14s.. Risks associated with contraceptives have been reported in the literature and range from mild and common, like nausea, headache, breast pain, anxiety, and irritability, to rare and severe, like thromboembolism and stroke, as an important cause of treatment switch and dropout ³⁹39. Braga G, Vieira C. Contracepção hormonal e tromboembolismo. Brasília Méd 2013; 50:58-62..

ADEs reported in the community are generally mild ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.^,⁸8. Alonso Carbonell L, García Milián AJ, López Puig P, Yera Alós I, Blanco Hernández N. Patrón de reacciones adversas a medicamentos referidas por la población mayor de 15 años. Rev Cubana Med Gen Integr 2009; 25:1-13. and considered preventable, since they usually do not require specific treatment or suspension of the drug ²⁴24. Menon SZ, Lima AC, Chorilli M, Franco YO. Reações adversas a medicamentos (RAMs). Saúde Rev 2005; 7:71-9.^,⁴⁰40. Fonteles MMF, Francelino EV, Santos LKX, Silva KM, Siqueira R, Viana GSB, et al. Reações adversas causadas por fármacos que atuam no sistema nervoso: análise de registros de um centro de farmacovigilância do Brasil. Rev Psiquiatr Clín 2009; 36:137-44.. However, the fact that they are mild does not minimize their importance, since they can interfere in quality of life, cause discomfort and malaise, and reduce treatment adherence and patients’ trust in their physicians ³3. Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.. They may also aggravate the patient’s clinical status, causing new adverse events if the patient fails to use other medicines to minimize or relieve the discomfort generated by the offending drug, triggering the so-called cascade effect ⁶6. Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009..

Analyzing the three most frequently reported ADEs (somnolence, epigastric pain, and nausea), in some treatments these are already expected and do not greatly compromise the individual’s quality of life, thus rarely resulting in hospitalization, but causing patient discomfort and potentially leading to other consequences (cited above) such as treatment dropout.

The study’s limitations include the population’s lack of knowledge for identifying the association between use of the medicine and the adverse event, probably due to the difficulty in differentiating between the problem caused by the drug and complications or evolution of the disease itself; the recall period used to investigate use of the medicine and appearance of the ADE; failure to detect more serious events leading to the treatment’s interruption; inclusion of contraceptives in the analysis, favoring the inclusion of more females than males; and the fact that the question on adverse effects was worded in the context of treatment adherence and not as an objective formulation for evaluation.

Although the questions on ADEs considered the time of use of the medicines, one cannot state for certain that the ADE actually occurred during this period, or that the problem was related to the reported drug, but at a different moment. In addition, since no investigation was performed to determine the correlation between use of the medicine and the appearance of ADEs, one cannot state with certainty whether the events are related to the drugs reported as causing the problems or that other factors are influencing the outcome.

Conclusion

The current study allowed identifying ADEs and their determinant factors in Brazil. The adverse events were mainly mild, avoidable, and associated with medicines frequently used by the population. This information will allow developing measures for the prevention and reduction of ADEs, thereby contributing to both patient safety and reduction in healthcare costs resulting from damage caused by the use of medicines, especially in primary care.

However, the scarcity of nationwide studies on this topic and the fact that Brazil is one of the world’s 10 leading pharmaceutical markets ⁴¹41. IMS Institute for Healthcare Informatics. The global use of medicines: outlook through 2017. http://www.quotidianosanita.it/allegati/allegato1501906.pdf (acessado em 16/Mar/2016).
http://www.quotidianosanita.it/allegati/... highlight the need to strengthen policies to promote the rational use of medicines.

Acknowledgments

The authors wish to thank the Departments of Science and Technology (Decit) and Pharmaceutical Care (DAF) of the Secretariat of Science, Technology, and Strategic Inputs of the Brazilian Ministry of Health for the funding and technical support for the Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines.

References

¹
Departamento de Atenção Básica, Secretaria de Políticas de Saúde, Ministério da Saúde. Política nacional de medicamentos. Brasília: Ministério da Saúde; 2001.
²
Uppsala Monitoring Centre; Organización Mundial de la Salud. Vigilancia de la seguridad de los medicamentos: guía para la instalación y puesta en funcionamiento de un centro de farmacovigilancia. Uppsala: Uppsala Monitoring Centre/Organización Mundial de la Salud; 2002.
³
Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.
⁴
Scripcaru G, Mateus C, Nunes C. Adverse drug events - analysis of a decade. A Portuguese case-study, from 2004 to 2013 using hospital database. PLoS One 2017; 12:e0178626.
⁵
Evans RS, Lloyd JF, Stoddard GJ, Nebeker RJ, Samore MH. Risk factors for adverse drug events: a 10 years analysis. Ann Pharmacother 2005; 39:1161-8.
⁶
Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.
⁷
Cano FG, Rozenfeld S. Adverse drug events in hospitals: a systematic review. Cad Saúde Pública 2009; 25 Suppl 3:S360-72.
⁸
Alonso Carbonell L, García Milián AJ, López Puig P, Yera Alós I, Blanco Hernández N. Patrón de reacciones adversas a medicamentos referidas por la población mayor de 15 años. Rev Cubana Med Gen Integr 2009; 25:1-13.
⁹
Lam CL, Catarivas MG, Munro C, Lauder IJ. Self-medication among Hong Kong Chinese. Soc Sci Med 1994; 39:1641-7.
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Leone R, Moretti U, D'Incau P, Conforti A, Magro L, Lora R, et al. Effect of pharmacist involvement on patient reporting of adverse drug reactions: first Italian study. Drug Saf 2013; 36:267-76.
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Arrais PSD, Fernandes MEP, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, et al. Prevalence of self-medication in Brazil and associated factors. Rev Saúde Pública 2016; 50 Suppl 2:13s.
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Bertoldi AD, Dal Pizzol TS, Ramos LR, Mengue SS, Luiza VL, Tavares NUL, et al. Sociodemographic profile of medicines users in Brazil: results from the 2014 PNAUM survey. Rev Saúde Pública 2016; 50 Suppl 2:5s.
²³
Bertoldi AD, Arrais PSD, Tavares NUL, Ramos LR, Luiza VL, Mengue SS et al. Utilização de medicamentos genéricos na população brasileira: uma avaliação da PNAUM 2014. Rev Saúde Pública 2016; 50 Suppl 2:11s.
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Menon SZ, Lima AC, Chorilli M, Franco YO. Reações adversas a medicamentos (RAMs). Saúde Rev 2005; 7:71-9.
²⁵
Marin MJS, Cecílio LCDO, Perez AEWUF, Santella F, Silva CBA, Gonçalves Filho JR, et al. Caracterização do uso de medicamentos entre idosos de uma unidade do Programa Saúde da Família. Cad Saúde Pública 2008; 24:1545-55.
²⁶
Domingues PHF, Galvão TF, Andrade KRCD, Sá PTTD, Silva MT, Pereira MG. Prevalence of self-medication in the adult population of Brazil: a systematic review. Rev Saúde Pública 2015; 49:36.
²⁷
Carvalho MF, Pascom ARP, Souza-Júnior PRB, Damacena GN, Szwarcwald CL. Utilization of medicines by the Brazilian population, 2003. Cad Saúde Pública 2005; 21 Suppl:S100-8.
²⁸
Secoli SR, Lebrão ML. Risco de eventos adversos e uso de medicamentos potencialmente interativos. Saúde Colet (Barueri) 2009; 6:113-8.
²⁹
Varallo FR, Costa MA, Mastroianni PC. Potenciais interações medicamentosas responsáveis por internações hospitalares. Rev Ciênc Farm Básica Apl 2013; 34:79-85.
³⁰
Lobo LB. Polifarmácia entre os idosos de Dourados, Mato Grosso do Sul: um estudo de base populacional [Dissertação de Mestrado]. Cuiabá: Faculdade de Ciências da Saúde, Universidade Federal da Grande Dourados; 2015.
³¹
Bertoldi AD, Barros AJD, Hallal PC, Lima RC. Utilização de medicamentos em adultos: prevalência e determinantes individuais. Rev Saúde Pública 2004; 38:228-38.
³²
Yu YM, Shin WG, Lee JY, Choi SA, Jo YH, Youn SJ, et al. Patterns of adverse drug reactions in different age groups: analysis of spontaneous reports by community pharmacists. PLoS One 2015; 10:e0132916.
³³
Asseray N, Ballereau F, Trombert-Paviot B, Bouget J, Foucher N, Renaud B, et al. Frequency and severity of adverse drug reactions due to self-medication: a cross-sectional multicentre survey in emergency departments. Drug Saf 2013; 36:1159-68.
³⁴
Musial DC, Dutra JS, Becker TC. A automedicação entre os brasileiros. SaBios (Campo Mourão) 2007; 2:5-8.
³⁵
Rêgo ARA, Peixoto MC. Uso racional de medicamentos versus automedicação: possíveis contribuições do profissional farmacêutico no contexto multiprofissional. Acta Científica 2012; 4:95-103.
³⁶
Wannmacher L. Uso racional de antidepressivos. In: Secretaria de Ciência e Tecnologia e Insumos Estratégicos, Ministério da Saúde, organizador. Uso racional de medicamentos: temas selecionados. Brasília: Editora MS; 2012. p. 83-9.
³⁷
Pinheiro RM, Wannmacher L. Uso racional de anti-inflamatórios não esteroides. In: Secretaria de Ciência e Tecnologia e Insumos Estratégicos, Ministério da Saúde, organizador. Uso racional de medicamentos: temas selecionados. Brasília: Editora MS; 2012. p. 41-50.
³⁸
Farias MR, Leite SN, Tavares NUL, Oliveira MA, Arrais PSD, Bertoldi AD, et al. Use of and access to oral and injectable contraceptives in Brazil. Rev Saúde Pública 2016; 50 Suppl 2:14s.
³⁹
Braga G, Vieira C. Contracepção hormonal e tromboembolismo. Brasília Méd 2013; 50:58-62.
⁴⁰
Fonteles MMF, Francelino EV, Santos LKX, Silva KM, Siqueira R, Viana GSB, et al. Reações adversas causadas por fármacos que atuam no sistema nervoso: análise de registros de um centro de farmacovigilância do Brasil. Rev Psiquiatr Clín 2009; 36:137-44.
⁴¹
IMS Institute for Healthcare Informatics. The global use of medicines: outlook through 2017. http://www.quotidianosanita.it/allegati/allegato1501906.pdf (acessado em 16/Mar/2016).
» http://www.quotidianosanita.it/allegati/allegato1501906.pdf

Publication Dates

Publication in this collection
29 Mar 2018

History

Received
08 Mar 2017
Reviewed
07 July 2017
Accepted
02 Oct 2017

Este é um artigo publicado em acesso aberto sob uma licença Creative Commons

[1] ¹
Departamento de Atenção Básica, Secretaria de Políticas de Saúde, Ministério da Saúde. Política nacional de medicamentos. Brasília: Ministério da Saúde; 2001.

[2] ²
Uppsala Monitoring Centre; Organización Mundial de la Salud. Vigilancia de la seguridad de los medicamentos: guía para la instalación y puesta en funcionamiento de un centro de farmacovigilancia. Uppsala: Uppsala Monitoring Centre/Organización Mundial de la Salud; 2002.

[3] ³
Souza TT, Godoy RR, Rotta I, Pontarolo R, Fernandez-Llimos F, Correr CJ. Morbidade e mortalidade relacionadas a medicamentos no Brasil: revisão sistemática de estudos observacionais. Rev Ciênc Farm Básica Apl 2014; 35:519-32.

[4] ⁴
Scripcaru G, Mateus C, Nunes C. Adverse drug events - analysis of a decade. A Portuguese case-study, from 2004 to 2013 using hospital database. PLoS One 2017; 12:e0178626.

[5] ⁵
Evans RS, Lloyd JF, Stoddard GJ, Nebeker RJ, Samore MH. Risk factors for adverse drug events: a 10 years analysis. Ann Pharmacother 2005; 39:1161-8.

[6] ⁶
Arrais PSD. Medicamentos: consumo e reações adversas - um estudo de base populacional. Fortaleza: Edições UFC; 2009.

[7] ⁷
Cano FG, Rozenfeld S. Adverse drug events in hospitals: a systematic review. Cad Saúde Pública 2009; 25 Suppl 3:S360-72.

[8] ⁸
Alonso Carbonell L, García Milián AJ, López Puig P, Yera Alós I, Blanco Hernández N. Patrón de reacciones adversas a medicamentos referidas por la población mayor de 15 años. Rev Cubana Med Gen Integr 2009; 25:1-13.

[9] ⁹
Lam CL, Catarivas MG, Munro C, Lauder IJ. Self-medication among Hong Kong Chinese. Soc Sci Med 1994; 39:1641-7.

[10] ¹⁰
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» http://www.quotidianosanita.it/allegati/allegato1501906.pdf

Variables	ADEs (%) *	95%CI	p-value **
Sex			0.000
Female	7.78	6.85-8.82
Male	4.53	3.61-5.68
Age (years)			0.000
0-9	3.31	2.34-4.64
10-19	7.79	5.93-10.16
20-39	8.17	7.07-9.42
40-59	7.13	6.18-8.23
≥ 60	4.88	3.95-6.01
Region			0.007
North	4.44	3.53-5.57
Northeast	7.15	6.11-8.35
Southeast	6.88	5.55-8.51
South	4.63	3.90-5.49
Central	8.40	6.88-10.22
ABEP classification ***			0.494
A/B	7.20	5.92-8.74
C	6.51	5.61-7.54
D/E	6.23	5.23-7.41
Schooling (years)			0.164
0-8	6.19	5.45-7.02
9-11	7.31	6.13-8.70
≥ 12	6.94	5.33-8.99
Self-rated health status			0.000
Very good	4.25	2.86-6.28
Good	5.73	4.83-6.79
Regular	9.60	8.32-10.98
Bad	14.81	12.02-18.13
Very bad	7.70	5.27-11.11
Medicines used			0.000
1	2.76	2.19-3.49
2	5.60	4.58-6.82
3-4	9.32	7.45-11.61
≥ 5	14.66	12.80-16.73
Self-mediciation			0.003
Yes	7.79	6.72-9.02
No	6.09	5.33-6.96

Variables	Crude PR (95%CI)	p-value *	Adjusted PR (95%CI)	p-value *
Sex		0.001		0.018
Female	1.72 (1.34-2.20)		1.34 (1.05-1.72)
Male	1.00		1.00
Age (years)		0.001		0.001
0-9	1.00		1.00
10-19	2.36 (1.59-3.50)		1.34 (0.73-2.45)
20-39	2.47 (1.74-3.49)		1.10 (0.61-1.99)
40-59	2.16 (1.50-3.11)		0.66 (0.36-1.22)
≥ 60	1.48 (1.01-2.14)		0.39 (0.20-0.72)
Region		0.001		0.000
North	1.00		1.00
Northeast	1.61 (1.22-2.12)		1.36 (1.04-1.79)
Southeast	1.55 (1.13-2.12)		1.21 (0.90-1.63)
South	1.04 (0.78-1.39)		0.82 (0.62-1.09)
Central	1.89 (1.40-2.56)		1.54 (1.16-2.02)
ABEP classification **		0.499
A/B	1.16 (0.90-1.48)
C	1.04 (0.85-1.29)
D/E	1.00
Schooling (years)		0.139
0-8	1.00
9-11	1.18 (0.99-1.41)
≥ 12	1.12 (0.87-1.45)
Self-rated health status		0.001		0.003
Very good	1.00		1.00
Good	1.35 (0.90-2.01)		1.15 (0.79-1.68)
Regular	2.26 (1.52-3.35)		1.47 (0.98-2.20)
Bad	3.48 (2.23-5.44)		1.90 (1.22-2.98)
Very bad	1.81 (1.03-3.17)		0.90 (0.50-1.62)
Medicines used		0.001		0.001
1	1.00		1.00
2	2.02 (1.51-2.70)		2.15 (1.59-2.91)
3-4	3.37 (2.52-4.51)		3.57 (2.54-5.01)
≥ 5	5.30 (4.15-6.80)		6.30 (4.64-8.55)
Self-mediciation		0.003		0.006
Yes	1.28 (1.09-1.50)		1.21 (1.02-1.44)
No	1.00		1.00

Variables	% *	95%CI
Principal anatomical group
Antineoplastic and immune-modulating agents	19.25	12.34-28.76
Genitourinary system and sex hormones	8.63	7.07-10.50
Anti-infectious agents for systemic use	8.05	5.82-1.03
Musculoskeletal system	7.09	5.84-8.60
Dermatological products	6.89	3.94-11.78
Blood and hematopoietic organs	6.65	4.10-10.59
Respiratory system	5.80	4.26-7.84
Anti-parasitic products, insecticides, and repellents	5.72	2.26-13.72
Nervous system	5.55	4.63-6.63
Systemic hormonal preparations except sex hormones and insulins	5.54	3.98-7.65
Herbal remedies, supplements, homeopathy, foods	5.15	3.80-6.95
Alimentary tract and metabolism	4.37	3.66-5.20
Cardiovascular system	4.02	3.28-4.93
Sense organs	3.66	1.95-6.77
Unknown	1.70	0.20-12.85
Various	0.79	0.10-5.83
Therapeutic subgroup
G03 Sex hormones and modulators of the genital system	8.24	6.64-10.19
N03 Anti-epileptics	7.89	5.24-11.73
M01 Anti-inflammatory and Antirheumatic products	7.33	5.78-9.26
J01 Antibacterial drugs for systemic use	7.07	5.01-9.88
R01 Nasal preparations	7.06	3.92-12.41
N06 Psychoanaleptics	7.04	5.30-9.29
M03 Muscle relaxants	6.96	5.05-9.53
R06 Antihistamines for systemic use	6.95	3.92-12.04
H02 Corticosteroids for systemic use	6.81	4.41-10.36
R03 Drugs for obstructive airway diseases	6.78	4.38-10.34
C01 Cardiac therapy	6.47	3.76-10.93
N05 Psycholeptics	5.23	3.30-8.19
A02 Drugs for acid related disorders	5.15	3.98-6.64
A10 Drugs used in diabetes	4.98	3.77-6.56
N02 Analgesics	4.79	3.84-5.96
H03 Thyroid therapy	4.76	2.92-7.68
C03 Diuretics	4.56	3.32-6.24
C07 Beta blocking agents	4.47	2.83-7.01
R05 Cough and cold preparations	3.08	1.88-4.99
C10 Lipid modifying agents	2.92	2.08-4.10
A11 Vitamins	2.57	1.58-4.14
C08 Calcium channel blockers	2.41	1.54-3.76
A03 Drugs for functional gastrointestinal disorders	2.21	1.27-3.81

Drugs	% *	95%CI
Fluoxetine	9.32	5.53-15.29
Diclofenac	9.05	5.12-15.50
Amitriptyline	8.54	5.45-13.13
Caffeine; carisoprodol; diclofenac; paracetamol	8.28	5.40-12.48
Prednisone	8.24	4.75-13.92
Nimesulide	8.04	4.60-13.70
Ethinylestradiol; levonorgestrel	7.60	5.68-10.10
Cyproterone; ethinylestradiol	7.29	4.25-12.24
Clonazepam	7.06	4.18-11.66
Amoxicillin	6.48	3.77-10.91
Metformin	6.41	4.74-8.62
Ibuprofen	6.27	4.16-9.34
Captopril	6.19	4.10-9.23
Dipyrone	5.26	3.85-7.15
Supplements	5.14	2.99-8.68
Omeprazole	4.99	3.61-6.85
Caffeine; dipyrone; orphenadrine	4.86	2.92-8.00
Levothyroxine	4.85	2.96-7.85
Hydrochlorothiazide	4.63	3.13-6.80
Enalapril	4.51	2.81-7.16
Caffeine; dipyrone; isometheptene	4.22	2.37-7.39
Ethinylestradiol; gestoden	3.89	2.15-6.92
Paracetamol	3.43	2.42-4.84
Atenolol	3.38	2.03-5.57
Acetyl salicylic acid	3.31	2.14-5.07
Simvastatin	2.60	1.76-3.83
Losartan	2.47	1.78-3.42
Amlodipine	2.26	1.30-3.90
Unknown	6.06	4.11-8.85

Variables	%	95%CI
Organ/System affected
Disorders of the gastrointestinal system	36.9	32.6-41.3
Psychiatric disorders	18.7	14.6-23.7
Disorders of overall health status	13.1	10.6-16.1
Disorders of the central and peripheral nervous systems	9.0	6.8-11.8
Disorders of the urinary system	4.1	2.7-6.1
Disorders of the respiratory system	3.8	2.5-5.7
Disorders of cardiac rate and rhythm	3.5	2.3-5.3
Disorders of the cardiovascular system	1.4	0.7-2.7
Disorders of the female reproductive system	1.4	0.7-2.7
Disorders of the liver and gallbladder	1.3	0.7-2.5
Conditions of the skin and related disorders	1.1	0.6-2.1
Disorders of the sense organs	0.9	0.5-1.8
Other problems, not health	4.8	3.5-6.6
ADE reported
Somnolence	12.5	9.6-16.0
Epigastric pain	10.5	8.3-13.3
Nausea	6.8	5.2-8.9
Gastric discomfort	4.6	3.1-6.7
Dizziness	4.4	2.8-6.7
Gastric hyperacidity	3.5	2.1-5.8
Tachycardia	3.2	2.0-5.0
Weight gain	3.4	2.3-5.0
Polyuria	3.4	2.1-5.3
Headache	3.1	1.9-4.8
Cough	3.0	2.0-4.5
Diarrhea	2.4	1.6-3.6
Weakness	2.3	1.2-4.2
Malaise	2.2	1.3-3.7
Dry mouth	1.5	0.7-3.3
Edema	1.2	0.6-2.3
Pain	1.0	0.5-1.9
Tremor	0.9	0.5-1.5
Vomiting	0.8	0.4-1.6
Decreased blood pressure	0.8	0.4-1.5
Insomnia	0.8	0.5-1.5
Not classified	2.6	1.8-3.9
Other *	25.2	21.6-29.2