Drug, Healthcare and Patient Safety Dovepress

open access to scientific and medical research

Open Access Full Text Article

ORIGINAL RESEARCH

Chemotherapy-Related Adverse Drug Reaction

and Associated Factors Among Hospitalized
Paediatric Cancer Patients at Hospitals in
North-West Ethiopia
This article was published in the following Dove Press journal:
Drug, Healthcare and Patient Safety

Gashaw Workalemahu 1 Background: One of the prevalent treatment modalities for cancer is chemotherapy.
2 Adverse drug reactions, however, are becoming the world’s major public health pro­
Ousman Abubeker Abdela
Melaku Kindie Yenit 3 blem. More than half (54.5 percent) of cancer patients need hospitalization for further
1
management, in addition to the increased health-care costs of treatment. The aim of this
Clinical Pharmacy Service Unit, Enat
Primary Hospital, Alemketema, Ethiopia; study was to evaluate adverse drug reactions associated with chemotherapy and related
2 factors in hospitalized paediatric cancer patients in Ethiopia’s north-west hospitals.
Department of Clinical Pharmacy,
School of Pharmacy, College of Medicine Methods: From July 1, 2017, to August 13, 2019, a cross-sectional study was carried out
and Health Sciences and Comprehensive
Specialized Hospital, University of among 311 paediatric cancer patients at Gondar Comprehensive University, Specialized
Gondar, Gondar, Ethiopia; 3Department Hospital and Felegehiwot referral hospital. The data were entered into Epi Info version 7
of Epidemiology and Biostatistics,
and exported for further analysis to Statistical Product and Service Solutions (SPSS). To
Institute of Public Health, College of
Medicine and Health Sciences and identify associated variables, both the bi-variate and multi-variate logistic regression ana­
Comprehensive Specialized Hospital, lyses were computed. Variables with a P-value of less than 0.05 were considered statistically
University of Gondar, Gondar, Ethiopia
significant in the multivariate logistic regression analysis.
Results: The overall adverse drug reaction in this study was 41.5 percent ((95% CI: 35.8–­
47.2%)). Patients who received concomitant medications were at higher risk of experiencing
adverse drug reactions (AOR: 2.60 (95% CI: 1.54–4.40)), according to the multivariate
logistic regression analysis. Similarly, there was a risk of developing adverse drug reactions
in patients taking four or more chemotherapy agents (AOR: 2.67 (95% CI: 1.52–4.68)). In
addition, regimens based on etoposide (AOR: 1.99 (95% CI: 0.93–4.27)), mercaptopurine
(AOR: 3.91 (95% CI: 1.06–14.46)) and doxorubicin (AOR: 2.32 (95% CI: 1.30–4.15)) were
at higher risk for adverse drug reactions in patients.
Conclusion: Adverse drug reactions developed in a significant proportion of the study
patients (2 out of 5 patients). Therefore, for pediatric cancer patients on concomitant
medications and for patients on etoposide, mercaptopurine and doxorubicin drug regimens,
efficient prevention and management of adverse drug reactions should be sought.
Keywords: adverse drug reaction, chemotherapy, cancer, paediatric, Ethiopia

Introduction
Adverse Drug Reaction (ADR) has been defined by the World Health
Organization (WHO) as the reaction to a drug that is noxious, unintended
and occurs at doses used for disease prophylaxis, diagnosis or treatment.1 ADR
Correspondence: Melaku Kindie Yenit has become a major concern for the general public, the medical profession, the
University of Gondar, Gondar, Ethiopia,
Email [email protected] pharmaceutical industry and regulatory authorities worldwide.2 It affects the

submit your manuscript | www.dovepress.com Drug, Healthcare and Patient Safety 2020:12 195–205 195
DovePress © 2020 Workalemahu et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/
http://doi.org/10.2147/DHPS.S254644
terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing
the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
Workalemahu et al Dovepress

recovery rate of patients and decreases the quality of a shortage of data in Africa showing drug reactions at
life.3–6 The effect of drug reaction given for treatment either regional or national levels.29,30 There are few
varies from a simple inconvenience to permanent dis­ studies available within the country, but the national
ability and death.7 As a result of its health implica­ ADR figure is not revealed. A study showed that 67%
tions, it has become one of the major causes of of patients experienced ADRs in South Africa.31 There
morbidity associated with higher hospital admission is a shortage of data in Africa showing drug reactions
rates and poor outcomes of treatment. About 6.5–­ at either regional or national levels. There are few
10.9% of admissions have been attributed to ADR studies available within the country, but the national
worldwide.11 ADR figure is not revealed. Although ADR can be
Cancer is a group of diseases characterized by the affected by various factors, some of the reported risk
growth and spread of abnormal cells that are factors for adverse drug reactions were gender, age,
uncontrolled.12 Various treatment modalities, including multiple medications, new medications, type of medi­
chemotherapy, radiotherapy, surgery, hormonal, immuno­ cation, race, alcohol intake, comorbidity, liver and kid­
logical and biological therapy, are available for cancer.12,13 ney status, anxiety and the perception of patients.32–35
One of the most common treatment modalities is che­ Studies have also shown that, due to developmental
motherapy, which is extremely useful for the treatment of changes affecting the pharmacokinetics of many of
cancer.14–16 As a result, it controls the spread of cancer the medications used in pediatrics, paediatric patients
cells, relieves tumor-related symptoms, improves the qual­ taking chemotherapy are among the most vulnerable to
ity of life and prolongs patient survival.14,17 ADRs.4,9
Although cancer treatment options exist, patients The World Health Organization (WHO), aware of
become vulnerable to ADR due to various reasons, the burden of the problem, has set up
including poor adherence to drugs and clinical a pharmacovigilance system to detect, assess and pre­
conditions.18 For a number of formerly fatal malignan­ vent adverse drug reactions.5,36,37 Thirty-five African
cies, such as lymphomas and leukemias, chemotherapy countries, including Ethiopia, cumulatively submitted
treatment is curative. Although anti-cancer drugs are almost 103,499 ADR cases to the global pharmacov­
well studied and highly beneficial for better treatment igilance database in this system up to 2015, represent­
outcomes, when compared to other classes of medica­ ing only 0.88% of global ADRs.36 The prevalence of
tions, they are associated with various forms of adverse chemotherapy-related ADRs and associated risk factors
drug reactions (ADRs).9,19,20 In Jordan, anti-neoplastic in paediatric cancer patients in Ethiopia, where self-
drugs (37.6%) followed by immune modulators medication and poor adherence to treatment is high, is
(14.1%), antibiotics (10.3%) and analgesics (6.6%) not well studied. This study, therefore evaluated the
were the more common classes of drugs involved in magnitude of ADRs associated with chemotherapy
ADRs.21 This is because anti-cancer medicines have and independent factors among patients with hospita­
a narrow therapeutic window and a highly toxic nature; lized pediatric cancer, which is critical for understand­
as a consequence, cells such as the bone marrow, ing the level of the problem.
gastrointestinal cell lining and hair follicle are
damaged.20,22–24 They therefore induce various forms
of ADRs, such as suppression of the bone marrow, hair Materials and Methods
loss, nausea and vomiting, oral mucositis, hepatotoxi­ Study Setting and Design
city, and nephrotoxicity.23–25 An institutional based cross-sectional study was con­
In different regions of the world, different studies ducted at the University of Gondar Comprehensive
have shown that the prevalence of ADRs during hospi­ Specialized Hospital (UoGCSH) and Felegehiwot
talization varies.26–28 In 11.5% of hospitalized patients Referral Hospital (FRH), North West, Ethiopia. The
in Australia, ADRs occurred, and in 1.7–50.9% of study was conducted from August 16 to
patients in Europe.27 The magnitude of hospitalization September 22, 2019. The hospitals selected are among
associated with ADR ranges from 0.2% to 54.5% the oldest hospitals in the country with a range of
worldwide.8 In Europe, adverse drug events accounted medical specialists and oncology centers in north-wes­
for 0.5% to 12.8% of hospital admissions.27 There is tern Ethiopia that provide cancer patients with

196 submit your manuscript | www.dovepress.com Drug, Healthcare and Patient Safety 2020:12
DovePress
Dovepress Workalemahu et al

treatment. In the catchment area, each hospital serves Data Entry, Analysis and Interpretation
more than 5 million individuals and has in-patient and The collected data were entered into Epi Info version
out-patient service units. 7, then exported and analyzed using Statistical Product
and Service Solutions (SPSS) version 22. For contin­
Population and Sampling uous variables such as age, height and weight, descrip­
All paediatric patients diagnosed in the selected hospitals tive statistics such as mean and standard deviations
with any type of cancer were included. The study popula­ were calculated. For variables including age, height,
tion was those hospitalized paediatric patients diagnosed weight, body surface area (BSA), cancer stage, number
with cancer that had taken at least one chemotherapy of chemotherapy, type of chemotherapeutic agents, pre­
treatment from July 1, 2017 to August 13, 2019. The vious history of chemotherapy, presence of co-
study excluded patients who were receiving radiotherapy. morbidity and concomitant medication, the Chi-square
Finally, this study included a total of 311 hospitalized assumption was tested.
paediatric cancer patients that were admitted to the two Those variables satisfied the assumptions were ana­
hospitals. lyzed using bivariate binary logistic regression to identify
associations with the outcome variable (ADRs). Variables
Variables and Measurement with a P-value of less than or equal to 0.2 at the bivariate
The dependent variable Adverse Drug Reaction (ADR) logistic regression analysis were taken for multivariate
is defined as any reaction to a noxious and unintended analysis. Variables with a P-value of less than 0.05 in the
chemotherapy that occurs during treatment in the usual multivariate logistic regression were considered as
clinical practice of paediatric cancer patients. The a significant association with ADRs.
causality of the ADRs was evaluated using the World
Health Organization-Uppsala Monitoring Centre Results
(WHO-UMC) causality assessment scale. The severity
Socio-Demographic Characteristics of
of ADR was also measured using the severity assess­
ment of the Hartwig and Siegel scales (Appendix Paediatric Cancer Patients
A and B). A total of 311 patient charts were reviewed and 287 were
eligible for analysis, while 24 of those charts were
Data Collection and Management excluded because of incomplete outcome variable records.
Medical records of paediatric cancer patients in both hos­ Almost two-thirds of the participants were males, 176
pitals (UoGCSH and FRH) were traced from the registra­ (61.3 percent). The mean age of patients was 7.06 years
tion book for oncology wards. Using a patient Medical with a standard deviation of ± 3.55. Nearly half (47.5%) of
Record Number (MRN), patient charts were drawn from the respondents were 6 to 12 years of age. The mean
the card room. Using the structured questionnaire, two weight was 18.06 Kg (± 6.8961 kg) for the patients. The
trained pharmacists collected the data from the charts. majority (83.6%) of patients were rural inhabitants
Data such as age, weight, height, sex, residence and (Table 1).
body surface area (BSA) were collected from demo­
graphics. In addition, type and number of chemotherapy, Clinical Characteristics of Paediatric
cycle of treatment, history of previous chemotherapy, type Cancer Patients
and stage of cancer, laboratory results, co-morbidity, con­ The most prevalent type of cancer, diagnosed in 67
comitant medications and ADR were also reviewed from (23.3%) patients, was acute lymphoblastic leukemia
the chart. (ALL), followed by Wilms tumor 65 (22.6%) and non-
Data collectors and supervisors were intensively Hodgkin lymphoma (NHL) 34 (11.8%) (Figure 1).
trained on questionnaire content, methods of data collec­ A total of 18 types of chemotherapeutic agents were
tion and ethical concerns. To check its consistency, twenty used to treat cancer. Vincristine, which was used by
questionnaires were pre-tested. After pre-testing, the ques­ 245 (85.4%) patients, was the most frequently pre­
tions were modified. During the data collection period, scribed agent, followed by doxorubicin 177 (61.7%)
data quality was ensured by the principal investigator for and cyclophosphamide 166 (57.8%) respectively
completeness. (Table 2).

submit your manuscript | www.dovepress.com

Drug, Healthcare and Patient Safety 2020:12 197
DovePress
Workalemahu et al Dovepress

Table 1 Socio-Demographic Characteristics of Pediatric Cancer malnutrition (41.7%), followed by anemia (24.4%), infec­
Patients at Northwest Hospitals, Ethiopia, from August 16 to – tious disease (18.9%) and other health conditions (15.0%).
September 22, 2019
Nearly half (45.6%) of patients with co-morbidities experi­
Variables Frequency (n) Percentage (%) enced adverse drug reactions (ADRs) in this study.
Age (year)
1–2 29 10.1 Causality and Severity Assessment of
3–6 111 38.7
7–12 128 44.6
Adverse Drug Reaction
>12 19 6.6
According to the World Health Organization-Uppsala
monitoring Centre (WHO-UMC) causality assessment
Weight (Kg)
scales, 98 (66.7%) were possible and 49 (33.3%) were
< 18 112 39.0
≥18 175 61.0
probable ADR cases. There were no certain and unlikely
category of ADRs. In addition, the Hartwig’s and Siegel
BSA (m2)
severity assessment Scale in this study indicated that most
< 0.727 125 43.6
of the ADR reactions were a moderate 109 (74.1%), and
≥ 0.727 162 56.4
mild 38 (25.9%) drug reactions.
Sex
Female 111 38.7
Male 176 61.3
Factors Associated with
Resident
Chemotherapy-Related Adverse Drug
Urban 47 16.4 Reaction
Rural 240 83.6 In a bivariate logistic regression analysis, concomitant
medicinal products, the number of chemotherapy drugs
and chemotherapy agents such as doxorubicin, etoposide
Out of the total patients included in this study (287), and mercaptopurine were found to be adverse drug reac­
a total of 172 (59.2%) had no defined stage of cancer. tion factors with a p-value of less than 0.2. Consequently,
Moreover, more than half 63 (52.9%) of patients who following the multivariate logistic regression analysis of
experienced ADRs had undecided stage of cancer these variables, only one variable (comorbidity) was not
(Table 3). found to be statistically significant in relation to adverse
drug reactions at a p-value lower than 0.05. The chi-square
Magnitude of Adverse Drug Reactions assumption was not met for variables such as sex, age,
In this study, a total of 119 paediatric patients were weight, residence, BSA, stage of cancer and prior history
developed Adverse Drug Reactions (ADRs). The pre­ of chemotherapy, so that regression analysis was not
valence of ADRs was 41.50% (95% CI: 35.8–47.2%). considered.
Vomiting, which accounted for 24 (16.3%), was the According to the multivariate logistic regression ana­
most common of the reported drug reactions, followed lysis, the presence of concomitant medication (AOR: 2.60
by alopecia 22 (15.0%) and febrile neutropenia 15 (1.54–4.40); p<0.000), etoposide (AOR: 3.97 (1.64–9.63);
(10.2%) (Figure 2). p<0.002), mercaptopurine (AOR: 3.91 (1.06–14.46);
In addition, more than half of the cases of ADRs p<0.041), doxorubicin (AOR: 2.32 (1.30–4.15); p<0.005)
reported among males were 69 (58.0%). Nearly half and the administration of four or more types of chemother­
(44.5%) of ADR cases were between the ages of 6–12 apeutic agents (AOR: 2.67 (1.52–4.68) and p<0.001) were
and about 42% were between the ages of 2–6. Acute significantly associated with the occurrence of ADRs
lymphoblastic treatment was diagnosed in a total of 35 (Table 4).
(23.8%) patients with ADR.
Discussion
Co-Morbidity and Concomitant In this study, among 287 paediatric cancer patients,
Medication in Paediatric Cancer Patients a total of 119 Adverse Drug Reactions (ADRs) was
There were comorbidities in a total of 180 (62.7%) of reported. The overall magnitude of chemotherapy-
cancer patients. The most common co-morbidity was related ADR was 41.5% (95% CI: 35.8–47.2%). This

198 submit your manuscript | www.dovepress.com Drug, Healthcare and Patient Safety 2020:12
DovePress
Dovepress Workalemahu et al

Figure 1 The type of cancer among paediatric patients attending in the University of Gondar comprehensive, specialized hospital and Felegehiwot referral hospital,
northwest Ethiopia, 2019.

finding was consistent with a study conducted in Tikur studies might be the other reason for such discrepancy;
Anbessa Specialized Hospital, Ethiopia that reported where our study included under-fifteen children while the
the prevalence of 45.5%.6 This is due to the similarity study from India included all age groups including
between the types of chemotherapy agents (vincristine, adults.19 Furthermore, the various combinations of medi­
doxorubicin and cyclophosphamide) prescribed in the cations given to prevent ADRs in Ethiopia can be the
two study settings. On the contrary, our outcome was reason for the lower ADR compared with studies in
lower than studies reported from Eastern India India and Mexico. For instance, medications such as
(86.53%),19 Mexico City (62.5%),38 and South Ondansetron, aprepitant and dexamethasone are given to
African (56.5%).39 The difference may be due to var­ prevent nausea and vomiting associated with moderate and
iation between study areas in the type of drugs admi­ high emetogenic chemotherapy. Mesna is also given for
nistered to cancer patients. prevention of chemotherapy associated hemorrhagic cysti­
In our study, the most anti-cancer medications cause tis such as cyclophosphamide. Filgrastim agent is also
for ADRs were vincristine, doxorubicin and cyclopho­ used to reduce the duration of neutropenia and incidence
sphamide; but in studies reported from India and Mexico, of febrile neutropenia (neutropenic fever) in cytotoxic
cisplatin based regimen, cyclophosphamide, chemotherapy such as cyclophosphamide. Allopurinol is
5-Fluorouracil and paclitaxel chemotherapeutic agents taken as prophylaxis to prevent hyperuricemia.
were involved in the occurrence of ADRs.19 In addition, Chemotherapy induced vomiting was among the major
the difference in the inclusion of study participants among ADR reported in our study that accounted for 16.2% (95%

submit your manuscript | www.dovepress.com

Drug, Healthcare and Patient Safety 2020:12 199
DovePress
Workalemahu et al Dovepress

Table 2 Type of Prescribed Chemotherapeutic Agents for Among the different type of cancer, almost
Paediatric Cancer Patients at UOGCSH and FRH, Amhara a quarter of ADRs, 23.8% (95% CI: 16.9–30.7%)
Region, Ethiopia, 2019
were reported from patient diagnoses with acute lym­
Type of Chemotherapeutic The Number of Patients phoblastic leukaemia (ALL). This can be explained in
Agents (%) both studies by the highest prevalence of patients diag­
Vincristine 245 (85.4) nosed with acute lymphoblastic leukaemia. In addition,
Doxorubicin 177 (61.7) when treated with chemotherapy, children diagnosed
Cyclophosphamide 166 (57.8)
with acute lymphoblastic leukaemia may have
Prednisolone 103 (35.9)
Actinomycin D 57 (19.9)
a higher rate of adverse drug reactions.42 The present
Methotrexate 57 (19.9) study finding, on the other hand, was lower compared
L-asparaginase 43 (15.0) to studies reported from Mexico (66.9%),43 and
Cisplatin 32 (11.1) Philadelphia (52.1%).44 The variation may be due to
Etoposide 30 (10.5)
the difference in patterns of drug use. The Mexican
Triple intrathecal 27 (9.4)
study showed that the three common anti-cancer
Dacarbazine 13 (4.5)
Mercaptopurine 13 (4.5) drugs caused by ADRs were indicated that cytarabine
Cytarabine 11 (3.8) (29.2%), methotrexate (18.1%), and L-asparaginase
Carboplatin 9 (3.1) (10.8%),43 whereas in our study, vincristine, doxorubi­
Carbinoside 5 (1.7)
cin, and cyclophosphamide were drugs that may have
Bleomycin 4 (1.4)
developed ADRs. The high occurrence of ADRs from
Vinblastine 4 (1.4)
Procarbazine 3 (1.0) Philadelphia, contrary to our finding, could be due to
co-administered concomitant medications such as acet­
aminophen and diphenhydramine.44
Table 3 ADR Developed by Stages of Cancer Among Paediatric Out of 115 patients who received concomitant
Cancer Patients Who Were Attending at University of Gondar
drugs, more than half (54%) of them had ADRs. This
Comprehensive Referral Hospital and Felegehiwot Hospital,
Northwest Ethiopia, 2019
is due to the fact that concomitant drugs are a potential
source of drug-drug interaction that could alter che­
Stages of Cancer Frequency Developed ADR
motherapy pharmacokinetics, thus increasing the occur­
(%) (%)
rence of ADRs.45 Vincristine is the most common
I 3 (1.1) 1(0.8)
chemotherapeutic agent used in more than two-thirds
II 37 (12.9) 13 (10.9)
(68.0%) of patients who have experienced ADR alone
III 60 (20.9) 35 (29.4)
IV 15 (5.2) 7 (5.9) or in combination with other anticancer drugs. This
Undefined 172 (59.9) 63 (52.9) finding is higher than studies reported from china
Co-morbidity
0.88%,46 and India (5.9%).47 This may be due to the
Yes 180 (62.7) fact that most of the ADR was associated with vincris­
No 107 (37.3) tine-based regimens. Likewise, in 55.8% of patients
Concomitant medication
who developed ADR in our study, Doxorubicin is
Yes 115(40) the second common chemotherapeutic agent used.
No 172(60) This result was higher than studies in New Delhi
(8%),12 east Indians (13.9%),47 and Iran (24%).41
This could be due to more prescribed anticancer
CI: 10.3–22.3%). This is due to the fact that most of the drugs that could be associated with ADRs based on
study population in our study took cyclophosphamide, doxorubicin regimens. Cyclophosphamide was the
doxorubicin, and vincristine based drug regimen that other chemotherapy agent used in 50.3% of patients
have a higher risk of emetogenic effect. A consistent find­ experiencing ADRs. This outcome was higher than
ing was also reported from the Kumaun region (17.5%),5 the Indian report (13.5%). The difference in the popu­
West Rajasthan (10.34%),38 and North Eastern parts of lation between studies might be such variations in
India (15.09%).40 chemotherapeutic agents. The study findings, collected

200 submit your manuscript | www.dovepress.com Drug, Healthcare and Patient Safety 2020:12
DovePress
Dovepress Workalemahu et al

Figure 2 Type and frequency of chemotherapy related adverse drug reactions among paediatric cancer patients at University of Gondar comprehensive specialized hospital
and Felege Hiwot Referral hospital in Amhara Region, Ethiopia, 2019.

from both pediatric and adult populations, were receiving etoposide-administered ADRs were 3.97
reported from India.47 times higher (AOR: 3.97 (95% CI: 1.64–9.63); p <
According to the multivariable logistic regression 0.002) than those not receiving etoposide. This may
analysis, paediatric cancer patients who received be due to the effect of etoposide on the induction of
a doxorubicin-based regimen had a higher chance of various ADRs such as myelosuppression, thrombocyto­
receiving adverse drug reactions (ADRs) (AOR: 2.32 penia, mucositis, stomatitis, nausea, diarrhea and
(95% CI: 1.30–4.15); p < 0.005) compared to patients alopecia.48 In addition, the ADR probability among
who were not on a doxorubicin-based regimen. This paediatric cancer patients who received four or more
finding was consistent with the study conducted in chemotherapeutic agents was 2.67 times higher (AOR:
Mexico.38 Similarly, the odds of ADRs among pedia­ 2.67 (95% CI: 1.52–4.68); p < 0.001) compared to
tric cancer patients who received mercaptopurine were patients who were exposed to less than four tons of
3.91 times higher in paediatric cancer patients (AOR: chemotherapeutic agents. This implies that the occur­
3.91 (95% CI: 1.06–14.46); p<0.041) than in patients rence of ADRs is significantly associated with increas­
who did not receive mercaptopurine therapeutic agents. ing the number of chemotherapeutic agents. This is
This means that mercaptopurine is an important factor also supported by a London study that reported
for ADRs to occur. In the current study, the chances of a significant association with ADRs in an increasing

submit your manuscript | www.dovepress.com

Drug, Healthcare and Patient Safety 2020:12 201
DovePress
Workalemahu et al Dovepress

Table 4 Bi-Variate and Multi-Variate Regression Analysis of Adverse Drug Reaction (ADR) Among Paediatric Cancer Patients Who
Were Attending at the University of Gondar Comprehensive Referral Hospital and Feleghiwot Hospital, Northwest Ethiopia, 2019
Variables ADR Event Bi-Variate Logistic P-value Multivariate Logistic P-value
Regression Regression
Yes No

N (%) N (%) COR (95% CI) AOR (95% CI)

Doxorubicin use 0.035 0.005

Yes 82 (46.3) 95 (53.7) 1.70 (1.04,2.8) 2.32 (1.30–4.2)*
No 37 (33.6) 73 (66.4) 1 1

Mercaptopurine 0.143 0.041

Yes 8 (61.5) 15 (38.5) 2.35 (0.75,7.4) 4, (1.06–14.4)*
No 111 (40.5) 163 (59.5) 1 1

Number of chemotherapeutic 0.12 0.001

agents
1–3 74 (74.0) 26 (26.0) 1 1
>4 94 (50.3) 93 (49.7) 2.82 (1.66,4.7) 2.67 (1.51–4.6)*

Type of cancer 0.151 0.175

NHL 101 (39.9) 152 (60.1) 1.69 (0.83, 30) 1.74 (0.78–3.8)
Others 18 (52.9) 16 (47.1) 1 1

Concomitant medication 0.041 0.001

Yes 63 (54.8) 52 (45.2) 2.51 (1.60 4.30) 2.60 (1.54–4.4)*
No 56 (32.6) 116 (67.4) 1 1

Co-morbidity 0.958
Yes 82 (45.6) 98 (54.4) 1.58 (0.97 2.60) 0.069 1.02 (0.55 −1.8)
No 37 (34.6) 70 (65.4) 1 1
Notes: *Variables with a p-value less than 0.05 that were significant association with the outcome variable.
Abbreviations: ADR, adverse drug reaction; AOR, adjusted odds ratio; CI, confidence interval; COR, crude odds ratio.

number of drugs.49 In addition, our finding also were independent predictors of chemotherapy-related
showed that in comparison with patients without con­ ADRs in the multivariable logistic regression analysis.
comitant medication, the higher odds of ADR were Therefore, for paediatric patients, early identification and
noted among patients with concomitant medication management of ADR is highly recommended.
(AOR: 2.60 (95%: CI 1.54–4.40); p<0.000). This find­
ing was supported by studies conducted in the Abbreviations
Netherlands,50 and Japan.51 This is due to the fact ADR, adverse drug reaction; AOR, adjusted odds ratio;
that concomitant medication results in potential drug- CI, confidence interval; COR, crude odds ratio; SPSS,
drug interactions that may alter the pharmacokinetics Statistical Package for Social Sciences; UoG, University
of chemotherapy agents and thus increase the incidence of Gondar; WHO, World Health Organization.
of ADRs.45

Data Sharing Statement

Conclusion Data will be shared upon request from the corresponding
This study found that a significant proportion (2 out of 5)
author.
of cancer patients experienced an adverse drug reaction
related to chemotherapy. Three-fourth of the patients had
moderate adverse drugs, according to the Hartwig and Ethical Approval and Consent to
Siegel severity assessment scale. Drugs (such as etoposide, Participate
mercaptopurine, and doxorubicin), concomitant medica­ After obtaining ethical approval from the ethics review
tion, and taking at least four chemotherapeutic agents committee of the Department of Clinical Pharmacy,

202 submit your manuscript | www.dovepress.com Drug, Healthcare and Patient Safety 2020:12
DovePress
Dovepress Workalemahu et al

School of Pharmacy, University of Gondar, the study was

conducted. The study was therefore a retrospective review References
of patient data; the committee took into account the nature 1. Organization WH. International Drug Monitoring: The Role of
National Centres, Report of a WHO Meeting [Held in Geneva from
of the research and waived the need for consent. Above 20 to 25 September 1971]. World Health Organization; 1972.
all, this study was carried out according to the Helsinki 2. Lihite RJ, Lahkar M, Das S, et al. A study on adverse drug reactions
Declaration of Ethical Principles for Research. After in a tertiary care hospital of Northeast India. Alexandria J Med.
2017;53(2):151–156. doi:10.1016/j.ajme.2016.05.007
obtaining permission from the two hospitals, the data 3. Gaur S, Sinha A, Gunjita B, Bhardwaj R, Renu K, Srivastava B
collection was started by the medical director and the Pattern of adverse drug reactions of various chemotherapeutic agents
in cancer patients in Kumaun Region.
coordinator of the oncology ward. The patient’s personal 4. Schatz S, Weber R. Adverse drug reactions. Pharm Pract (Granada).
identifiers, such as name, were not used in the research 2015;1:1.
report or any other in order to maintain patient confidenti­ 5. Sunny S, Thampi A, Johnkennedy NS, Babasahib SK, Chacko C.
Assessment of adverse effects of most commonly prescribed antic­
ality. Also, the patient’s chart was not removed from the ancer drugs in a Tertiary Care Teaching Hospital. Int J Pharm Pract.
chart space and was not exposed to anyone other than data 2017;10(4):271.
6. Sisay EA, Engidawork E, Yesuf T, Ketema E. Drug related problems
collectors. They returned to their shelf properly after the in chemotherapy of cancer patients. J Cancer Sci Ther. 2015;7
graphs were reviewed. (2):55–59.
7. Joseph SG, Badyal DK. Spontaneous adverse drug reaction monitoring in
a tertiary care hospital in Northern India. JK Science. 2016;18(2):103.
Acknowledgments 8. Angamo M. Adverse Drug Reaction-Related Hospitalisation in
Ethiopia. University of Tasmania; 2018.
The authors are indebted to the University of Gondar for the 9. Parande F, Anand A, Khaparde M, Pawar S. Chemotherapy-induced
approval of the ethical clearance, University of Gondar adverse drug reactions in pediatric oncology. J Young Pharm.
2018;10(3):340. doi:10.5530/jyp.2018.10.75
Specialized comprehensive hospital and Felegehiwot refer­ 10. Suyagh M, Farah D, Farha RA. Pharmacist’s knowledge, practice and
ral hospital for giving us permission to collect data. The attitudes toward pharmacovigilance and adverse drug reactions
reporting process. Saudi Pharm J. 2015;23(2):147–153.
authors also forward its gratitude to study participants, data doi:10.1016/j.jsps.2014.07.001
collectors and supervisors who participated in the study. 11. Angiji A Adverse drug reactions related to mortality and morbidity:
drug-drug interactions and overdoses. Xendo. 2010. Available from:
http://wwwxendocom/images/pdf/ADRs-by-Majorsystems-II-Final-
Author Contributions Reportpdf. Accessed October 22, 2020.
12. Aggarwal M, Chawla S, Singh K, Rana P. Evaluation of anticancer
GW designed the study, supervised data collection, per­ drug utilization and monitoring of adverse drug reaction in the indoor
formed data analysis and interpretation, and drafted the patients receiving cancer chemotherapy in a Tertiary Care Hospital in
New Delhi. J Basic Clin Pharmacol. 2018;9:2.
manuscript. OA assisted in designing the study, did data 13. Brunton LL. Goodman & Gilman’s the Pharmacological Basis of
analysis and interpretation, and critical review of the Therapeutics. Univerza v Ljubljani, Medicinska fakulteta; 2011.
manuscript. MKY assisted in designing the study, did 14. Dewan P, Singhal S, Harit D. Management of chemotherapy-induced
nausea and vomiting. Indian Pediatr. 2010;47(2):149–155.
data analysis and interpretation, drafted the manuscript, 15. Ng CY, Chen C-B, Wu M-Y, et al. Anticancer drugs induced severe
and substantially revised the manuscript. All authors read adverse cutaneous drug reactions: an updated review on the risks
associated with anticancer targeted therapy or immunotherapies.
and approved the final manuscript and agree to be accoun­ J Immunol Res. 2018;2018.
table for all the contents of the work in the manuscript. 16. Visacri MB, Souza C, Pimentel R, et al. Pharmacovigilance in oncol­
ogy: pattern of spontaneous notifications, incidence of adverse drug
reactions and under-reporting. Braz J Pharm Sci. 2014;50
Funding (2):411–422. doi:10.1590/S1984-82502014000200021
17. Baudino AT. Targeted cancer therapy: the next generation of cancer
There was no specific funding obtained for this study. treatment. Curr Drug Discov Technol. 2015;12(1):3–20. doi:10.2174/
1570163812666150602144310
18. Rout A, Panda RK, Mishra V, Parida P, Mohanty S.
Disclosure Pharmacovigilance in cancer chemotherapy in regional cancer center
of Eastern India: prospective observational study. Int J Basic Clin
Gashaw Workalemahu reports the study was conducted Pharmacol. 2017;6(8):1910.
after getting ethical approval from the ethics review com­ 19. Prasad A, Datta PP, Bhattacharya J, Pattanayak C, Chauhan AS, Panda P.
mittee of the Department of Clinical Pharmacy, School Pattern of adverse drug reactions due to cancer chemotherapy in a tertiary
care teaching hospital in Eastern India. J Pharmacovigil. 2013;1
of Pharmacy, and University of Gondar. I have official (2):1000107.
letter from the department of clinical pharmacy. The 20. Behera SK, Kishtapati CR, Gunaseelan V, Dubashi B,
Chandrasekaran A, Selvarajan S. Chemotherapy induced adverse
authors declare that they have no other potential conflicts drug reactions in cancer patients in a tertiary care hospital in South
of interest for this work. India. J Young Pharm. 2017;9(4):593. doi:10.5530/jyp.2017.9.113

submit your manuscript | www.dovepress.com

Drug, Healthcare and Patient Safety 2020:12 203
DovePress
Workalemahu et al Dovepress

21. Alsbou M, Abdeen G, Batarseh A, Bawaresh N, Jaber J, Qawasmi G. 37. Goshime A. Assessment of Knowledge, Attitude and Practices on
Analysis of the National Pharmacovigilance Database in Jordan (2010– Adverse Drug Reaction Reporting Among Pharmacy Personnel
2014). Biomed Pharmacol J. 2017;10(1):319–328. doi:10.13005/bpj/ Working at Community Pharmacy, Addis Ababa, Ethiopia. Addis
1112 Ababa University; 2015.
22. Åvall Lundqvist E, Fujiwara K, Seoud M. Principles of 38. Castelán-Martínez OD, Rodríguez-Islas F, Vargas-Neri JL, et al. Risk
chemotherapy. Int J Gynaecol Obstet. 2015;131:S146–S149. factors for febrile neutropenia in children with solid tumors treated
doi:10.1016/j.ijgo.2015.06.011 with cisplatin-based chemotherapy. J Pediatr Hematol Oncol.
23. Chan H-K, Ismail S. Side effects of chemotherapy among cancer patients 2016;38(3):191–196. doi:10.1097/MPH.0000000000000515
in a Malaysian General Hospital: experiences, perceptions and informa­ 39. Makiwane M, Decloedt E, Chirehwa M, Rosenkranz B, Kruger M.
tional needs from clinical pharmacists. Asian Pac J Cancer Prev. 2014;15 Adverse drug reactions in paediatric in-patients in a South African
(13):5305–5309. doi:10.7314/APJCP.2014.15.13.5305 tertiary hospital. J Trop Pediatr. 2019;65(4):389–396. doi:10.1093/
24. Zhang Q-Y, Wang F-X, Jia -K-K, Kong L-D. Natural product inter­ tropej/fmy067
ventions for chemotherapy and radiotherapy-induced side effects. 40. Wahlang JB, Laishram PD, Brahma DK, Sarkar C, Lahon J,
Front Pharmacol. 2018;9:1253. Nongkynrih BS. Adverse drug reactions due to cancer chemotherapy
25. Poulopoulos A, Papadopoulos P, Andreadis P. Chemotherapy: oral in a tertiary care teaching hospital. Ther Adv Drug Saf. 2017;8
side effects and dental interventions. A review of the literature. (2):61–66. doi:10.1177/2042098616672572
Stomatological Dis Sci. 2017;2573–0002:2017. 41. Vaseghi G, Abed A, Jafari E, Eslami N, Eshraghi A. Assessment of
26. Alhawassi TM, Krass I, Bajorek BV, Pont LG. A systematic review adverse drug reaction due to cancer chemotherapy in a teaching oncology
of the prevalence and risk factors for adverse drug reactions in the hospital in Isfahan, central of Iran. Rev Recent Clin Trials. 2016;11
elderly in the acute care setting. Clin Interv Aging. 2014;9:2079. (3):266–272. doi:10.2174/1574887110666150818112648
27. Bouvy JC, De Bruin ML, Koopmanschap MA. Epidemiology of adverse 42. Özdemir BC, Csajka C, Dotto G-P, Wagner AD. Sex differences in
drug reactions in Europe: a review of recent observational studies. Drug efficacy and toxicity of systemic treatments: an undervalued issue in
Saf. 2015;38(5):437–453. doi:10.1007/s40264-015-0281-0 the era of precision oncology. J Clin Oncol. 2018;36(26):2680.
28. Miguel A, Azevedo LF, Araújo M, Pereira AC. Frequency of adverse doi:10.1200/JCO.2018.78.3290
drug reactions in hospitalized patients: a systematic review and meta- 43. Rivera-Luna R, Cárdenas-Cardós R, Velasco-Hidalgo L, et al.
analysis. Pharmacoepidemiol Drug Saf. 2012;21(11):1139–1154. A profile of the adverse effects of antineoplastic agents for the
doi:10.1002/pds.3309 treatment of children with cancer. J Cancerol. 2015;2.
29. Angamo MT, Chalmers L, Curtain CM, Bereznicki LR. Adverse-drug 44. Barrett JS, Patel D, Dombrowsky E, Bajaj G, Skolnik JM. Risk
-reaction-related hospitalisations in developed and developing coun­ assessment of drug interaction potential and concomitant dosing
tries: a review of prevalence and contributing factors. Drug Saf. pattern on targeted toxicities in pediatric cancer patients. AAPS J.
2016;39(9):847–857. doi:10.1007/s40264-016-0444-7 2013;15(3):775–786. doi:10.1208/s12248-013-9489-z
30. Eshetie TC, Hailemeskel B, Mekonnen N, Paulos G, Mekonnen AB, 45. Hanigan MH, Dela Cruz BL, Shord SS, Medina PJ, Fazili J,
Girma T. Adverse drug events in hospitalized children at Ethiopian Thompson DM. Optimizing chemotherapy: concomitant medication
University Hospital: a prospective observational study. BMC Pediatr. lists. Clin Pharmacol Ther. 2011;89(1):114–119. doi:10.1038/
2015;15(1):83. doi:10.1186/s12887-015-0401-0 clpt.2010.253
31. Geel JA. Toxicity and survival rates in 75 paediatric patients with 46. Guo H-J, Ren F, Zhang D, Ji M. Monitoring report on 341 cases of
germ cell tumours treated over a 28 year period at the Charlotte adverse reactions caused by antitumor drugs. Afr J Microbiol Res.
Maxeke Johannesburg academic hospital. 2012;6(16):3774–3777.
32. Alomar MJ. Factors affecting the development of adverse drug reactions. 47. Chopra D, Rehan HS, Sharma V, Mishra R. Chemotherapy-induced
Saudi Pharm J. 2014;22(2):83–94. doi:10.1016/j.jsps.2013.02.003 adverse drug reactions in oncology patients: a prospective observa­
33. Amartya D. Monitoring of suspected adverse drug reactions in oncol­ tional survey. Indian J Med Paediatr Oncol. 2016;37(1):42.
ogy unit of an urban multispeciality teaching hospital. Int J Res doi:10.4103/0971-5851.177015
Pharm Biomed Sci. 2010;1(2):1–32. 48. Fujiwara T, Kenmotsu H, Naito T, et al. The incidence and risk
34. Bhabhor PH, Patel TK, Vahora R, Patel PB, Desai N. Adverse drug factors of febrile neutropenia in chemotherapy-naïve lung cancer
reactions in a tertiary care teaching hospital in India: analysis of patients receiving etoposide plus platinum. Cancer Chemother
spontaneously reported cases. Int J Basic Clin Pharmacol. 2014;3 Pharmacol. 2017;79(6):1229–1237. doi:10.1007/s00280-017-3324-7
(6):1078–1086. doi:10.5455/2319-2003.ijbcp20141228 49. Zopf Y, Rabe C, Neubert A, Hahn EG, Dormann H. Risk factors associated
35. Ruggiero A, Rizzo D, Catalano M, Coccia P, Triarico S, Attiná G. with adverse drug reactions following hospital admission. Drug Saf.
Acute chemotherapy-induced nausea and vomiting in children with 2008;31(9):789–798. doi:10.2165/00002018-200831090-00007
cancer: still waiting for a common consensus on treatment. J Int Med 50. Van Leeuwen R, Brundel D, Neef C, et al. Prevalence of potential
Res. 2018;46(6):2149–2156. doi:10.1177/0300060518765324 drug–drug interactions in cancer patients treated with oral anticancer
36. Ampadu HH, Hoekman J, de Bruin ML, et al. Adverse drug reaction drugs. Br J Cancer. 2013;108(5):1071. doi:10.1038/bjc.2013.48
reporting in Africa and a comparison of individual case safety report 51. Sasaki T, Fujita K-I, Sunakawa Y, et al. Concomitant polypharmacy
characteristics between Africa and the rest of the world: analyses of is associated with irinotecan-related adverse drug reactions in patients
spontaneous reports in VigiBase®. Drug Saf. 2016;39(4):335–345. with cancer. Int J Clin Oncol. 2013;18(4):735–742. doi:10.1007/
doi:10.1007/s40264-015-0387-4 s10147-012-0425-5

204 submit your manuscript | www.dovepress.com Drug, Healthcare and Patient Safety 2020:12
DovePress
Dovepress Workalemahu et al

Drug, Healthcare and Patient Safety Dovepress

Publish your work in this journal
Drug, Healthcare and Patient Safety is an international, peer-reviewed literacy and educational programs across all areas of healthcare
open-access journal exploring patient safety issues in the healthcare delivery. The manuscript management system is completely online
continuum from diagnostic and screening interventions through to and includes a very quick and fair peer-review system. Visit
treatment, drug therapy and surgery. The journal is characterized by http://www.dovepress.com/testimonials.php to read real quotes from
the rapid reporting of reviews, original research, clinical, epidemiolo­ published authors.
gical and post-marketing surveillance studies, risk management, health
Submit your manuscript here: https://www.dovepress.com/drug-healthcare-and-patient-safety-journal

submit your manuscript | www.dovepress.com

Drug, Healthcare and Patient Safety 2020:12 205
DovePress