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Analysis of data on capecitabine-related adverse drug reactions from the Korean adverse event reporting system database
European Journal of Oncology Nursing 34 (2018) 55–60
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European Journal of Oncology Nursing journal homepage: www.elsevier.com/locate/ejon
Analysis of data on capecitabine-related adverse drug reactions from the Korean adverse event reporting system database
T
Jeong Yun Park Dept. of Clinical Nursing, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea
A R T I C LE I N FO
A B S T R A C T
Keywords: Oral chemotherapy Capecitabine Adverse drug reactions Serious adverse events Korea institute of drug safety and risk management Korean adverse event reporting system database
Purpose: The purpose of this study was to evaluate the adverse drug reactions (ADRs) and serious adverse events associated with capecitabine use in Korean patients by analyzing data from a comprehensive national database of adverse events. Method: Data from all reports concerning capecitabine (Anatomical Therapeutic Chemical code: L01BC06) generated between January 2011 and December 2014 were collected from the Korean Adverse Event Reporting System database (KAERS). Results: A total of 676 reports and 1069 capecitabine-related ADRs were identified. Ninety-nine cases (14.6%) were classified as serious adverse events. The most commonly reported capecitabine-related ADRs involved gastrointestinal system disorders (324, 30.3%), including diarrhea, nausea, vomiting, and stomatitis, followed by skin and appendage reactions (220, 20.6%), which included symptoms such as skin discoloration/disorder/ dryness, itching, and rash. Conclusions: Patients need to be educated about the common ADRs associated with capecitabine intake in a clinical setting. Patient characteristics must be considered when determining the capecitabine dosage and risk of ADRs, and nursing intervention is critical for preventing exacerbation of these ADRs.
1. Introduction Since early 2000, there has been an increase in the development and use of oral chemotherapeutic agents (Ahn, 2007; Yap et al., 2010), which play an important role in cancer treatment. As intravenous therapy requires invasive medical procedures, it tends to cause discomfort and interfere with the patients' daily life because of the need for hospitalization or frequent outpatient visits for treatment. Both medical staff and patients prefer oral chemotherapy, which improves the quality of life of cancer patients, as long as it provides similar treatment outcomes (Lee et al., 2011; Lee and Jeong, 2013). Capecitabine, an antimetabolic chemotherapeutic agent, inhibits the ability of cancer cells to produce the materials required for their growth (Saif et al., 2008). Diverse large-scale clinical trials conducted in the 2000s have demonstrated the anti-cancer effects of capecitabine, specifically against colorectal and breast cancer (Hoff et al., 2001; Talbot et al., 2002; Van Cutsem et al., 2001). In addition to being used as monotherapy for palliative chemotherapy in inoperable patients, capecitabine is currently being used, in combination with preoperative radiotherapy, as postoperative adjuvant therapy, or in combination with other chemotherapeutic agents that are effective against certain types of cancer (Lee et al., 2011; Saif et al., 2008; Yarbro et al., 2013).
Intravenous administration of 5-fluorouracil (5-FU), another antimetabolite chemotherapeutic agent, may require hospitalization for the delivery of continuous injections through a peripheral catheter, or if the vein condition is poor, a central venous catheter. In contrast, oral capecitabine chemotherapy circumvents any such discomfort or inconvenience to the patient and is safer because of the lower incidence of leukopenia. Thus, capecitabine is considered as efficacious as 5-FU, and its use is gradually increasing (Lee et al., 2011). Generally, when used for monotherapy, capecitabine is administered at a daily dose of 2500 mg/m2 of body surface area in 21-day cycles where the patients receive the drug for 14 of the 21 days and rest for the remaining 7 days (Saif et al., 2008). Capecitabine has several notable adverse effects involving the hands and feet, such as hand and skin pain, tenderness on pressure, edema, blisters, and peeling (Abushullaih et al., 2002; Park, 2014; Park et al., 2009), which occur in 54–60% of patients receiving the drug. Because oral chemotherapy decreases the number of required hospital visits, it decreases the number of opportunities for patient interaction with medical staff. Therefore, medical staff may be unable to immediately identify any adverse effects or drug interactions, and may not be able to accurately evaluate the effectiveness of the treatment (Gerbrecht and Kangas, 2004; Choi and Oh, 2005). Therefore, hospitals emphasize the need for patient education to improve self-care
E-mail address: [email protected]. https://doi.org/10.1016/j.ejon.2018.03.004 Received 19 September 2017; Received in revised form 5 March 2018; Accepted 6 March 2018 1462-3889/ © 2018 Published by Elsevier Ltd.
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J.Y. Park
competency, which allows outpatients taking capecitabine at home to evaluate any adverse effects and control their dosages accordingly (Moore, 2007; Park et al., 2009). Adverse drug reactions (ADRs) are defined as negative and unintended reactions to normal dosages of drugs. ADRs to anti-cancer drugs are as significant as the effectiveness of these drugs because they may lead to physical and mental damage to patients and increase medical costs by extending the duration of hospitalization for treatment (Choi et al., 2012; Rhew and Lee, 2011). With the increasing use of drugs, these ADRs to chemotherapy may appear even years after taking the drug, and as such, continuous monitoring is required. The United States presently operates a spontaneous adverse event reporting system, which was established in the early 1960s. In Korea, the regulations on drug safety information management were enacted in 1985, marking the beginning of adverse event monitoring, and the monitoring institution was designated in 1988, enabling patients to report adverse events spontaneously (Choi et al., 2012). In addition, regional pharmacovigilance centers have been established since 2006, and Regional Drug Monitoring Project Teams began operations in 2009 under the Ministry of Food and Drug Safety, thereby establishing specialized ADR reporting policies and systems. Cases of adverse events can be reported to the Korea Institute of Drug Safety and Risk Management (KIDS) or the regional drug safety center by medical professionals, manufacturers, and consumers through a website or by email, fax, mail, or telephone. The cases are comprehensively managed by the Korean Adverse Event Reporting System (KAERS), leading to a rapidly increasing number of reports (Choi et al., 2012; Rhew and Lee, 2011). Since capecitabine was made available commercially to patients, no large-scale analyses of capecitabine-related ADRs have been performed using data from various institutions. Therefore, the aim of this study was to evaluate the ADRs and serious adverse events associated with capecitabine use in Korean patients by analyzing data from a comprehensive national database of adverse events. The findings of this study may provide useful basic data for the development of effective patient education materials.
3)
4)
5)
6)
7)
action taken after the manifestation of ADRs, such as “drug cessation,” “dose maintenance” and “dose reduction.” Adverse drug reaction information: Adverse drug reactions were classified using WHO-Adverse Reaction Terminology, which was developed by the WHO Uppsala Monitoring Center (Lim et al., 2007); system-organ classes were used to classify the side effects. Serious adverse event information: Serious adverse events were classified as life-threatening, temporary or permanent disabilities, and prolonged hospitalization. Reporter information: This included information regarding the original reporter, defined as the person who first identified the side effect, as well as the person(s) who filed the actual report. These data were classified as doctor, pharmacist, nurse, consumer, and others. Causality evaluation information: ADRs were classified, in accordance with the causality evaluation criteria of the WHO Uppsala Monitoring Centre, into “certain,” “probable,” “possible,” “unlikely,” “unclassified,” and “unassessable.” Medical history: Korean Standard Classification of Diseases codes were used.
2.4. Data collection and ethical considerations This study received an approval exemption permit from the Institutional Review Board (No. 1040968-E-2015-003). We also obtained approval from KIDS for the use of the KIDS-KD by submitting a request and pledge for KIDS-KD in October 2015. 2.5. Statistical analyses
2. Methods
All statistical analyses were performed using Windows SPSS version 22.0 (IBM SPSS Statistics, Chicago, IL, USA). Descriptive statistics were used to summarize data regarding the capecitabine-related ADRs and severe events. General characteristics were compared between the serious adverse events and non-serious adverse events groups by using the independent t-test and the chi-square test. A P value of 0.01 was considered statistically significant.
2.1. Study design
3. Results
This study was a secondary data analysis study using the Korean Database of Spontaneously Reported Adverse Drug Reactions to confirm ADRs to capecitabine.
3.1. General features of spontaneously reported data on capecitabinerelated ADRs The general features of capecitabine-related ADR reports are listed in Table 1. There were 676 reports: 44 cases (6.5%) in 2011, 125 cases (18.5%) in 2012, 277 cases (41.0%) in 2013, and 230 cases (34.0%) in 2014. Pharmacists were the largest group of reporters at 224 cases (33.1%), followed by 183 cases (27.1%) reported by nurses, and 106 cases (15.7%) by doctors. In terms of location of reporting, 548 cases were reported at the regional drug safety center (81.1%), followed by 78 cases (11.5%) at manufacturer/importers, 30 cases (4.4%) at pharmacies, and 20 cases (3.0%) at hospitals. An average of 1.58 ADRs were included in each report, with 212 reported cases (31.4%) consisting of two or more ADRs. Serious adverse events were recorded in 99 cases (14.6%), with 1 case of permanent disability (0.2%), 4 cases of death (0.6%), and 46 cases of hospitalization/prolongation of hospital stay (6.6%). In terms of drug-related action after the manifestation of ADRs, the drug dose was maintained in 155 cases (22.9%) and reduced in 53 cases (7.8%), and drug treatment was terminated in 42 cases (6.2%); for 368 cases (54.4%), no records were available.
2.2. Subjects This study used the KIDS KAERS Database (KIDS-KD), comprising data from KAERS, a system collecting data on adverse events through KIDS, compiled over 48 months from January 2011 to December 2014. This study included all ADRs relating to the use of capecitabine, coded “L01BC06” in the Anatomical Therapeutic Chemical (ATC) code, and excluded “unlikely,” “unclassified,” and “unassessable” adverse event cases. Overall, this study analyzed data from a total of 1069 cases with a causal relationship between ADRs and capecitabine use, including 41 “certain” cases (3.8%), 325 “probable” cases (30.4%), 376 “possible” cases (35.2%), and 327 cases (30.6%) with no assessment. 2.3. Study parameters 1) General information: These data included reporting year, presence of serious adverse events, patient sex, and patient age. 2) Drug information: The drug contents in the reports were classified using ATC codes, which are managed by the World Health Organization (WHO) Collaborating Centre for Drug Statistics Methodology. The data collected included the ingredient name, administration purpose, administration date, and drug-related
3.2. General characteristics of patients The demographic and clinical characteristics of patients with capecitabine-related ADRs are listed in Table 2. The reported cases comprised 339 male (50.1%) and 312 female (46.2%) patients, with 56
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Table 1 General features of capecitabine-related adverse drug reactions reports (n = 676). Characteristics
Categories
n (%) or mean ± SD
No. of reports by year
2010 2011 2013 2014 Doctor Pharmacist Nurse Patient Others No answer Regional drug safety center Manufacturer (Importers) Hospital Pharmacy
44 (6.5) 125 (18.5) 277 (41.0) 230 (34.0) 106 (15.7) 224 (33.1) 183 (27.1) 13 (1.9) 99 (14.6) 51 (7.5) 548 (81.1) 78 (11.5) 20 (3.0) 30 (4.4) 1.58 ± 1.24
1 2–3 ≥4 Yes Disability Life-threatening/Death Hospitalization/ prolongation of hospital stay Others No Drug cessation Dose maintenance Dose reduction Unknown No action No record
464 (68.6) 174 (25.8) 38 (5.6) 99 (14.6) 1 (0.2) 4 (0.6) 46 (6.6)
Reporter
Reporter information
Adverse drug reactions per report
Serious adverse events
Drug-related action after adverse drug reactions
Table 3 Capecitabine-related adverse drug reactions classified by system-organ classes (n = 1069). SOC code
SOC classification
n
%
0600
Gastrointestinal system disorders DIARRHEA NAUSEA VOMITING STOMATITIS Others (Constipation, dyspepsia, dysphagia, hiccups, abdominal distress, etc.) Skin and appendage disorders SKIN DISCOLORATION/DISORDER ITCHING RASH Others (pruritus, nail disorder, alopecia, etc.) Body as a whole -general disorders HAND–FOOT SYNDROME Others (fever, weakness generalized, asthenia, pain, etc.) Central and peripheral nervous system disorders NEUROPATHY TINGLING SKIN Others (dizziness, headache, tingling skin, etc.) White blood cell and RES disorders NEUTROPENIA Others (leucopenia, eosinophilia, etc.) Psychiatric disorders ANOREXIA Others (insomnia, depression, mental disorder, etc.) Red blood cell disorders (anemia, blood disorder, etc.) Hepatic and biliary system disorders (elevated liver enzymes, etc.) Platelet, bleeding, and clotting disorders (thrombocytopenia, etc.) Respiratory system disorders (pneumonia, dyspnea, etc.) Metabolic and nutritional disorders (hyperglycemia, hyponatremia, etc.) Urinary system disorders (creatinine increased, azotemia, etc.) Musculoskeletal system disorders (myalgia, muscle weakness, etc.) Vision disorders (Pigment precipitation, vision deterioration, etc.) Resistance mechanism disorders (infection, sepsis, etc.) Vascular (extracardiac) disorders (cerebral infarction, etc.) Productive disorders, female (break-through bleeding, vaginitis, etc.) Neoplasm (melanoma, rectosigmoid cancer, elevated CA125, etc.) Application site disorders (injection site pain) Special senses other, disorders (dysgeusia, metallic taste) Cardiovascular disorders, general (circulatory instability, heart disorder) Secondary terms-events (spinal cord injury, off label use) Hearing and vestibular disorders (ear pain, etc.) Heart rate and rhythm disorders (tachycardia) Fetal disorders (abortion)
324 78 71 51 37 87
30.3 7.3 6.6 4.8 3.5 8.1
220 88 24 18 90 148 81 68
20.6 8.3 2.2 1.7 8.4 13.9 7.6 6.3
110 48 16 46 91 63 28 49 35 13 19 18
10.3 4.5 1.5 4.3 8.5 5.9 2.6 4.6 3.3 1.3 1.8 1.7
18
1.7
14 11
1.3 0.7
8
0.7
7
0.7
6
0.6
5 3
0.5 0.3
3
0.3
3
0.3
3 2
0.3 0.2
2
0.2
2
0.2
1 1 1
0.1 0.1 0.1
0100
1810
0410
1220
0500 48 (7.2) 577 (85.4) 42 (6.2) 155 (22.9) 53 (7.8) 51 (7.5) 67 (9.9) 308 (45.6)
1210 0700 1230 1100 0800
SD, standard deviation. 1300 Table 2 General characteristics of patients with capecitabine-related adverse drug reaction reports (n = 676). Characteristics
Categories
n (%) or mean ± SD
Sex
Female Male Unknown
312 (46.2) 339 (50.1) 25 (3.7) 54.8 ± 12.4 53 (7.8) 107 (15.8) 167 (24.7) 154 (22.8) 112 (16.6) 83 (12.3) 47 (7.0) 118 (17.5) 115 (17.0) 20 (3.0) 13 (1.9) 363 (53.7)
Age (years)
Medical history
≤39 40–49 50–59 60–69 ≥70 Unknown Breast cancer Colorectal cancer Stomach/esophageal cancer Liver-pancreas-gallbladder cancer Others No record
0200 0431 1830 1040 1420 1700 1820 0433 1010 2000 0432 1030 1500
RES, reticuloendothelial system; SOC, system-organ class.
SD, standard deviation.
common at 324 cases (30.3%): 78 cases (7.3%) of diarrhea, 71 cases (6.6%) of nausea, and 51 cases (4.8%) of vomiting and stomatitis. The second most common ADRs were skin and appendage reactions, which occurred in 220 cases (20.6%), with symptoms such as skin discoloration/disorder/dryness, itching, and rash. There were 148 cases (13.9%) of general ADRs, including 81 cases of hand–foot syndrome (8.3%). Other symptoms were related to central and peripheral nervous system disorders (110 cases, 10.3%), and white blood cell and RES disorders (Table 3).
patient sex not reported in 25 cases (3.7%). Patient age was not reported in 83 cases (12.3%), and the average age of 593 patients was 54.8 ± 12.4 years. The 50–59-year age group had the highest number of patients with 167 cases (24.7%). Medical history data showed that 118 patients (17.5%) had colorectal cancer, followed by 115 cases (17.0%) of stomach/esophageal cancer, and 47 cases (7.0%) of breast cancer. 3.3. Capecitabine-related ADRs classified by system-organ class Among 1069 cases of ADRs, gastrointestinal reactions were the most 57
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Table 4 Comparison of serious and non-serious capecitabine-related adverse events. Characteristics
Sex
Categories
Female Male No record
Age (years)
Medical history
SOC classification
Adverse drug reactions per report Drug-related action after events
≤39 40–49 50–59 60–69 ≥70 No record Breast cancer Colorectal cancer Stomach/esophageal cancer No record Gastrointestinal system disorders Skin and appendage disorders Body as a whole-general disorders Central and peripheral nervous system disorders White blood cell and RES disorders 2.46 (2.38) Stop Dose maintenance Dose reduction Unknown No action No record
t or χ2
P
4.39
0.036
11.56 16.09
0.001 0.003
1.41 14.13 15.48
0.236 < 0.001 < 0.001
8.10 52.55 4.65 4.77
0.004 < 0.001 0.031 0.029
58 (7.0) 64.89
10.20 < 0.001
0.001
65 (11.3) 35 (6.1) 152 (26.3) 51 (8.8) 47 (8.1) 227 (39.3)
17.05
0.002
Serious adverse event (n = 99)
Non-serious adverse event (n = 577)
n (%) or mean ± SD
n (%) or mean ± SD
45 (45.5) 31 (31.3) 23 (23.2) 53.6 ± 11.8 13 (13.1) 15 (15.2) 20 (20.2) 14 (14.1) 5 (5.1) 32 (32.3) 4 (4.1) 4 (4.1) 3 (3.0) 88 (88.8) 56 (23.0) 10 (4.1) 44 (18.0) 16 (6.6)
267 (46.3) 308 (53.4) 2 (0.3) 59.0 ± 12.4 40 (6.9) 92 (15.9) 147 (25.5) 140 (24.3) 107 (18.5) 51 (8.8) 43 (7.5) 115 (19.9) 112 (19.4) 307 (53.2) 268 (32.5) 210 (25.5) 104 (12.6) 94 (11.4)
33 (13.5) 1.43 (0.82) 2 (2.0) 7 (7.1) 3 (3.1) 2 (2.0) 4 (4.0) 81 (81.8)
RES, reticuloendothelial system; SOC, System-Organ class.
4. Discussion
3.4. Comparison of serious and non-serious capecitabine-related adverse events
In this study, we analyzed the trends in the occurrence of capecitabine-related ADRs by evaluating the KAERS adverse event reports; however, we were unable to analyze the frequency of specific ADRs because of limitations associated with spontaneous data reports. ADR reports can be accessed through the Ministry of Food and Drug Safety website, which is open to medical professionals, pharmaceutical companies, regional pharmacies, and general consumers. However, this reporting structure is spontaneous in nature, and does not include ADRs that were not reported. Therefore, the reported ADR data do not represent the entire spectrum and frequency of real-world ADRs. Reports of capecitabine-related ADR increased almost three-fold from 44 cases in 2011 to 125 cases in 2012, and have continued to increase since 2012. This trend relates to the implementations of policies and system enhancements to encourage spontaneous reporting. The total number of reports increased from 64,143 cases in 2010 to 183,554 cases in 2014. Pharmacists comprised the largest proportion of reporters who first noticed ADRs, followed by nurses. Pharmacists dispense medications as prescribed by the physician, and generally, pharmacists are expected to provide information about the drug at discharge. The pharmacist is recognized as an expert on drugs and has a coordinating role when hospitals wish to report adverse events (van Grootheest et al., 2004). Nurses also play an important role in identifying and reporting ADRs, and can thereby facilitate the safe utilization of drugs (Gerbrecht and Kangas, 2004). The results of previous studies indicated that female patients were more vulnerable to ADRs than male patients were. However, in the present study, capecitabine-related ADRs occurred at a similar frequency in both male and female patients. As the total number of patients taking capecitabine could not be confirmed in this study, it is impossible to identify the prevalence rate of capecitabine-related ADRs according to patient sex. However, according to the National Cancer Information Center statistics (2014), males are more likely to develop
As shown in Table 4, there was a significant difference in the patient sex ratio between cases of serious adverse events and non-serious adverse events, after excluding non-reporters (p = 0.036). The average patient age in the serious adverse event group was significantly younger than that in the non-serious adverse event group (53.6 ± 11.8 years vs. 59.0 ± 12.4 years; p = 0.001), with significant differences in the distribution of age between the serious and non-serious adverse group (p = 0.003). Moreover, there were no differences between the number of serious and non-serious adverse events among breast cancer cases, but the number of non-serious adverse events was significantly higher than the number of serious adverse events in colorectal (p < 0.001), and stomach/esophageal (p < 0.001) cancer cases. The action taken after the manifestation of a capecitabine-related serious adverse event was only recorded in 18 cases (18.2%). The most common action taken after the manifestation of a serious adverse event was dose maintenance (7 cases, 7.1%), whereas the most common post-event drug-related action in the non-serious adverse event group was dose reduction (152 cases, 26.3%). 3.5. Capecitabine-related ADRs classified by system-organ class in serious adverse events The one case leading to permanent disability involved a red blood cell disorder. Deaths were attributable to general disorders in two cases of general disorders, and to one case each of liver & biliary system disorders, and respiratory system disorders. The most common ADR in patients with hospitalization/prolonged duration of hospital stay was gastrointestinal system-related disorders, with 13 cases (28.3%), followed by 6 cases of general disorders (13.0%) and 5 cases (10.9%) of psychiatric disorders, including anorexia and insomnia (10.9%; Table 5). 58
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Table 5 Capecitabine-related ADRs classified by system-organ class in Serious adverse events (n = 99). SOC code
0600 0100 1810 0410 1220 0500 1210 0700 1230 1100 1300 0431 1700 2000 1500
SOC classification
Gastrointestinal system disorders Skin and appendage disorders Body as a whole-general disorders Central and peripheral nervous system disorders White blood cell and RES disorders Psychiatric disorders Red blood cell disorders Hepatic and biliary system disorders Platelet, bleeding, and clotting disorders Respiratory system disorders Urinary system disorders Vision disorders Neoplasm (melanoma, rectosigmoid cancer, elevated CA125) Secondary terms-events (spinal cord injury, off label use) Fetal disorders (abortion)
Seriousness, n (%) Disability (n = 1)
Death (n = 4)
Hospitalization/prolongation of hospital stay (n = 46)
Others (n = 48)
0 0 0 0 0 0 1 (100.0) 0 0 0 0 0 0
0 0 2 (50.0) 0 0 0 0 1 (25.0) 0 1 (25.0) 0 0 0
13 (28.3) 3 (6.5) 6 (13.0) 4 (8.7) 3 (6.5) 5 (10.9) 0 1 (2.2) 3 (6.5) 2 (4.3) 1 (2.2) 1 (2.2) 2 (4.3)
10 (20.8) 0 13 (27.1) 10 (20.8) 2 (4.2) 0 2 (4.2) 3 (6.3) 2 (4.2) 3 (6.3) 0 0 0
0 0
0 0
2 (4.3) 2 (4.3)
0 0
ADR, adverse drug reaction; RES, reticuloendothelial system; SOC, system-organ class.
determining the capecitabine dosage, and the dosage must be appropriately adjusted accordingly (Gerbrecht, 2003; Saif et al., 2008). The most common drug-related action after capecitabine-related ADRs was dose maintenance, followed by dose reduction or drug cessation. Patients being discharged from the hospital who continue capecitabine treatment at home are educated on the evaluation of side effects and are instructed to reduce dosage or cease drug treatment until symptoms improve. Because most cancer patients believe that completing their treatment regimen will result in the best outcome, they tend to continue treatment at the same dosage and refuse to reduce or stop drug intake despite its side effects (Gerbrecht, 2003). This overcompliance is more common in patients who have previously received anticancer chemotherapy (Abushullaih et al., 2002; Park et al., 2009). However, symptoms relating to hand–foot syndrome, a dose-limiting ADR, or gastro-intestinal disorders such as diarrhea can be improved by reducing the capecitabine dosage, which does not lower its effectiveness. It is important to educate patients about the avoidability of unnecessary side effects and about delaying the treatment schedule until the side effects are resolved (Abushullaih et al., 2002; Lee et al., 2013). Patient education, self-monitoring programs, family therapy, psychological therapy, telephone follow-up, and other supportive care measures effectively increase the safety of oral chemotherapy (Checchi et al., 2014; Moore, 2007). Electronic medication packaging devices remind patients to take their medication and provide physicians or caregivers with alternatives when preprogrammed drug use schedules are missed (Checchi et al., 2014). However, high-technology devices focus on medication adherence, not at-home patient monitoring. Moreover, remote monitoring devices are not presently used widely in our healthcare system. Currently, patient self-monitoring is the most important intervention for early detection and management of capecitabine-related ADRs at home. Nursing education programs provide the necessary knowledge and skill for close monitoring of patients at home. In conclusion, this study shows that administration of capecitabine at home is associated with the occurrence of serious adverse events. Future studies with ADR reporting data would help confirm the safety of oral chemotherapeutic agents and provide basic data for the development of effective patient education programs.
cancer than females, especially colorectal and stomach cancer. Therefore, male patients are more likely to have received chemotherapy containing capecitabine, making it more likely for them to have experienced capecitabine-related ADRs. In the present study, patients aged 50–59 years had a high frequency of ADRs (24.7%) and serious adverse events (20.2%). This finding is inconsistent with the results of a previous study in which the frequency of ADRs was found to be higher in individuals aged > 70 years (Routledge et al., 2004). Moreover, in the present study, the frequency of cases with “no record” of post-event action was higher in the serious adverse event group (32.3%) than in the non-serious adverse event group (8.8%). Further research is needed to confirm the relationship between age and the occurrence of serious adverse events. Gastrointestinal system disorders were frequently reported as capecitabine-related ADRs in the present study. This was an expected finding because a previous clinical study revealed that diarrhea, stomatitis, nausea, and vomiting occurred very frequently at all doses of capecitabine studied (Saif et al., 2008). The prevalence rate of white blood cell and RES disorders was low in the present study. Because these disorders are commonly expected side effects of chemotherapy, they are less likely to be spontaneously reported as ADRs; thus, the low occurrence of these disorders in this study might not reflect their actual prevalence. The frequency of the capecitabine-related ADR of hand–foot syndrome was 7.6%. However, skin and appendage disorders such as skin discoloration, drying, rubefaction, and rashes, and central nervous system disorders such as neuropathy and tingling skin may be considered part of hand–foot syndrome, leading to higher rates of reporting. Hand–foot syndrome is a common side effect of capecitabine that most frequently involves the palm and sole, but may occur anywhere on the skin (Abushullaih et al., 2002; Park et al., 2009). While the specific mechanisms responsible for its occurrence remain unclear, the accumulation of byproducts of capecitabine metabolism is believed to play a role (Gerbrecht, 2003; Saif et al., 2008). Symptoms include sensory skin disorders, pain, erythema, and edema. Serious cases of hand–foot syndrome may lead to skin cracking and blisters, which can result in secondary infections (Abushullaih et al., 2002), and severe sensory disorders may lead to the loss of hand function or ambulatory capacity. Thus, early-stage symptom management and conservative treatment are important, in addition to patient tracking to reduce the development of serious adverse events (Moore, 2007). While the hepatic metabolism of capecitabine is essential for its anticancer actions, the metabolic byproducts are generally excreted from the kidney; therefore, the patients' kidney function must be checked prior to
5. Conclusion and recommendations In this study, we analyzed capecitabine-related ADRs, including serious ADR cases, using ADR report data logged with KIDS in order to identify the characteristics of the ADRs, age and sex of patients, and 59
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nature of the reported data. The most commonly reported capecitabinerelated ADRs were gastrointestinal system disorders, including diarrhea, nausea, vomiting, and stomatitis. Other common ADRs were skin discoloration, itching, and rash, appendage disorders, hand–foot syndrome, and central and peripheral nervous system disorders, which were reported as tingling skin and neuropathy. Patients need to be educated about the common ADRs associated with capecitabine intake in a clinical setting. Patient characteristics must be considered when determining the capecitabine dosage and risk of ADRs, and nursing intervention is critical for preventing the exacerbation of these ADRs. Furthermore, it must be for pharmacists and nurses to work in collaboration on patient education needs in this area.
Lee, J.Y., Jung, J.W., Kang, H.R., Lee, S.H., Kim, H.S., Cho, S.H., 2013. Data analysis for anti-neoplastic chemotherapy-related adverse events reported to the Korean pharmacovigilance regional network. Korean J. Med. 85 (4), 385–395. Lee, N., Kim, K.H., Lee, S.C., 2011. Oral chemotherapeutic agents in current use. J. Korean Med. Assoc. 54 (11), 1191–1198. Lee, Y.H., Jeong, I.S., 2013. Factors influencing medication adherence to oral anticancer drug. Asian Oncol. Nurs 13 (4), 201–209. Lim, K.H., Shin, H.T., Sohn, H.S., Jun, H.J., Lee, J.H., Lee, Y.J., Lee, Y.S., Song, I.S., 2007. Comparison of WHO-ART versus MedDRA, internationally standardized terminology of adverse drug reaction classification. Korean J. Clin. Pharm 17 (1), 46–52. Moore, S., 2007. Facilitating oral chemotherapy treatment and compliance through patient/family–focused education. Cancer Nurs. 30 (2), 112–122. National Cancer Information Center, 2014 May. Cancer Facts & Figures 2014 in the Republic of Korea. https://ncc.re.kr/Publications.ncc?fileName=20141.pdf, Accessed date: 9 February 2018. Park, J.Y., 2014. Differential diagnosis between hand-foot syndrome and gout in colorectal cancer with capecitabine: a case study and review of the literature. Asian Oncol. Nurs. 14 (1), 1–6. Park, S.D., Lee, K.Y., Park, S.J., Lee, S.H., Lee, S.M., 2009. Hand-foot syndrome following capecitabine (Xeloda) monotherapy for colorectal cancer. J. Korean Soc. Coloproctol. 25 (4), 227–233. Rhew, K.Y., Lee, S.H., 2011. Analysis of the Korea Food and drug administration adverse drug reaction reports. Korean J. Clin. Pharm 21 (2), 138–144. Routledge, P.A., O'mahony, M., Woodhouse, K., 2004. Adverse drug reactions in elderly patients. Br. J. Clin. Pharmacol. 57 (2), 121–126. Saif, M.W., Katirtzoglou, N.A., Syrigos, K.N., 2008. Capecitabine: an overview of the side effects and their management. Anti Cancer. Drugs 19 (5), 447–464. Talbot, D., Moiseyenko, V., Van Belle, S., O'Reilly, S., Conejo, E.A., Ackland, S., Eisenberg, P., Melnychuk, D., Pienkowski, T., Burger, H.U., Laws, S., Osterwalder, B., 2002. Randomised, phase II trial comparing oral capecitabine (Xeloda®) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br. J. Cancer 86 (9), 1367–1372. van Grootheest, K., Olsson, S., Couper, M., de Jong van den Berg, L., 2004. Pharmacists' role in reporting adverse drug reactions in an international perspective. Pharmacoepidemiol. Drug Saf. 13 (7), 457–464. Van Cutsem, E., Twelves, C., Cassidy, J., Allman, D., Bajetta, E., Boyer, M., Bugat, R., Findlay, M., Frings, S., Jahn, M., McKendrick, J., Osterwalder, B., Perez-Manga, G., Rosso, R., Rougier, P., Schmiegel, W.H., Seitz, J.F., Thompson, P., Vieitez, J.M., Weitzel, C., Harper, P., Xeloda Colorectal Cancer Study Group, 2001. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J. Clin. Oncol. 19 (21), 4097–4106. Yap, T.A., Sandhu, S.K., Workman, P., De Bono, J.S., 2010. Envisioning the future of early anticancer drug development. Nat. Rev. Cancer 10 (7), 514–523. Yarbro, C.H., Wujcik, D., Gobel, B.H., 2013. Cancer Symptom Management. Jones & Bartlett Learning, Burlington MA.
Conflicts of interest None. References Abushullaih, S., Saad, E.D., Munsell, M., Hoff, P.M., 2002. Incidence and severity of hand–foot syndrome in colorectal cancer patients treated with capecitabine: a singleinstitution experience. Cancer Invest. 20 (1), 3–10. Ahn, S.K., 2007. Development and trends of cancer therapeutics. Korean J. Clin. Oncol 3 (2), 6–10. Checchi, K.D., Huybrechts, K.F., Avorn, J., Kesselheim, A.S., 2014. Electronic medication packaging devices and medication adherence: a systematic review. J. Am. Med. Assoc. 312 (12), 1237–1247. Choi, D., Choi, M., Ko, A., 2012. Current status of pharmaceutical safety management in Korea. J. Korean Med. Assoc. 55 (9), 827–834. Choi, K., Oh, O., 2005. Drug information development for drug utilization review system in USA. J. Korean Acad. Manag. Care Pharm 1, 28–32. Gerbrecht, B.-M., Kangas, T., 2004. Implications of capecitabine (Xeloda®) for cancer nursing practice. Eur. J. Oncol. Nurs. 8 (Suppl. 1), S63–S71. https://doi.org/10. 1016/j.ejon.2004.06.010. Gerbrecht, B.M., 2003. Current Canadian experience with capecitabine: partnering with patients to optimize therapy. Canc. Nurs. 26 (2), 161–167. Hoff, P.M., Ansari, R., Batist, G., Cox, J., Kocha, W., Kuperminc, M., Maroun, J., Walde, D., Weaver, C., Harrison, E., Burger, H.U., Osterwalder, B., Wong, A.O., Wong, R., 2001. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J. Clin. Oncol. 19 (8), 2282–2292.
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European Journal of Oncology Nursing journal homepage: www.elsevier.com/locate/ejon
Analysis of data on capecitabine-related adverse drug reactions from the Korean adverse event reporting system database
T
Jeong Yun Park Dept. of Clinical Nursing, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea
A R T I C LE I N FO
A B S T R A C T
Keywords: Oral chemotherapy Capecitabine Adverse drug reactions Serious adverse events Korea institute of drug safety and risk management Korean adverse event reporting system database
Purpose: The purpose of this study was to evaluate the adverse drug reactions (ADRs) and serious adverse events associated with capecitabine use in Korean patients by analyzing data from a comprehensive national database of adverse events. Method: Data from all reports concerning capecitabine (Anatomical Therapeutic Chemical code: L01BC06) generated between January 2011 and December 2014 were collected from the Korean Adverse Event Reporting System database (KAERS). Results: A total of 676 reports and 1069 capecitabine-related ADRs were identified. Ninety-nine cases (14.6%) were classified as serious adverse events. The most commonly reported capecitabine-related ADRs involved gastrointestinal system disorders (324, 30.3%), including diarrhea, nausea, vomiting, and stomatitis, followed by skin and appendage reactions (220, 20.6%), which included symptoms such as skin discoloration/disorder/ dryness, itching, and rash. Conclusions: Patients need to be educated about the common ADRs associated with capecitabine intake in a clinical setting. Patient characteristics must be considered when determining the capecitabine dosage and risk of ADRs, and nursing intervention is critical for preventing exacerbation of these ADRs.
1. Introduction Since early 2000, there has been an increase in the development and use of oral chemotherapeutic agents (Ahn, 2007; Yap et al., 2010), which play an important role in cancer treatment. As intravenous therapy requires invasive medical procedures, it tends to cause discomfort and interfere with the patients' daily life because of the need for hospitalization or frequent outpatient visits for treatment. Both medical staff and patients prefer oral chemotherapy, which improves the quality of life of cancer patients, as long as it provides similar treatment outcomes (Lee et al., 2011; Lee and Jeong, 2013). Capecitabine, an antimetabolic chemotherapeutic agent, inhibits the ability of cancer cells to produce the materials required for their growth (Saif et al., 2008). Diverse large-scale clinical trials conducted in the 2000s have demonstrated the anti-cancer effects of capecitabine, specifically against colorectal and breast cancer (Hoff et al., 2001; Talbot et al., 2002; Van Cutsem et al., 2001). In addition to being used as monotherapy for palliative chemotherapy in inoperable patients, capecitabine is currently being used, in combination with preoperative radiotherapy, as postoperative adjuvant therapy, or in combination with other chemotherapeutic agents that are effective against certain types of cancer (Lee et al., 2011; Saif et al., 2008; Yarbro et al., 2013).
Intravenous administration of 5-fluorouracil (5-FU), another antimetabolite chemotherapeutic agent, may require hospitalization for the delivery of continuous injections through a peripheral catheter, or if the vein condition is poor, a central venous catheter. In contrast, oral capecitabine chemotherapy circumvents any such discomfort or inconvenience to the patient and is safer because of the lower incidence of leukopenia. Thus, capecitabine is considered as efficacious as 5-FU, and its use is gradually increasing (Lee et al., 2011). Generally, when used for monotherapy, capecitabine is administered at a daily dose of 2500 mg/m2 of body surface area in 21-day cycles where the patients receive the drug for 14 of the 21 days and rest for the remaining 7 days (Saif et al., 2008). Capecitabine has several notable adverse effects involving the hands and feet, such as hand and skin pain, tenderness on pressure, edema, blisters, and peeling (Abushullaih et al., 2002; Park, 2014; Park et al., 2009), which occur in 54–60% of patients receiving the drug. Because oral chemotherapy decreases the number of required hospital visits, it decreases the number of opportunities for patient interaction with medical staff. Therefore, medical staff may be unable to immediately identify any adverse effects or drug interactions, and may not be able to accurately evaluate the effectiveness of the treatment (Gerbrecht and Kangas, 2004; Choi and Oh, 2005). Therefore, hospitals emphasize the need for patient education to improve self-care
E-mail address: [email protected]. https://doi.org/10.1016/j.ejon.2018.03.004 Received 19 September 2017; Received in revised form 5 March 2018; Accepted 6 March 2018 1462-3889/ © 2018 Published by Elsevier Ltd.
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competency, which allows outpatients taking capecitabine at home to evaluate any adverse effects and control their dosages accordingly (Moore, 2007; Park et al., 2009). Adverse drug reactions (ADRs) are defined as negative and unintended reactions to normal dosages of drugs. ADRs to anti-cancer drugs are as significant as the effectiveness of these drugs because they may lead to physical and mental damage to patients and increase medical costs by extending the duration of hospitalization for treatment (Choi et al., 2012; Rhew and Lee, 2011). With the increasing use of drugs, these ADRs to chemotherapy may appear even years after taking the drug, and as such, continuous monitoring is required. The United States presently operates a spontaneous adverse event reporting system, which was established in the early 1960s. In Korea, the regulations on drug safety information management were enacted in 1985, marking the beginning of adverse event monitoring, and the monitoring institution was designated in 1988, enabling patients to report adverse events spontaneously (Choi et al., 2012). In addition, regional pharmacovigilance centers have been established since 2006, and Regional Drug Monitoring Project Teams began operations in 2009 under the Ministry of Food and Drug Safety, thereby establishing specialized ADR reporting policies and systems. Cases of adverse events can be reported to the Korea Institute of Drug Safety and Risk Management (KIDS) or the regional drug safety center by medical professionals, manufacturers, and consumers through a website or by email, fax, mail, or telephone. The cases are comprehensively managed by the Korean Adverse Event Reporting System (KAERS), leading to a rapidly increasing number of reports (Choi et al., 2012; Rhew and Lee, 2011). Since capecitabine was made available commercially to patients, no large-scale analyses of capecitabine-related ADRs have been performed using data from various institutions. Therefore, the aim of this study was to evaluate the ADRs and serious adverse events associated with capecitabine use in Korean patients by analyzing data from a comprehensive national database of adverse events. The findings of this study may provide useful basic data for the development of effective patient education materials.
3)
4)
5)
6)
7)
action taken after the manifestation of ADRs, such as “drug cessation,” “dose maintenance” and “dose reduction.” Adverse drug reaction information: Adverse drug reactions were classified using WHO-Adverse Reaction Terminology, which was developed by the WHO Uppsala Monitoring Center (Lim et al., 2007); system-organ classes were used to classify the side effects. Serious adverse event information: Serious adverse events were classified as life-threatening, temporary or permanent disabilities, and prolonged hospitalization. Reporter information: This included information regarding the original reporter, defined as the person who first identified the side effect, as well as the person(s) who filed the actual report. These data were classified as doctor, pharmacist, nurse, consumer, and others. Causality evaluation information: ADRs were classified, in accordance with the causality evaluation criteria of the WHO Uppsala Monitoring Centre, into “certain,” “probable,” “possible,” “unlikely,” “unclassified,” and “unassessable.” Medical history: Korean Standard Classification of Diseases codes were used.
2.4. Data collection and ethical considerations This study received an approval exemption permit from the Institutional Review Board (No. 1040968-E-2015-003). We also obtained approval from KIDS for the use of the KIDS-KD by submitting a request and pledge for KIDS-KD in October 2015. 2.5. Statistical analyses
2. Methods
All statistical analyses were performed using Windows SPSS version 22.0 (IBM SPSS Statistics, Chicago, IL, USA). Descriptive statistics were used to summarize data regarding the capecitabine-related ADRs and severe events. General characteristics were compared between the serious adverse events and non-serious adverse events groups by using the independent t-test and the chi-square test. A P value of 0.01 was considered statistically significant.
2.1. Study design
3. Results
This study was a secondary data analysis study using the Korean Database of Spontaneously Reported Adverse Drug Reactions to confirm ADRs to capecitabine.
3.1. General features of spontaneously reported data on capecitabinerelated ADRs The general features of capecitabine-related ADR reports are listed in Table 1. There were 676 reports: 44 cases (6.5%) in 2011, 125 cases (18.5%) in 2012, 277 cases (41.0%) in 2013, and 230 cases (34.0%) in 2014. Pharmacists were the largest group of reporters at 224 cases (33.1%), followed by 183 cases (27.1%) reported by nurses, and 106 cases (15.7%) by doctors. In terms of location of reporting, 548 cases were reported at the regional drug safety center (81.1%), followed by 78 cases (11.5%) at manufacturer/importers, 30 cases (4.4%) at pharmacies, and 20 cases (3.0%) at hospitals. An average of 1.58 ADRs were included in each report, with 212 reported cases (31.4%) consisting of two or more ADRs. Serious adverse events were recorded in 99 cases (14.6%), with 1 case of permanent disability (0.2%), 4 cases of death (0.6%), and 46 cases of hospitalization/prolongation of hospital stay (6.6%). In terms of drug-related action after the manifestation of ADRs, the drug dose was maintained in 155 cases (22.9%) and reduced in 53 cases (7.8%), and drug treatment was terminated in 42 cases (6.2%); for 368 cases (54.4%), no records were available.
2.2. Subjects This study used the KIDS KAERS Database (KIDS-KD), comprising data from KAERS, a system collecting data on adverse events through KIDS, compiled over 48 months from January 2011 to December 2014. This study included all ADRs relating to the use of capecitabine, coded “L01BC06” in the Anatomical Therapeutic Chemical (ATC) code, and excluded “unlikely,” “unclassified,” and “unassessable” adverse event cases. Overall, this study analyzed data from a total of 1069 cases with a causal relationship between ADRs and capecitabine use, including 41 “certain” cases (3.8%), 325 “probable” cases (30.4%), 376 “possible” cases (35.2%), and 327 cases (30.6%) with no assessment. 2.3. Study parameters 1) General information: These data included reporting year, presence of serious adverse events, patient sex, and patient age. 2) Drug information: The drug contents in the reports were classified using ATC codes, which are managed by the World Health Organization (WHO) Collaborating Centre for Drug Statistics Methodology. The data collected included the ingredient name, administration purpose, administration date, and drug-related
3.2. General characteristics of patients The demographic and clinical characteristics of patients with capecitabine-related ADRs are listed in Table 2. The reported cases comprised 339 male (50.1%) and 312 female (46.2%) patients, with 56
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Table 1 General features of capecitabine-related adverse drug reactions reports (n = 676). Characteristics
Categories
n (%) or mean ± SD
No. of reports by year
2010 2011 2013 2014 Doctor Pharmacist Nurse Patient Others No answer Regional drug safety center Manufacturer (Importers) Hospital Pharmacy
44 (6.5) 125 (18.5) 277 (41.0) 230 (34.0) 106 (15.7) 224 (33.1) 183 (27.1) 13 (1.9) 99 (14.6) 51 (7.5) 548 (81.1) 78 (11.5) 20 (3.0) 30 (4.4) 1.58 ± 1.24
1 2–3 ≥4 Yes Disability Life-threatening/Death Hospitalization/ prolongation of hospital stay Others No Drug cessation Dose maintenance Dose reduction Unknown No action No record
464 (68.6) 174 (25.8) 38 (5.6) 99 (14.6) 1 (0.2) 4 (0.6) 46 (6.6)
Reporter
Reporter information
Adverse drug reactions per report
Serious adverse events
Drug-related action after adverse drug reactions
Table 3 Capecitabine-related adverse drug reactions classified by system-organ classes (n = 1069). SOC code
SOC classification
n
%
0600
Gastrointestinal system disorders DIARRHEA NAUSEA VOMITING STOMATITIS Others (Constipation, dyspepsia, dysphagia, hiccups, abdominal distress, etc.) Skin and appendage disorders SKIN DISCOLORATION/DISORDER ITCHING RASH Others (pruritus, nail disorder, alopecia, etc.) Body as a whole -general disorders HAND–FOOT SYNDROME Others (fever, weakness generalized, asthenia, pain, etc.) Central and peripheral nervous system disorders NEUROPATHY TINGLING SKIN Others (dizziness, headache, tingling skin, etc.) White blood cell and RES disorders NEUTROPENIA Others (leucopenia, eosinophilia, etc.) Psychiatric disorders ANOREXIA Others (insomnia, depression, mental disorder, etc.) Red blood cell disorders (anemia, blood disorder, etc.) Hepatic and biliary system disorders (elevated liver enzymes, etc.) Platelet, bleeding, and clotting disorders (thrombocytopenia, etc.) Respiratory system disorders (pneumonia, dyspnea, etc.) Metabolic and nutritional disorders (hyperglycemia, hyponatremia, etc.) Urinary system disorders (creatinine increased, azotemia, etc.) Musculoskeletal system disorders (myalgia, muscle weakness, etc.) Vision disorders (Pigment precipitation, vision deterioration, etc.) Resistance mechanism disorders (infection, sepsis, etc.) Vascular (extracardiac) disorders (cerebral infarction, etc.) Productive disorders, female (break-through bleeding, vaginitis, etc.) Neoplasm (melanoma, rectosigmoid cancer, elevated CA125, etc.) Application site disorders (injection site pain) Special senses other, disorders (dysgeusia, metallic taste) Cardiovascular disorders, general (circulatory instability, heart disorder) Secondary terms-events (spinal cord injury, off label use) Hearing and vestibular disorders (ear pain, etc.) Heart rate and rhythm disorders (tachycardia) Fetal disorders (abortion)
324 78 71 51 37 87
30.3 7.3 6.6 4.8 3.5 8.1
220 88 24 18 90 148 81 68
20.6 8.3 2.2 1.7 8.4 13.9 7.6 6.3
110 48 16 46 91 63 28 49 35 13 19 18
10.3 4.5 1.5 4.3 8.5 5.9 2.6 4.6 3.3 1.3 1.8 1.7
18
1.7
14 11
1.3 0.7
8
0.7
7
0.7
6
0.6
5 3
0.5 0.3
3
0.3
3
0.3
3 2
0.3 0.2
2
0.2
2
0.2
1 1 1
0.1 0.1 0.1
0100
1810
0410
1220
0500 48 (7.2) 577 (85.4) 42 (6.2) 155 (22.9) 53 (7.8) 51 (7.5) 67 (9.9) 308 (45.6)
1210 0700 1230 1100 0800
SD, standard deviation. 1300 Table 2 General characteristics of patients with capecitabine-related adverse drug reaction reports (n = 676). Characteristics
Categories
n (%) or mean ± SD
Sex
Female Male Unknown
312 (46.2) 339 (50.1) 25 (3.7) 54.8 ± 12.4 53 (7.8) 107 (15.8) 167 (24.7) 154 (22.8) 112 (16.6) 83 (12.3) 47 (7.0) 118 (17.5) 115 (17.0) 20 (3.0) 13 (1.9) 363 (53.7)
Age (years)
Medical history
≤39 40–49 50–59 60–69 ≥70 Unknown Breast cancer Colorectal cancer Stomach/esophageal cancer Liver-pancreas-gallbladder cancer Others No record
0200 0431 1830 1040 1420 1700 1820 0433 1010 2000 0432 1030 1500
RES, reticuloendothelial system; SOC, system-organ class.
SD, standard deviation.
common at 324 cases (30.3%): 78 cases (7.3%) of diarrhea, 71 cases (6.6%) of nausea, and 51 cases (4.8%) of vomiting and stomatitis. The second most common ADRs were skin and appendage reactions, which occurred in 220 cases (20.6%), with symptoms such as skin discoloration/disorder/dryness, itching, and rash. There were 148 cases (13.9%) of general ADRs, including 81 cases of hand–foot syndrome (8.3%). Other symptoms were related to central and peripheral nervous system disorders (110 cases, 10.3%), and white blood cell and RES disorders (Table 3).
patient sex not reported in 25 cases (3.7%). Patient age was not reported in 83 cases (12.3%), and the average age of 593 patients was 54.8 ± 12.4 years. The 50–59-year age group had the highest number of patients with 167 cases (24.7%). Medical history data showed that 118 patients (17.5%) had colorectal cancer, followed by 115 cases (17.0%) of stomach/esophageal cancer, and 47 cases (7.0%) of breast cancer. 3.3. Capecitabine-related ADRs classified by system-organ class Among 1069 cases of ADRs, gastrointestinal reactions were the most 57
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Table 4 Comparison of serious and non-serious capecitabine-related adverse events. Characteristics
Sex
Categories
Female Male No record
Age (years)
Medical history
SOC classification
Adverse drug reactions per report Drug-related action after events
≤39 40–49 50–59 60–69 ≥70 No record Breast cancer Colorectal cancer Stomach/esophageal cancer No record Gastrointestinal system disorders Skin and appendage disorders Body as a whole-general disorders Central and peripheral nervous system disorders White blood cell and RES disorders 2.46 (2.38) Stop Dose maintenance Dose reduction Unknown No action No record
t or χ2
P
4.39
0.036
11.56 16.09
0.001 0.003
1.41 14.13 15.48
0.236 < 0.001 < 0.001
8.10 52.55 4.65 4.77
0.004 < 0.001 0.031 0.029
58 (7.0) 64.89
10.20 < 0.001
0.001
65 (11.3) 35 (6.1) 152 (26.3) 51 (8.8) 47 (8.1) 227 (39.3)
17.05
0.002
Serious adverse event (n = 99)
Non-serious adverse event (n = 577)
n (%) or mean ± SD
n (%) or mean ± SD
45 (45.5) 31 (31.3) 23 (23.2) 53.6 ± 11.8 13 (13.1) 15 (15.2) 20 (20.2) 14 (14.1) 5 (5.1) 32 (32.3) 4 (4.1) 4 (4.1) 3 (3.0) 88 (88.8) 56 (23.0) 10 (4.1) 44 (18.0) 16 (6.6)
267 (46.3) 308 (53.4) 2 (0.3) 59.0 ± 12.4 40 (6.9) 92 (15.9) 147 (25.5) 140 (24.3) 107 (18.5) 51 (8.8) 43 (7.5) 115 (19.9) 112 (19.4) 307 (53.2) 268 (32.5) 210 (25.5) 104 (12.6) 94 (11.4)
33 (13.5) 1.43 (0.82) 2 (2.0) 7 (7.1) 3 (3.1) 2 (2.0) 4 (4.0) 81 (81.8)
RES, reticuloendothelial system; SOC, System-Organ class.
4. Discussion
3.4. Comparison of serious and non-serious capecitabine-related adverse events
In this study, we analyzed the trends in the occurrence of capecitabine-related ADRs by evaluating the KAERS adverse event reports; however, we were unable to analyze the frequency of specific ADRs because of limitations associated with spontaneous data reports. ADR reports can be accessed through the Ministry of Food and Drug Safety website, which is open to medical professionals, pharmaceutical companies, regional pharmacies, and general consumers. However, this reporting structure is spontaneous in nature, and does not include ADRs that were not reported. Therefore, the reported ADR data do not represent the entire spectrum and frequency of real-world ADRs. Reports of capecitabine-related ADR increased almost three-fold from 44 cases in 2011 to 125 cases in 2012, and have continued to increase since 2012. This trend relates to the implementations of policies and system enhancements to encourage spontaneous reporting. The total number of reports increased from 64,143 cases in 2010 to 183,554 cases in 2014. Pharmacists comprised the largest proportion of reporters who first noticed ADRs, followed by nurses. Pharmacists dispense medications as prescribed by the physician, and generally, pharmacists are expected to provide information about the drug at discharge. The pharmacist is recognized as an expert on drugs and has a coordinating role when hospitals wish to report adverse events (van Grootheest et al., 2004). Nurses also play an important role in identifying and reporting ADRs, and can thereby facilitate the safe utilization of drugs (Gerbrecht and Kangas, 2004). The results of previous studies indicated that female patients were more vulnerable to ADRs than male patients were. However, in the present study, capecitabine-related ADRs occurred at a similar frequency in both male and female patients. As the total number of patients taking capecitabine could not be confirmed in this study, it is impossible to identify the prevalence rate of capecitabine-related ADRs according to patient sex. However, according to the National Cancer Information Center statistics (2014), males are more likely to develop
As shown in Table 4, there was a significant difference in the patient sex ratio between cases of serious adverse events and non-serious adverse events, after excluding non-reporters (p = 0.036). The average patient age in the serious adverse event group was significantly younger than that in the non-serious adverse event group (53.6 ± 11.8 years vs. 59.0 ± 12.4 years; p = 0.001), with significant differences in the distribution of age between the serious and non-serious adverse group (p = 0.003). Moreover, there were no differences between the number of serious and non-serious adverse events among breast cancer cases, but the number of non-serious adverse events was significantly higher than the number of serious adverse events in colorectal (p < 0.001), and stomach/esophageal (p < 0.001) cancer cases. The action taken after the manifestation of a capecitabine-related serious adverse event was only recorded in 18 cases (18.2%). The most common action taken after the manifestation of a serious adverse event was dose maintenance (7 cases, 7.1%), whereas the most common post-event drug-related action in the non-serious adverse event group was dose reduction (152 cases, 26.3%). 3.5. Capecitabine-related ADRs classified by system-organ class in serious adverse events The one case leading to permanent disability involved a red blood cell disorder. Deaths were attributable to general disorders in two cases of general disorders, and to one case each of liver & biliary system disorders, and respiratory system disorders. The most common ADR in patients with hospitalization/prolonged duration of hospital stay was gastrointestinal system-related disorders, with 13 cases (28.3%), followed by 6 cases of general disorders (13.0%) and 5 cases (10.9%) of psychiatric disorders, including anorexia and insomnia (10.9%; Table 5). 58
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Table 5 Capecitabine-related ADRs classified by system-organ class in Serious adverse events (n = 99). SOC code
0600 0100 1810 0410 1220 0500 1210 0700 1230 1100 1300 0431 1700 2000 1500
SOC classification
Gastrointestinal system disorders Skin and appendage disorders Body as a whole-general disorders Central and peripheral nervous system disorders White blood cell and RES disorders Psychiatric disorders Red blood cell disorders Hepatic and biliary system disorders Platelet, bleeding, and clotting disorders Respiratory system disorders Urinary system disorders Vision disorders Neoplasm (melanoma, rectosigmoid cancer, elevated CA125) Secondary terms-events (spinal cord injury, off label use) Fetal disorders (abortion)
Seriousness, n (%) Disability (n = 1)
Death (n = 4)
Hospitalization/prolongation of hospital stay (n = 46)
Others (n = 48)
0 0 0 0 0 0 1 (100.0) 0 0 0 0 0 0
0 0 2 (50.0) 0 0 0 0 1 (25.0) 0 1 (25.0) 0 0 0
13 (28.3) 3 (6.5) 6 (13.0) 4 (8.7) 3 (6.5) 5 (10.9) 0 1 (2.2) 3 (6.5) 2 (4.3) 1 (2.2) 1 (2.2) 2 (4.3)
10 (20.8) 0 13 (27.1) 10 (20.8) 2 (4.2) 0 2 (4.2) 3 (6.3) 2 (4.2) 3 (6.3) 0 0 0
0 0
0 0
2 (4.3) 2 (4.3)
0 0
ADR, adverse drug reaction; RES, reticuloendothelial system; SOC, system-organ class.
determining the capecitabine dosage, and the dosage must be appropriately adjusted accordingly (Gerbrecht, 2003; Saif et al., 2008). The most common drug-related action after capecitabine-related ADRs was dose maintenance, followed by dose reduction or drug cessation. Patients being discharged from the hospital who continue capecitabine treatment at home are educated on the evaluation of side effects and are instructed to reduce dosage or cease drug treatment until symptoms improve. Because most cancer patients believe that completing their treatment regimen will result in the best outcome, they tend to continue treatment at the same dosage and refuse to reduce or stop drug intake despite its side effects (Gerbrecht, 2003). This overcompliance is more common in patients who have previously received anticancer chemotherapy (Abushullaih et al., 2002; Park et al., 2009). However, symptoms relating to hand–foot syndrome, a dose-limiting ADR, or gastro-intestinal disorders such as diarrhea can be improved by reducing the capecitabine dosage, which does not lower its effectiveness. It is important to educate patients about the avoidability of unnecessary side effects and about delaying the treatment schedule until the side effects are resolved (Abushullaih et al., 2002; Lee et al., 2013). Patient education, self-monitoring programs, family therapy, psychological therapy, telephone follow-up, and other supportive care measures effectively increase the safety of oral chemotherapy (Checchi et al., 2014; Moore, 2007). Electronic medication packaging devices remind patients to take their medication and provide physicians or caregivers with alternatives when preprogrammed drug use schedules are missed (Checchi et al., 2014). However, high-technology devices focus on medication adherence, not at-home patient monitoring. Moreover, remote monitoring devices are not presently used widely in our healthcare system. Currently, patient self-monitoring is the most important intervention for early detection and management of capecitabine-related ADRs at home. Nursing education programs provide the necessary knowledge and skill for close monitoring of patients at home. In conclusion, this study shows that administration of capecitabine at home is associated with the occurrence of serious adverse events. Future studies with ADR reporting data would help confirm the safety of oral chemotherapeutic agents and provide basic data for the development of effective patient education programs.
cancer than females, especially colorectal and stomach cancer. Therefore, male patients are more likely to have received chemotherapy containing capecitabine, making it more likely for them to have experienced capecitabine-related ADRs. In the present study, patients aged 50–59 years had a high frequency of ADRs (24.7%) and serious adverse events (20.2%). This finding is inconsistent with the results of a previous study in which the frequency of ADRs was found to be higher in individuals aged > 70 years (Routledge et al., 2004). Moreover, in the present study, the frequency of cases with “no record” of post-event action was higher in the serious adverse event group (32.3%) than in the non-serious adverse event group (8.8%). Further research is needed to confirm the relationship between age and the occurrence of serious adverse events. Gastrointestinal system disorders were frequently reported as capecitabine-related ADRs in the present study. This was an expected finding because a previous clinical study revealed that diarrhea, stomatitis, nausea, and vomiting occurred very frequently at all doses of capecitabine studied (Saif et al., 2008). The prevalence rate of white blood cell and RES disorders was low in the present study. Because these disorders are commonly expected side effects of chemotherapy, they are less likely to be spontaneously reported as ADRs; thus, the low occurrence of these disorders in this study might not reflect their actual prevalence. The frequency of the capecitabine-related ADR of hand–foot syndrome was 7.6%. However, skin and appendage disorders such as skin discoloration, drying, rubefaction, and rashes, and central nervous system disorders such as neuropathy and tingling skin may be considered part of hand–foot syndrome, leading to higher rates of reporting. Hand–foot syndrome is a common side effect of capecitabine that most frequently involves the palm and sole, but may occur anywhere on the skin (Abushullaih et al., 2002; Park et al., 2009). While the specific mechanisms responsible for its occurrence remain unclear, the accumulation of byproducts of capecitabine metabolism is believed to play a role (Gerbrecht, 2003; Saif et al., 2008). Symptoms include sensory skin disorders, pain, erythema, and edema. Serious cases of hand–foot syndrome may lead to skin cracking and blisters, which can result in secondary infections (Abushullaih et al., 2002), and severe sensory disorders may lead to the loss of hand function or ambulatory capacity. Thus, early-stage symptom management and conservative treatment are important, in addition to patient tracking to reduce the development of serious adverse events (Moore, 2007). While the hepatic metabolism of capecitabine is essential for its anticancer actions, the metabolic byproducts are generally excreted from the kidney; therefore, the patients' kidney function must be checked prior to
5. Conclusion and recommendations In this study, we analyzed capecitabine-related ADRs, including serious ADR cases, using ADR report data logged with KIDS in order to identify the characteristics of the ADRs, age and sex of patients, and 59
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nature of the reported data. The most commonly reported capecitabinerelated ADRs were gastrointestinal system disorders, including diarrhea, nausea, vomiting, and stomatitis. Other common ADRs were skin discoloration, itching, and rash, appendage disorders, hand–foot syndrome, and central and peripheral nervous system disorders, which were reported as tingling skin and neuropathy. Patients need to be educated about the common ADRs associated with capecitabine intake in a clinical setting. Patient characteristics must be considered when determining the capecitabine dosage and risk of ADRs, and nursing intervention is critical for preventing the exacerbation of these ADRs. Furthermore, it must be for pharmacists and nurses to work in collaboration on patient education needs in this area.
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