INTRODUCTION
Breast cancer is the most common type of cancer found in women, in Indonesia [1]. Older age (more than 50 years old) is one of the risk factors for increasing the incidence of breast cancer [2]. In 2018, Indonesia Basic Health Research reported that new cases of malignancy increased in the age group over 60 years[3].
The 2018 Indonesia Basic Health Research reported that chemotherapy is the first line of treatment for
malignancy cases, in which around 24% of patients are given chemotherapy for cancer treatment [3]. Indonesian guidelines for cancer treatment mentioned that anthracyclines (doxorubicin and epirubicin) are the first- line chemotherapy for the treatment of breast cancer.
Anthracyclines are given in combination with other types of chemotherapy [4]. Doxorubicin is a type of anthracycline that is included in the list of essential drugs for the treatment of breast cancer [5]. Epirubicin is the isomer of doxorubicin and has similar characteristics to
The Identification and Analysis of Adverse Events in Elderly Female Breast Cancer Patients Using Anthracycline-Based Regimens at Dharmais Cancer Hospital
Ester Marsaulina
1*, Retnosari Andrajati
2, Yuri Pertamasari
3, Alvinda Heriza Nasution
41 Postgraduate of Clinical Pharmacy, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia
2 Department of Clinical Pharmacy, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia
3 Pharmacy Installation, Dharmais Cancer Hospital – National Cancer Center, Jakarta, Indonesia
4 Pharmacy Installation, Dharmais Cancer Hospital – National Cancer Center, Jakarta, Indonesia
A B S T R A C T
Background: Anthracycline is the first-choice chemotherapy for the treatment of breast cancer, particularly in elderly patients. However, several studies reported adverse events in the treatment of using anthracyclines. This study aims to identify adverse events. It is also to find out more about how independent variables are related to adverse events.
Method: An observational retrospective study of elderly patients (≥ 60 years old) was conducted in a tertiary cancer hospital in Jakarta. Data were collected from January 2018 to December 2020.
We used an oncology-specific trigger tool to identify adverse events during anthracycline-based regimens. Independent variables were evaluated in univariate analysis: age, weight loss, marital status, total cumulative dose, polypharmacy, types of anthracyclines, and metastatic status.
Bivariate and multivariate analyses were conducted to find out the relationship between the independent variables and adverse events.
Results: In total, 107 subject records were collected and reviewed. Triggers were identified 122 times in 86 medical records. Blood transfusion, the most common trigger, was found in 35% of subjects. We found the number of triggers and adverse events more commonly identified in the first and second cycles of chemotherapy. The prevalence of adverse events is detected in 80%
of subjects. Of these 86 subjects, 74% were detected in doxorubicin and 26% were detected in epirubicin. All the adverse events were categorized as The National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) harm category E.
Conclusion: Trigger tools specific for cancer patients can be used to identify adverse events.
Blood transfusion was the common trigger to detect adverse events in our study. Adverse events with category E were identified in all the subjects. Neutropenia and anemia were the most common adverse events in all cycles of chemotherapy. Weight loss was the independent variable related to adverse events in elderly breast cancer patients (p <0.003).
A R T I C L E I N F O Received : 10 December 2021 Reviewed : 11 February 2022 Accepted : 11 July 2022 Keywords:
cancer, elderly patient, adverse event, anthracycline, trigger tools
*Corresponding author:
Ester Marsaulina
Clinical Pharmacy, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia [email protected], [email protected]
in the emergency department; this method was able to identify adverse events in 4.6% of 951 visits to the emergency department [17]. In hospitalized patients, the trigger tool can identify adverse events where 144 out of 240 inpatients experienced 336 adverse events and generally fall into the dangerous category [18].
Trigger tools are also used to identify adverse events in pediatric patients [19] and geriatric patients [20].
Lipitz-Snyderman et al. [21] used a trigger tool to identify adverse events in 400 cancer patients in a retrospective cohort. The results of the study reported that the trigger tool could identify 790 triggers (or 1.98 triggers per patient). Weingart et al. [22] have validated sixteen specific trigger tools for cancer patients. The results showed that the trigger tool could be used to identify adverse events in cancer patients.
The anthracycline-based chemotherapy is the most widely used chemotherapy treatment at Dharmais Cancer Hospital. This is because anthracyclines-based chemotherapy (doxorubicin and epirubicin) has a broad spectrum as antineoplastic. In addition, anthracyclines are the first-choice chemotherapy for the treatment of breast cancer, especially in elderly patients. However, several studies reported adverse events in the treatment of using anthracyclines. Therefore, this study aims to identify adverse events using a special trigger tool for cancer patients. This identification was carried out on breast cancer patients using anthracycline-based chemotherapy regimens.
METHODS
Study designThis is an observational retrospective cross-sectional study on elderly breast cancer patients receiving anthracycline-based regimens. This study was conducted in a tertiary cancer referral hospital in Jakarta, Dharmais Cancer Hospital.
Data collection
The elderly in Indonesia are defined as those aged 60 years and above. The subjects who received doxorubicin or epirubicin for the first cycle and had not received previous chemotherapy were included in the study. The exclusion criteria include having received radiotherapy before chemotherapy, incomplete medical record, and having kidney disease. We assessed 155 medical records collected from January 2018 to December 2020.
We used an oncology-specific trigger tool to identify adverse events during anthracycline-based chemotherapy.
There were 11 specific triggers to identify adverse events specific to chemotherapy care. The trigger is associated with abnormal laboratory results: abnormal serum bicarbonate <18 and >36 mEq/L; elevated creatinine >1 mg/dL and 50% greater than baseline; abnormal serum doxorubicin. These two types of anthracycline are used
as systemic therapy for early and metastatic stages of breast cancer, which is not caused by the hormone estrogen (negative hormonal receptor/HR) [6].
Several studies reported that adverse events within anthracyclines treatment occurred in the short or long term after chemotherapy was given. Indications of adverse events from the administration of drugs or treatment related to health services are prescribing new drugs, administering new actions, increasing pain, and dysfunction of limbs [7]. Adverse events due to anthracyclines happen when anthracyclines block the topoisomerase II enzyme. This enzyme is required for cells that grow rapidly, such as cancer cells [8].
Adverse events, such as hair loss, myelosuppression, gastrointestinal complications, and damage to reproductive cells, occur in a short-term period and are generally reversible [9]. Cardiomyopathy, impairment of the ventricular function of the heart is reported as a long-term adverse event whose onset is influenced by the dose of the medicine, and it is irreversible [13]. Elderly patients who use anthracyclines are prone to adverse events. The risk factors for adverse events in elderly patients are demographic factors (such as increasing age, gender (female), and marital status) [10,11]. In addition, the other risk factors, such as polypharmacy, high doses of anthracyclines, metastatic status, and comorbidities, are also related to adverse events [10,12–15].
A previous cohort study in elderly patients reported that the increase in adverse events is along with the increasing age. This study also reported that many adverse events, such as blood disorders (neutropenia and anemia), occurred with the use of first-line chemotherapy [16]. Meanwhile, adverse events that are not related to blood disorders are fatigue diarrhea, constipation, pain, rash, and mucositis [14].
Institute for Healthcare Improvement provides an easy-to-use method for accurately identifying adverse events (harm) and measuring the rate of adverse events over time. Adverse events are tracked based on the use of drugs, medical devices, and health services. The concept of a “trigger” (or clue) is to identify adverse events in the medical record. Identification is carried out by retrospective and random tracing of the patient’s medical records. The National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) classified adverse events into two categories; the first category consists of A to D (harmless events) and the second consists of E to I (harmful events) [15].
In 2012, a study in Turkey used a trigger tool for the retrospective identification of adverse events. The results showed that, in a hospital, there were 80.72 adverse events per 1,000 patient days, or there were 29.39 adverse events per 100 registrations [16]. Another study also used a trigger tool to identify adverse events
potassium >6 and <2.5 mEq/L; absolute neutrophil count
<0.5 x 109/L; Clostridium difficile toxin positive and positive blood culture; medication-related trigger using anticoagulant (warfarin, enoxaparin, apixaban, rivaroxaban, dabigatran, fondaparinux, and edoxaban);
order trigger (blood transfusion, contact precautions/
isolation); vital sign trigger (low oximetry results, i.e., arterial oxygen saturation <88% and febrile neutropenia with fever (>38.2 °C) and decreased ANC; consultation to nephrology trigger [9,19]. The study involved an Internist Consultant of Hematology and Medical Oncology to assess eleven specific triggers. This study used eight triggers because three triggers related to the laboratory test could not be applied to breast cancer patients. Adverse events were identified by the researcher and clinical pharmacist. This cross-sectional study was performed to obtain the prevalence of triggers and adverse events. Furthermore, this study aims to find out more about how independent variables including age, marital status, weight loss, polypharmacy, total cumulative dose anthracycline, and metastatic stage are related to adverse events in elderly breast cancer patients using anthracycline-based regimens.
Data analysis
The prevalence of triggers and adverse events was obtained by calculating the proportions of triggers and adverse events from the total subjects. Independent variables were evaluated in univariate analysis. Furthermore, bivariate and multivariate analyses were conducted to find out the association between independent variables and adverse events through logistic regression analysis. p <0.05 is significant statistically as the independent variable is associated with adverse events.
Figure 1. Flow chart of sample selection
Elderly Female Breast Cancer Patient Using Anthracycline Based Regimens
N=155 subject
periode 2018 – 2020 (n=155 pasien)
Excluded = 37 subject
•Subject received radiotherapy before chemotherapy
• Kidney disease
N = 107 subject N = 118 subject
Excluded = 11 subject Incomplete medical record
RESULTS
Subject characteristics
As shown in Figure 1, in total, 107 subject records were collected and reviewed. Forty-eight subjects’
medical records were initially excluded from the review process. They were not suited to the selection criteria (receiving radiotherapy before chemotherapy, having kidney disease, and having incomplete medical records).
All the subjects were female with a mean age of 65 years (approximately 65%). Among those subjects, 96%
were married, 80% used five or more drugs, 85% had no metastases, 74% used doxorubicin, 79% had decreased body weight less than 5%, and 97% received anthracycline lower than total cumulative dose (Table 1).
The bivariate analysis showed that weight loss (OR 0,747; 95% CI 0.659–0.847) was found to be significantly associated with adverse events p = 0.003 (Table 4).
Identification of adverse events using a trigger tool We used 8 of 11 oncology triggers specific to chemotherapy. There were three laboratory triggers excluded from our study (Clostridium difficile toxin positive, positive blood culture, and abnormal serum bicarbonate).
Triggers were identified 122 times in 86 medical records.
In this study, most of the subjects experienced one trigger, and at least four patients had experienced triggers. Blood transfusion as the most common trigger was found in 35% of subjects (n = 30). Triggers more commonly identified in the first and second cycles of chemotherapy were 36 and 26 events, respectively (Table 2).
As shown in Table 3, the prevalence of adverse events was detected with the oncology trigger tool in 80% of the subjects (n = 86). Of these 86 subjects, 64
(74%) were detected in doxorubicin and 22 (26%) in epirubicin. Among the subjects detected of having adverse events in doxorubicin, 35 (55%) subjects suffered from one AE, 21 (33%) suffered from two AE, and 7 (11%) suffered from three AE. The adverse events were identified in 22 subjects who used epirubicin. A total of 16 (73%) subjects suffered from one AE, 6 (27%) subjects suffered from two AE, and 1 (5%) subject suffered from three AE. All the adverse events were categorized as NCC MERP harm category E. Category E events are temporary and require brief interventions for handling adverse events. We identified 251 events.
Most events occurred in the first and second cycles of chemotherapy (Figure 2).
DISCUSSION
There were 107 female subjects. Therefore, This study was to identify adverse events in female breast cancer patients who used anthracycline-based chemotherapy. In this study, blood transfusion was the most trigger we found in the identification of adverse events with the oncology trigger tool. This trigger was found in 35% of subjects (n = 30), and blood transfusions did not cause chemotherapy delay. Blood transfusion is usually reserved for subjects with anemia (hemoglobin
level <10 mg/dL). WHO recommends giving blood transfusions with a hemoglobin level <8 mg/dL or to patients with severe anemia [26]. A patient who receives a blood transfusion is at risk of hemolytic reactions, iron overload, and infection transmission. Furthermore, blood transfusion in cancer patients has been associated with an increase in cancer recurrence rates [27,28].
Triggers using anticoagulants were also found in this study. There are 22% of subjects (n = 19) used anticoagulants. We found most of the subjects used anticoagulants in the first-cycle chemotherapy.
Doxorubicin and epirubicin as anticancer agents were associated with an increased risk of VTE [26]. Both chemotherapies are risk factors for inducing thromboembolism. Anticoagulants are indicated for cancer patients who are at high risk for VTE. However, anticoagulation is contraindicated for patients at high risk for major bleeding [27].
In this study, there were four triggers related to the laboratory value as the ‘signs’ of adverse events.
Certain abnormal laboratory values are triggers for identifying adverse events. The absolute neutrophil count is <0.5 x 109/L as a sign of neutropenia event [13,28], hemoglobin value <10 g/dL as a sign of anemia event [13,29], D-dimer value 1,440 ng/mL as a sign of hypercoagulation [13,30], and rising level of serum creatinine (serum creatinine >1 mg/dL or greater than 2 times baseline) [13]. We found the number of adverse events that occurred in the first and second cycles of chemotherapy was greater than that in other cycles, with 53 and 48 events respectively (Figure 2).
All the subjects experienced adverse events in category E. We found 251 adverse events, and the prevalence was 80% of the subjects (n = 86). A previous study reported more than half of elderly cancer patients (>65 years) who used chemotherapy would experience adverse events [9]. In our study, 59% (n = 51) had one adverse event (neutropenia). Furthermore, 31% (n = 27) had two adverse events (neutropenia and anemia). All the adverse events occurred in the first and second cycles of chemotherapy, namely 53 and 48 events. The results of this study were like the finding in the Korean study, in which neutropenia and anemia were the most common adverse events in elderly cancer patients. The study of Kim et al. [31] shows that adverse events are more common in the first cycle of chemotherapy.
The decrease in absolute neutrophil count (ANC) or neutropenia was the most common adverse event in our study. Neutropenia occurred in 82 subjects where 52 subjects experienced mild and moderate neutropenia and 30 subjects experienced severe neutropenia. Figure 2 shows that a total of 141 events of neutropenia occurred during chemotherapy. All cases of neutropenia occurred in patients who received doxorubicin (FAC combination). In our study, all the subjects who suffered from neutropenia did not progress to febrile neutropenia.
Table 1. Characteristics of the subject included in the trigger tool screening process
Characteristic (N=107) n (%)
Age
>65 years 70 (65)
60–65 years 37 (35)
Marital status
Married 103 (96)
Unmarried 4 (4)
Polypharmacy 5 or more drugs
Less than 5 drugs 22 (20)
85 (80) Metastatic status
No metastatic 91 (85)
Metastastic 16 (15)
Type of anthracycline
Doxorubicin 79 (74)
Epirubicin 28 (26)
Weight loss
≤5% 84 (79)
>5% 23 (21)
Total cumulative dose
Lower than total cumulative dose 104 (97) Higher than total cumulative dose 3 (3)
Trigger tool Number of triggers detected in each cycle Total of trigger
I II III IV V VI
Anticoagulant 12 8 3 5 1 2 31
Blood transfusion 10 10 8 13 7 6 54
Hypoxemia 2 0 0 0 0 0 2
Neutropenic fever 4 1 1 1 1 1 9
Isolation 1 3 1 1 0 0 6
Elevated serum creatinine 7 4 2 3 1 3 20
Nephrology consult 0 0 0 0 0 0 0
Abnormal serum potassium 0 0 0 0 0 0 0
Table 3. Characteristic adverse event in woman elderly breast cancer Number of adverse
event (n=107)
(n = 86 or 80%)AE No AE
(n = 21 or 20 %) 1 AE
(n = 51) 2 AE
(n = 27) 3 AE
(n = 8)
Type of adverse event N : 30 N-A : 12 N-A-H : 5
A : 9 N-C : 6 N-A-C : 3
H : 8 A-H : 4
C : 4 N-H : 3
A-C : 2
Total cumulative dose >TCD : 3 >TCD : 0 >TCD : 0 >TCD : 0
<TCD : 48 <TCD : 27 <TCD :8 <TCD : 21
Poly-pharmacy 5 or more drugs: 39 5 or more drugs: 24 5 or more drugs: 3 5 or more drugs: 14 Less than 5 drugs: 12 Less than 5 drugs: 3 Less than 5 drugs: 5 Less than 5 drugs: 7
Age >65 years: 19 >65 years: 7 >65 years: 5 >65 years: 6
≤65 years: 32 ≤65 years: 20 ≤65 years: 3 ≤65 years: 15
Marital status Married: 49 Married:26 Married: 7 Married: 21
Unmarried: 2 Unmarried: 1 Unmarried: 1 Unmarried: 0
Weight loss More than 5%: 15 More than 5%: 6 More than 5%: 3 More than 5%: 0
5% or less: 36 5% or less: 21 5% or less: 5 5% or less: 21
Type of anthracycline Doxorubicin: 35 Doxorubicin: 21 Doxorubicin: 7 Doxorubicin: 16
Epirubicin: 16 Epirubicin: 6 Epirubicin: 1 Epirubicin: 5
Metastatic status Metastatic: 6 Metastatic: 8 Metastatic: 2 Metastatic: 1
none: 45 none: 19 none: 6 none: 20
Abbreviations: AE, adverse event; N, neutropenia; A, anemia; H, hypercoagulation; C, elevated serum creatinine; TCD, total cumulative dose Figure 2. Adverse event
per cycle chemotherapy Table 2. Trigger tool per cycle chemotherapy
Trigger neutropenic fever was identified nine times in six subjects. Anthracycline is chemotherapy-induced neutropenia influenced by an increased dose [32]. A previous study reported that neutropenia increased in elderly patients aged >60 years who received FAC (5-fluorouracil-doxorubicin-cyclophosphamide) [10].
We found that anemia was the second most common adverse event in this study with 66 events. This event mostly occurred in the first cycle of the FAC combination.
In this study, the signs of anemia in the subjects were known through the results of screening by nurses who stated that the subjects were experiencing fatigue;
besides that, it was supported by the result of hemoglobin tests <10 mg/dL [23]. According to the previous study by Chaumard et al. [33], anemia is the most common in elderly patients aged >60–70 years who have baseline hemoglobin of <13.5 g/dL and a BMI <25.
Hypercoagulation was the third most common adverse event, with 24 events. It occurred more in the first cycle of chemotherapy. The impacts of hypercoagulation are venous thromboembolism (VTE) and arterial thrombosis [34]. Anthracycline (doxorubicin) is associated with an increased risk of VTE [35]. Anticoagulants are a treatment to overcome hypercoagulability. Of 24 events, 21 were treated with anticoagulants, such as heparin and warfarin.
In addition to identifying adverse events, this study also aims to determine the relationship between adverse events and several variables. The relationship between independent variables and adverse events was determined using a statistical test (logistical regression, p <0.05). The independent variables are demographic factors (i.e., age, marital status) [7,36] and non- demographic factors are reported as risk factors for adverse events of anthracyclines (i.e., weight loss, cumulative total dose, polypharmacy, type of anthracycline, and metastatic status) [9,37–40].
Several studies reported that adverse events in anthracyclines are dose-dependent. There is an association between total cumulative doses of anthracycline and adverse events, particularly in the elderly [7]. As we know, adverse events occur when a patient receives more than 550 mg/m2 of doxorubicin or 900 mg/m2 of epirubicin [38]. In our study, all the subjects (n = 3) who were given a dose greater than the cumulative total dose of anthracycline experienced adverse events (Table 4).
Polypharmacy is reported as a major cause of adverse events in elderly patients receiving chemotherapy [10]. Similar to our study, adverse events occurred in 66 subjects who received polypharmacy (83%). Overall, polypharmacy is given as a cytotoxic agent and supportive therapy (i.e., anticoagulants, vitamin K, antihypertensives, acetaminophen, ferrous sulfate, furosemide, antiemetics, antihistamines, antiarrhythmics, antibiotics, analgesics, proton pump inhibitors, and diuretics). Adverse events occur with the increasing number of medications [41].
A previous study reported that admission to the hospital increased polypharmacy in the elderly. This occurs due to side effects that arise from the use of polypharmacy [42]. However, in our study, polypharmacy (p >0.05) did not have a relationship with the adverse event.
Drug interaction (taking more than one drug) can increase toxicity or decrease efficacy [43]. In our study, a potential drug interaction occurred in subjects who used five or more drugs. Based on searching the clinical resources (Lexycomp and Micromedex), we found that the potential drug interaction occurred in 65.4% of subjects (n = 70), with 111 drugs used. The potential drug-drug interaction was most found in subjects who used doxorubicin. Doxorubicin can interact with drugs such as ondansetron, rifampin, palonosetron/netupitant, and dexamethasone. In our study, we found ondansetron, palonosetron/netupitant, dexamethasone, and tuberculostatic agents (rifampin) decreased the efficacy of chemotherapy (doxorubicin and cyclophosphamide).
Prescription of medications (amiodarone and carvedilol) has a potential effect to increase the toxicity of Table 4. Adverse event in every cycle of chemotherapy
Variable
Adverse event (N = 107) No p
N (%) Yes
N (%) Age
>65 years 15 (21%) 55 (79%) 0.697 60–65 years 6 (16%) 31 (84%) Weight loss
>5% 0 (0%) 24 (100%) 0.003
≤5% 21 (25%) 62 (74%)
Marital status
Married 0 (0%) 4 (100%) 0.584
Unmarried 21 (20%) 82 (80%)
Total cumulative dose Lower than the total
cumulative dose 21 (20%) 83 (80%) 1.000 Higher than the total
cumulative dose 0 (0%) 3 (100%) Polypharmacy
5 or more drugs 14 (18%) 66 (82%) 0.501 Less than 5 drugs 7 (26%) 20 (74%) Type of anthracycline
Doxorubicin 16 (20%) 63 (80%) 1.000
Epirubicin 5 (18%) 23 (82%)
Metastatic status
Metastase 1 (6%) 16 (94,1%) 0.184
No metastase 20 (22%) 70 (78%)
doxorubicin. Furthermore, subjects who used doxorubicin can increase the toxicity of warfarin and morphine.
Weight loss is a risk factor for adverse events [44].
In our study, we found that adverse events occurred in 74% of subjects (n = 62). All these subjects decreased by less than 5% of body weight. In cancer patients, chemotherapy may induce weight loss. Particularly in anthracycline, nausea and vomiting are the result of using chemotherapy and affect weight loss in elderly cancer patients. Anthracyclines are emetogenic chemotherapy, additionally, doxorubicin is high emetogenic chemotherapy, while epirubicin is emetogenic chemotherapy [45]. Weight loss (p = 0.003) shows that this variable is related to adverse events.
In our study, adverse events are more common in subjects receiving doxorubicin. Several studies reported more adverse events occurred in doxorubicin rather than epirubicin [46,47]. Differences in pharmacokinetic profiles affected the increase in adverse events in both types of anthracyclines. Epirubisinol (a metabolite of epirubicin) has less cytotoxic activity than epirubicin. Meanwhile, doxorubinol (a metabolite of doxorubicin) has greater cytotoxic activity than doxorubicin [47,48]. However, this variable (p >0.05) shows there is no relationship between types of anthracyclines and adverse events.
In this study, the frequency of triggers and adverse events was higher during the early chemotherapy administration (first and second cycles). These results are similar to those of several studies in which adverse events are more commonly identified in the first and second cycles of chemotherapy [7,9,13,49].
Our study is the first which uses an oncology trigger tool to identify adverse events in female breast cancer patients. All the subjects received anthracycline-based regimens. However, there are several limitations; first, patient history such as undergoing mastectomy and length of stay in hospital was not considered; second, three triggers were not used to identify adverse events due to blood culture and Clostridium difficile not being applied to breast cancer patients; third, data collection was carried out retrospectively so that not all data needed for identification of adverse events were available in medical records.
CONCLUSIONS
Oncology-specific trigger tools can be used to identify adverse events. In our study, blood transfusion was the common trigger to detect adverse events. Adverse events category E were identified in all the subjects.
Neutropenia and anemia were the most common adverse events in all cycles of chemotherapy. Weight loss was the independent variable associated with adverse events in elderly breast cancer patients (p = 0.003).
DECLARATIONS
Ethics ApprovalEthical approval was obtained from Dharmais Cancer Hospital (022/KEPK/III/2021).
Competing of Interest
I declare that this study doesn’t have a conflict of interest with any party.
Acknowledgment
The authors would like to give their gratitude to the Faculty of Pharmacy, University of Indonesia, and Dharmais Hospital for providing the opportunity to conduct this research.
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