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  • Center for Drug Reevaluation, National Medical Products Administration; Chinese Pharmacists Association et al
    Adverse Drug Reactions Journal. 2022, 24(6): 284-294.
    As stated by article 12 of the Drug Administration Law of the People′s Republic of China, the state shall construct pharmacovigilance regulations to monitor, identify, assess, and control adverse drug reactions and other harmful events related to medication. Pharmacovigilance runs throughout the whole life cycle of drug from research and development to clinical use, and the core idea is to prevent and control medication risks and ensure the safety of patients and the general public. As the main places for drug consumption and the key participants in pharmacovigilance activities, the construction of pharmacovigilance system in health facilities is an important part in the construction of national pharmacovigilance regulations. At present, we are at the initial stage of the implementation of national pharmacovigilance regulations. In order to promote the establishment of pharmacovigilance system in health facilities, domestic pharmacovigilance monitoring institutions, relevant academic groups, medical colleges and universities, periodical offices, and social welfare organizations jointly initiate the compilation of Expert consensus on construction of pharmacovigilance system in health facilities by inviting experts and scholars in relevant fields to discuss, distinguish, and analyze the important concepts on adverse drug reactions/events, medication safety, pharmacovigilance, etc., in combination with cutting-edge developments. The consensus puts forward systematic principles and methods on establishing pharmacovigilance system, expecting to provide reference to health facilities in pharmacovigilance system establishment.
  • Tian Danxing
    Adverse Drug Reactions Journal. 2022, 24(10): 554-556.
    A 67-year-old male patient received immunotherapy with intravenous infusion of sintili- mab 200-mg once every 3 weeks due to postoperative recurrence of liver cancer, and the efficacy and tolerance was good. After 12 doses of sintilimab treatment, the patient developed a bright red skin rashes on the chest, abdomen, and extremities with itching. Oral loratadine and topical halometasone cream were given, and the rashes were improved slightly. The rashes did not spread in the next 2 doses of sintilimab treatment. But after the 3rd dose of continuing sintilimab, the patient suddenly developed a large-area rashes all over the body, which rapidly developed into blisters, ulcers, accompanied by oozing blood and fluid on the skin, itching, and pain. Drug eruptions were diagnosed, which was considered to be induced by sintilimab. The drug was stopped. After 1 week of treatments with intravenous infusion of methylprednisolone 60-mg once daily, anti-allergy, anti-infection, mucosal protection, and skin care, the rashes were repeated. Then the dose of methylprednisolone was increased, the rashes were still not relieved 1 week later, and gastrointesting bleeding occurred. After liver cancer surgery, the patient was accompanied by hypoproteinemia, liver dysfunction, and long-term high-dose glucocorticoid use. Therefore, despite active treatment measures, the patient still died of ineffective rescue.
  • Liu Ting, Fan Xiaohong, Zeng Yueping, Qin Yan, Ai Sanxi, Li Xuemei
    Adverse Drug Reactions Journal. 2022, 24(6): 332-334.
    A 69-year-old man was treated with adalimumab 80-mg subcutaneously for psoriasis for the first time. Two days later, the patient developed diffuse erythema with pruritus. Because the active stage of psoriasis was not excluded, adalimumab 40-mg subcutaneous injection was continued once a week for 4 times. The patient′s skin erythema and pruritus continued to worsen. After intravenous infusion of methylprednisolone sodium succinate 40-mg/d for 1 week, the systemic erythema and pruritus were slightly relieved, but the condition was repeated after stopping the drug. Urine routine and sediment analysis showed urinary occult blood (+++), 190 red blood cells/μl, urinary protein(+), and serum creatinine 80-μmol/L. Renal biopsy and skin histopathology suggested IgA nephropathy and psoriasiform dermatitis, respectively. After consultation with dermatologists, erythroderma caused by deterioration of psoriasis was considered. Excluding other factors, it is considered that IgA nephropathy and erythroderma were probably induced by adalimumab. Methotrexate 10-mg per week was given orally and halometasone ointment was used externally. The skin damage in the patient was gradually improved. Hematuria and proteinuria were self-relieved slowly.At one-year of follow-up, the patient′s renal function and urine routine remained normal, and nephropathy and rash did not recur.
  • Li Chen, Su Haibin, Hu Jinhua, Shi Chenhui
    Adverse Drug Reactions Journal. 2022, 24(9): 502-504.
    A 37-year-old female patient took orlistat capsules 120-mg thrice daily orally for weight loss. Four weeks later, she developed fatigue, poor appetite, and nausea; 6 weeks later, jaundice and decreased urine volume occurred and laboratory tests showed alanine aminotransferase (ALT) 7-631-U/L, aspartate aminotransferase (AST) 6-295-U/L, total bilirubin (TBil) 46.0-μmol/L, serum creatinine (Scr) 266-μmol/L, and international normalized ratio (INR) 1.73. Acute liver and kidney injury caused by orlistat capsules was considered. Then orlistat was discontinued, and symptomatic and supportive treatments such as liver protection, enzyme lowering, fluid replacement, and renal perfusion improvement were given. Ten days later, the symptoms above-mentioned in the patient were improved obviously, and laboratory tests showed ALT 181-U/L, AST 25-U/L, TBil 9.8-μmol/L, Scr 121-μmol/L, and INR 0.9. The liver and renal function in the patient was normal both at 3 months and 1 year of follow-up.
  • Yu Lihong, Zhao Ting, Ma Wenming
    Adverse Drug Reactions Journal. 2022, 24(7): 387-389.
    A 31-year-old pregnant woman was treated with progesterone soft capsule 0.2 g vaginally twice daily and nadroparin calcium injection 4 100 U subcutaneously once daily due to threatened abortion at 23+1 weeks of menopause. On the 16th day of treatments, laboratory tests showed alanine aminotransferase (ALT) 766-U/L, aspartate aminotransferase (AST) 411-U/L, γ-glutamyl transferase (γ-GT) 98-U/L, alkaline phosphatase (ALP) 180-U/L, and total bile acid (TBA) 40.1-μmol/L. Liver injury caused by nadroparin calcium was considered. The drug was stopped and liver protective treatments were given. On the 21st day of nadroparin calcium withdrawal, the patient had inevitable abortion and delivered a dead baby through vagina. Laboratory tests showed ALT 83 U/l, AST 103 U/l, γ-GT 37-U/L, ALP 157-U/L, and TBA 42.0-μmol/L. Liver protective treatments were continued After 35 days of nadroparin calcium withdrawal, laboratory tests showed ALT 18-U/L, AST 15-U/L, γ-GT 33-U/L, ALP 156-U/L, and TBA 6.2-μmol/L.
  • Ma Jianping, Gu Lili
    Adverse Drug Reactions Journal. 2022, 24(10): 557-558.
    A 31-year-old female patient took ibuprofen sustained-release capsules (ibuprofen) 0.3 g by herself due to persistent dull pain in both sides of the waist during menstruation. Three hours later, she developed nausea and vomiting, weakness, and poor appetite. Laboratory tests showed serum creatinine 173-μmol/L, glomerular filtration rate 33-ml/(min·1.73 m2), urea 10.7-mmol/L, and uric acid 428-μmol/L. Ibuprofen-related acute kidney injury was considered. Then she received intravenous injection of methylprednisolone sodium succinate 20-mg once daily by micro injection pump and symptomatic treatments. After 14 days of treatments, her serum creatinine was 89-μmol/L, glomerular filtration rate 84.1-ml/(min·1.73 m2), and urea 8.0-mmol/L; after 21 days, her serum creatinine was 78-μmol/L, urea 3.9-mmol/L, and uric acid 313-μmol/L.
  • Zhang Hongmei, Guo Qiushi, Tian Xu, Sun Lirui
    Adverse Drug Reactions Journal. 2022, 24(7): 376-377.
    A 45-year-old male patient was treated with canagliflozin 100-mg once daily orally for type 2 diabetes mellitus due to poor blood sugar control. On the 4th day of medication, the patient developed slight abdominal distension and fatigue; on the 5th day, the patient felt nausea and general fatigue, and the color of urine became dark brown. The laboratory tests showed serum creatinine (Scr) 136-μmol/L, blood urea nitrogen (BUN) 9.7-mmol/L, urine protein (+), and urinary occult blood (++). Acute kidney injury induced by canagliflozin was considered. Canagliflozin was stopped, and acarbose 50-mg (before meal), 2 Haikun Shenxi capsules (海昆肾喜胶囊), and 3 Jinshuibao capsules (金水宝胶囊) orally thrice daily were given. After 2 days of drug withdrawal, the symptoms of nausea and fatigue disappeared, and the color of urine was normal. After 5 days of drug withdrawal, laboratory tests showed fasting blood glucose 5.6-mmol/L, Scr 112-μmol/L, BUN 8.5-mmol/L, urine protein (-), and urine occult blood (-). After 19 days of drug withdrawal, the patient′s renal function indexes were all within the normal range, and no discomfort symptoms recurred.
  • Hu Xiaoling, Niu Yazhen, Cui Yadeng, Wang Shuai
    Adverse Drug Reactions Journal. 2022, 24(8): 437-438.
    A 75-year-old male patient with pulmonary infection received an IV infusion of piperacillin sodium and tazobactam sodium 4.5 g twice daily. Fifteen minutes after the first medication, the patient developed patches on the skin of both upper limbs with pruritus, chest tightness and suffocation. Physical examination showed heart rate 110 beats/min, breathing rate 26 breaths/min, blood pressure 196/118-mmHg, and oxygen saturation 0.85. Immediate-type hypersensitivity related to piperacillin sodium and tazobactam sodium was considered. The drug was discontinued and symptomatic treatments including glucocorticoids and antiasthma were given. Two hours later, the skin itching was alleviated, the color of erythema became lighter, and the symptoms of chest tightness and suffocation were relieved. Physical examination showed that the heart rate was 100 beats/min, the blood pressure was 150/90-mmHg, and the blood oxygen saturation was 0.90.
  • Lu Hong, Liu Fangqun, Zhao Chaohui, Zhang Hengbei
    Adverse Drug Reactions Journal. 2022, 24(6): 324-326.
    A 73-year-old male patient was given intravenous infusion of ketorolac tromethamine injection 60-mg diluted in 0.9% sodium chloride injection 250-ml once daily for gouty arthritis. At about half of the third infusion, he developed dull pain in the stomach, but did not pay much attention to it. Then vomiting (with blood in the vomitus) and melena accompanied by epigastric discomfort occurred later. The symptoms were considered to be related to ketorolac tromethamine injection, the drug was stopped, and the patient′s condition was observed. But the above symptoms continued and worsened, and palpitation, dizziness, fatigue, hematemesis, fresh blood on defecation, syncope, etc. occurred. The patient′s blood pressure was 58/33-mmHg and hemoglobin was 92-g/L. Gastroscopy and pathological examination showed multiple ulcers in antrum and the angle of the stomach, chronic superficial and erosive gastritis, duodenal bulbar inflammation, and Helicobacter pylori (+). The patients were diagnosed with peptic ulcer and hemor- rhagic shock. Norepinephrine, somatostatin, esomeprazole, and nutritional and supportive treatments were given, and 2 weeks later, the patient gradually recovered and the fecal occult blood was negative.
  • Li Jiale, Li Haipian, Huang Zhaoqi, Mo Xiaolan
    Adverse Drug Reactions Journal. 2022, 24(10): 508-514.
    Objective To explore the efficacy and safety of crisaborole ointment (crisaborole) treatment in children with atopic dermatitis (AD). Methods PubMed, Embase, Medline, CNKI, Wanfang Medicine, VIP, and Chinese Medical Journal Databases were searched (up to March 2022) and the literature on randomized controlled trials (RCTs) and cohort studies of crisaborole treatment in children with AD was collected. The quality of RCTs and cohort studies was evaluated using the modified Jadad scale and Newcastle- Ottawa scale, respectively. Data on effective rate and incidence of adverse event in children treated with crisaborole were extracted. The meta-analysis of single proportions was performed with Stata 15-software. Results A total of 8 studies (4 RCTs and 4 prospective cohort studies, respectively) were entered in the analysis, including 1-855 children (aged from 3 months to 17 years) treated with crisaborole. The 8 studies were all of high quality. The meta-analysis of single proportions showed that the effective rate of children with AD treated with crisaborole for 14-28 days was 46% [95% confidence interval (CI): 32%-61%], the incidence of adverse events during treatment was 28% (95%CI: 19%-38%), and the incidence of treatment discontinuation due to adverse events was 1% (95%CI: 0-2%). Most of the adverse events caused by crisaborole were local skin reactions, mainly characterized by local pain, itching, dermatitis, paresthesia, and local infection, etc. Seven of the 8 studies reported the pain at the application site, and the incidence of pain at the application site was 17% (95%CI: 11%-24%). Most adverse events were mild to moderate and could be alleviated without treatment. Serious adverse events occurred in 8 patients (0.4%), 7 of which were unrelated to the treatment drugs. Conclusion Crisaborole has good efficacy and safety in the treatment of mild to moderate AD in children.
  • Wu Yupei, Yin Yuesong, Wang Qian, Wang Dongmiao, Zhang Lina
    Adverse Drug Reactions Journal. 2022, 24(9): 494-496.
    A 66-year-old female patient with infiltrating adenocarcinoma in left lung received anlotinib 12-mg orally once daily (2-week medication followed by 1-week discontinuation, 3 weeks was a cycle). After 14 months of regular medication, the patient developed palpitation and chest tightness. Laboratory tests showed that the N-Terminal pro-brain natriuretic peptid (NT-proBNP) was 1-698-ng/L; echocardiography showed decreased apical wall motion and left ventricular diastolic dysfunction. Heart failure was condsidered, which was suspected to be related to anlotinib. Anlotinib was stopped and symptomatic treatments were given. Eight days later, her symptoms above-mentioned were alleviated and NT-proBNP was 485-ng/L. Because of the illness condition, the patient took anlotinib again at original dose according to the doctor′s instructions. Three months later, the above symptoms recurred and ventricular fibrillation occurred suddenly. Considering that the heart failure in the patient might be caused by anlotinib. Anlotinib was stopped again. After 11 days of treatments with diuretics, cardiac function improvement, myocardial nutrition, and potassium supplement, the patient′s condition was improved obviously. After that, the patient did not take anlotinib again.
  • Ma Jie, Liu Min, Cao Yidan, Wang Nan
    Adverse Drug Reactions Journal. 2022, 24(7): 380-382.
    A 37-year-old female patient with psoriasis received subcutaneous injection of secukinumab 300-mg once a week. Four weeks later, it was changed to subcutaneous injection of 300-mg once every 4 weeks. Seventy-five days later, the patient developed abdominal pain, diarrhea, and fever. The patient had no previous intestinal disease and family history of inflammatory bowel disease. Ulcerative colitis (initial, whole colon, and severe type) was diagnosed by enteroscopy, which was considered to be related to secukinumab. After 2 days of anti-inflammatory treatment with glucocorticoid, the patient′s body tempera- ture returned to normal and the abdominal pain was alleviated; after 9 days, the patient only had a dull abdo- minal pain at night and no other discomfort occurred.
  • Cai Yue, Wang Yanchun, Zhou Xiaohui, Zhu Xiaoran, Tian Dongdong, Dong Zhanjun
    Adverse Drug Reactions Journal. 2022, 24(12): 664-666.
    A 49-year-old male patient with type 2 diabetes mellitus and diabetic nephropathy received long term use of retaglinide thrice daily orally, 1-mg in the morning, 2-mg in the afternoon and 1-mg in the evening. Because of the sudden acute cerebral infarction, clopidogrel was added, on the 4th day of the medication, the fasting blood glucose in the patient decreased to 2.6-mmol/L. It was considered that the interaction of clopidogrel and repaglinide caused the increase of repaglinide plasma concentration, which resulted in severe hypoglycemia in the patient. Clinical pharmacist suggested stopping repaglinide and using insulin. The physician reduced the dosage of repaglinide to twice daily, 1-mg in the morning and 0.5-mg in the afternoon, and after 3 days the patient′s fasting blood glucose fluctuated between 4.0 and 4.5-mmol/L. Since the patient had diabetes nephropathy and renal insufficiency, which might increase the risk of hypoglycemia, repaglinide was stopped, and insulin glutamine 3 U was injected subcutaneously before meals, at the same time blood glucose was closely monitored. Fasting blood glucose fluctuated between 4.9 and 5.4-mmol/L after insulin treatment.
  • Peng Jin'e, Liu Hui, Li Xiao, Wang Lijun, Wang Shuo, Su Haofan, Zhan Hanqiu, Zhang Wei
    Adverse Drug Reactions Journal. 2023, 25(1): 11-16.
    Objective To explore the safety of nirmatrelvir/ritonavir (Paxlovid) in the treatment of coronavirus disease 2019 (COVID-19). Methods Medical records of adult patients with COVID-19 who were hospitalized and treated with Paxlovid in Beijing Ditan Hospital, Capital Medical University between March 23 and May 31, 2022 were collected through the hospital electronic medical record system. The occurrence (time of occurrence, clinical manifestations, severity, etc.) and outcomes of adverse reactions were analyzed retrospectively and the clinical characteristics of patients with or without adverse reactions were compared. Paxlovid was administered orally with nirmatrelvir 300-mg and ritonavir 100-mg every 12-hours for 5 consecutive days. Results Three hundred and sixty-four patients were entered in the analy- sis, including 200 males (54.9%) and 164 females (45.1%), with a median age of 60 (19, 92) years. The incidence of adverse reactions of Paxlovid was 13.2% (48/364), and the adverse reactions occurred 1 to 7 days after taking Paxlovid. Among the 48 patients, 37 patients had digestive system symptoms (mainly manifested as diarrhea in 17 patients, bitter mouth in 14 patients, etc.), 7 patients had nervous system symptoms (dizziness in 5 patients, headache in 2 patients), 4 patients had respiratory system symptoms (pharyngalgia in 3 patients, pharyngeal itching in 1 patient), 2 patients had kidney injury, 1 patient had elevated blood uric acid, 1 patient had myalgia, and 1 patient had rash. Of them, 2 patients had digestive and neurological symptoms at the same time, 1 patient had digestive and respiratory symptoms at the same time, and 1 patient had digestive, neurological, and respiratory symptoms at the same time. The severity of adverse reactions was grade 1 in 33 patients (68.8%) and grade 2 in 15 patients (31.2%), and no serious adverse reactions of grade 3 and above occurred. All patients completed 5 days of treatment except 1 patient who discontinued the drug because of intolerance to grade 2 digestive symptoms (nausea and bitter mouth). There were no significant differences in gender, age, body mass index, smoking status, underlying diseases, and COVID-19 clinical classification between the patients with and without adverse reactions (all P>0.05). Conclusions Paxlovid has a good safety in the treatment of COVID-19. The main adverse reaction is digestive system symptoms, mainly diarrhea and bitter mouth. Most of the symptoms are mild and the patient′s tolerance is good.
  • Chen Huiying, Xu Daliang, Zhu Ying
    Adverse Drug Reactions Journal. 2022, 24(7): 378-380.
    A 17-year-old male patient received rituximab due to nephrotic syndrome. No obvious discomfort occurred during the first treatment (500-mg by intravenous infusion). After half a year, when the second treatment (300-mg by intravenous infusion) was given, the patient developed symptoms such as fatigue of limbs and inability to lift both lower limbs. Laboratory test showed blood potassium 2.37-mmol/L. Before treatment, the serum potassium was 4.16-mmol/l, and other laboratory test indicators were basically normal. Acute hypokalemia caused by rituximab was considered. Oral potassium chloride was given. On the 2nd day, the symptoms in the patient were relieved, the feeling of powerlessness disappeared, and the blood potassium was 3.06-mmol/L. On the 3rd day, the blood potassium was 4.34-mmol/L. the potassium supplement was stopped after 3 days of medication. The next day, the blood potassium was 4.70-mmol/l, and the patient′s limb weakness and discomfort symptoms disappeared. After that, the patient did not use rituximab again, and no hypokalemia recurred.
  • Medication Safety Panel in China Core Group of International Network for the Rational Use of Drugs, et al
    Adverse Drug Reactions Journal. 2022, 24(8): 396-403.
    There are risks in the use and management of perioperative analgesics, which may be caused by analgesic methods, individual patient factors, or medication errors. In order to reduce the risk in perioperative analgesics use and improve the level of safe drug use, Medication Safety Panel in China Core Group of International Network for the Rational Use of Drugs, Chinese Pharmacological Society Professional Committee of Drug-induced Diseases, Adverse Drug Reactions Journal Agency, Beijing Municipal Health Commission Clinical Safety Medication Working Group organize the domestic pharmacy experts and anesthesiology experts to formulate the guideline. The risks prevention and management measures of perioperative analgesics were described from 3 aspects including management, drugs, and special populations. The management- related risks include the risks during the formulation of analgesia plan, the risks in information/goods/drugs transmission, the risks in the use of intraoperative analgesics and analgesia pumps, which can be prevented by formulating rules and regulations, strengthening training, and improving information technology. Drug-related risks are inherent properties of drugs. Analgesics are classified into narcotic analgesics, antipyretic analgesics, and analgesic auxiliary drugs. Corresponding prevention strategies can be formulated according to the risk points of specific drugs. Special populations including the elderly, pregnant and lacta- ting women, and children, etc. have their own physiological and pharmacokinetic characteristics and countermeasures can be formulated according to specific conditions. Through comprehensive monitoring of perioperative analgesics use, the risk can be predicted, the circumvention plan can be formulated, and the pharmaceutical care can be implemented, so as to ensure the medication safety of patients. This guideline is applicable to all medical personnel who use and monitor perioperative analgesics.
  • Wang Le, Yuan Haiyan, Ye Xi
    Adverse Drug Reactions Journal. 2022, 24(7): 373-375.
    A 52-year-old male patient with primary bronchogenic carcinoma received an IV infusion of sintilimab 200-mg on the first day, oral anlotinib capsules 12-mg once daily on day 1-14, and 3 weeks were a cycle. At the 3rd cycle of treatments, the laboratory tests showed thyroid stimulating hormone (TSH) 0.08 mU/L, and no intervention was given. At the 5th cycle, his free thyroxine (FT4) was 11.45-pmol/L and TSH was 8.19 mU/L, indicating hypothyroidism. The patient received levothyroxine sodium tablets 50-μg orally once daily. Fifty-six days later, his thyroid function returned to normal. On the 3rd day of the 8th cycle of treatments, the patient developed dry mouth, polydipsia, polyuria, nausea, and vomiting, and laboratory tests showed blood pH 7.02, β-hydroxybutyric acid 6.740-mmol/L, and random blood glucose 66.0-mmol/L, indicating diabetes ketoacidosis. Sintilimab and anlotinib were stopped and fluid replacement and insulin hypoglycemic therapy were given. Eleven days later, his ketone body turned negative, and the fasting blood glucose was 5.8-mmol/L. About 2 weeks later, the laboratory tests showed that hemoglobin A1c was 7.8%, the serum C-peptide levels on an empty stomach and 2 hours after breakfast both were less than 0.01-nmol/L, and the islet cell antibody, insulin autoantibody, glutamic acid decarboxylase antibody, and protein tyrosine phosphatase autoantibody were negative, which was consistent with the characteristics of fulminant type 1 diabetes (T1DM). On the morning of the 32nd day of sintilimab and anlotinib withdrawal, laboratory tests showed cortisol 50.7-nmol/L and adrenocorticotropic hormone (ACTH) 2.73-pmol/L, indicating hypoadreno- corticism. Treatment with glucocorticoid was given. It was considered that the patient was with  autoimmune polyendocrinopthy syndrome (APS) type II (hypothyroidism,fulminant T1DM,hypoadrenocorticism) caused by sintilimab. After 9 months of glucocorticoid treatment, cortisol was 16.6, 79.4, and 17.2-nmol/L at 8:00,16:00, and 24:00, respectively, and ACTH was 1.12-pmol/L. The patient still needed maintenance treatment with alternative hormone.
  • Liu Jinchun, Yan Xiaomin
    Adverse Drug Reactions Journal. 2022, 24(12): 667-669.
    A 38-year-old female patient with thyroid nodule received Xingqi Sanjie cream 30 g orally twice daily for 4 treatment courses in total. Each treatment course was 1 month and the interval between the 2 courses was 14 days. On the 29th day of the 4th treatment course, the patient developed poor appetite, yellowish skin and sclera, and dark urine. Laboratory tests showed alanine aminotransferase (ALT) 3-201-U/L, aspartate aminotransferase (AST) 2-262-U/L, total bilirubin (TBil) 257.2-μmol/L, direct bilirubin (DBil) 186.9-μmol/L, and alkaline phosphatase (ALP) 159-U/L. Drug-induced liver injury (severe) was diagnosed, which was considered to be related to Xingqi Sanjie cream. The drug was stopped, and symptomatic and supportive treatments including hepatoprotection and rehydration were given. Twenty-two days later, the above symptoms in the patient were improved. Laboratory tests showed ALT 209-U/L, AST 117-U/L, TBil 92.7-μmol/L, DBil 63.2-μmol/L, and ALP 82-U/L. Fifty-one days later, the yellowish skin and sclera in the patient subsided, and the urine color returned to normal. Laboratory tests showed ALT 37-U/L, AST 22-U/L, TBil 30.3-μmol/L, DBil 14.7 μ mol/L, and ALP 58-U/L.
  • Yuan Meng, Yang Chunyan, Wu Yuanzhu, Ye Mingqi, Luan Jiajie
    Adverse Drug Reactions Journal. 2022, 24(10): 549-551.
    A 69-year-old female patient received olaparide 300-mg orally twice daily after 6 cycles of chemotherapy with albumin paclitaxel+carboplatin regimen after cytoreductive surgery for ovarian cancer. The platelet count (PLT) was 151×109/L before the olaparide treatment, and on the 14th day of medication, her platelet count (PLT) was 17×109/L and platelet-associated immunoglobulin was positive. Immune thrombocytopenia due to olaparib was considered. The patient did not take the drug again. Thrombopoietin, eltrombopag, methylprednisolone, and platelet transfusion were given successively, but the PLT in the patients increased and decreased repeatedly, with the highest being 67×109/L, minimum 4×109/L.
  • Zhao Yanyan, Zhang Huixian, Meng Luhua, Feng Jianbo
    Adverse Drug Reactions Journal. 2022, 24(8): 424-429.
    Objective To explore the risk of cholangitis induced by different immune checkpoint inhibitors (ICIs). Methods Through the OpenVigil data platform, adverse event (AE) reports related to nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, ipilimumab, and tremelimu- mab from the first quarter of 2011 to the third quarter of 2021 in the US FDA Adverse Event Reporting System (FAERS) database were collected. Risk signal mining for cholangitis was performed using reported odds ratio (ROR) method. The detection threshold of the risk signal was set as that the number of AE reports was greater than or equal to 3 and the lower limit of the 95% confidence interval (CI) of the ROR was greater than 1. The higher the ROR and its 95%CI lower limit, the stronger the signal intensity. The intensity of the risk signal of cholangitis due to different ICIs was compared and the main characteristics (sex, age, type of primary tumor, time of occurrence of AE, and outcome) of patients with ICIs-related cholangitis were analyzed descriptively. Results A total of 52-440 AE reports related to the above 8 ICIs were collected, of which 410 cases were about cholangitis. The drugs that were detected with positive risk signals were nivolumab, pembrolizumab, atezolizumab, durvalumab monotherapy, and ipilimumab combined with nivolumab. Their number of AE reports were 213, 107, 48, 5, and 29 (402 patients in total), and the corresponding ROR (lower limit of 95%CI) were 37.88 (32.89), 26.07 (21.46), 32.12 (24.10), 13.63 (5.65), and 14.46 (10.02), respectively. The risk signal intensity was nivolumab, atezolizumab, pembrolizumab, ipilimu- mab combined with nivolumab, and durvalumab in order. Seeing from the available data among the reports, males were more than females (233∶110=2.1∶1), 55.2% (222/402) of patients were 65 years old and over, and 48.0% (193/402) of patients were non-small cell lung cancer. ICIs-related cholangitis could result in hospitalization or prolongation of hospitalization in 42.3% (170/402), requiring emergency treatment in 40.0% (161/402), life-threatening in 2.0% (8/402), and death in 15.7% (63/402) of patients. Conclusions The risk of cholangitis induced by ICIs is different and the risk signal of nivolumab is the strongest. Cholangitis is a serious AE of ICI, which should attract clinical attention.
  • Wang Yu, Li Jia, Pan Yunyan, Zheng Yifan, Chen Pan, Chen Jie
    Adverse Drug Reactions Journal. 2022, 24(7): 347-352.
    Objective To explore the risk signals of edoxaban-related adverse reactions and provide reference for the clinical safety of edoxaban. Method The US FDA adverse Event Reporting System database was searched and the adverse event (AE) reports on edoxaban as the suspicious drug from the second quarter of 2011 to the first quarter of 2022 were collected. An AE with reports>3, 95% confidence interval (CI) lower limit of ROR>1, PRR>2, and χ2>4 was defined as a positive signal. AEs were counted and classified using the preferred term (PT) and system organ class of Medical Dictionary for Regulatory Activities 25.0. The PTs of top 50 in AE report amount and signal intensity were selected and analyzed. Results A total of 4-113 AE reports on edoxaban as the suspicious drug were collected and 996 PTs were involved. After calculation using ROR and PRR methods, 158 positive risk signals were obtained, involving 1-898 AE reports. PTs of the top 50 in AE report amount and signal intensity were merged 89 PTs were selected after screening out duplicates, involving 1-468 AE reports. The top 5 PTs in report amount were dyspnea, anemia, atrial fibrillation, melena, and cardiac failure; the top 5 PTs in signal intensity were angiodysplasia, urogenital haemorrhage, cardiac amyloidosis, chorea, and ischaemic cerebral infarction/cardioac- tive drug level increased. Fourty-five PTs were not included in the drug labels. Of them, acute renal injury, renal impairment, and interstitial lung disease were with more AE reports and stronger signals. Conclusions Bleeding-related events are still the key AEs that need to be monitored during the use of edoxaban. Edoxaban may also lead to renal injury and interstitial lung disease, which requires special attention.
  • Liang Xiao, Shen Shan, Wei Duncan, Zhang Yahui, Zhang Wen, Lu Cuicui
    Adverse Drug Reactions Journal. 2022, 24(8): 429-434.
    Objective To know the clinical characteristics of liver injury related to levetiracetam (LEV). Methods The relevant databases at home and abroad (up to August 31st, 2021) were searched and the case reports on LEV-associated liver injury were collected. Clinical information including patients′ basic characteristics, LEV application, concomitant medication, and occurrence, treatment, and outcome of liver injury, etc. were collected and analyzed by descriptive statistical method. Results A total of 17 patients were enrolled in the study, including 9 males and 8 females, aged from 1 month to 76 years with an average age of 35 years. The primary disease was idiopathic epilepsy in 7 patients and secondary epilepsy in 10 patients. Five cases had comorbidities. Thirteen patients had drug dosage records, all of which were within the range recommended in the labels; 13 patients had concomitant medication. The time from LEV treatment to the occurrence of liver injury ranged from several hours to 5 months in 17 patients and it was ≤2 months in 14 patients. The classification of liver injury was hepatocellular type in 7 patients, cholestasis type in 1 patient, mixed type in 1 patient, and unable to be determined due to lack of relevant data in 8 patients. Clinical symptoms were recorded in 10 patients, including yellowish skin and sclera in 5 cases, fever in 4 cases, nausea in 2 cases, vomiting in 2 cases, and biliuria in 2 cases. LEV was discontinued in 14 patients, 4 of whom did not received other interventions and the liver function was improved or returned to normal 2 to 20 days after drug withdrawal; LEV was replaced with other antiepileptic drugs and/or sympto- matic treatments in 10 patients, 9 patients′ liver function were improved or returned to normal (the recovery time was 5-37 days in 5 patients and not recorded in 4 patients), 1 patient had normal liver function after liver transplantation, but the liver injury recurred after LEV use again and was improved after drug withdrawal. Two patients did not stop LEV, one underwent liver transplantation due to liver failure and hepatic encephalopathy, and the prognosis was unknown; the other one developed fulminant liver failure and died. One patient had no record of whether or not stopping LEV, and the liver function returned to normal after artificial liver support treatment. Conclusions LEV-related liver injury mostly occurred within 2 months after drug administration. The clinical manifestations were similar to the liver injury caused by other drugs. Liver function usually was improved or returned to normal after the drug withdrawal. The patients who did not stop LEV had poor prognosis, and severe cases could lead to liver failure or death.
  • Zhang Zhiqi, Gao Jie
    Adverse Drug Reactions Journal. 2022, 24(8): 439-441.
    A 58-year-old female patient with breast cancer received cyclophosphamide and doxorubicin hydrochloride liposome injection chemotherapy twice after modified radical mastectomy. The patient was pretreated with dexamethasone injection 5-mg before chemotherapy. After each chemotherapy, mucosal ulcer of different degrees occurred, and both hands and feet were red and swollen, which showed an aggravating trend, but were all improved after a few days. After the 3rd chemotherapy, the patient′s hands and feet were red and swollen, accompanied by blisters and exudation, her body temperature rose up to 40.0 ℃, with large area of erythema on his back, axillary erythema with erosion exudation, and oral mucosal ulcer. It was considered that the patient was likely to have hand-foot syndrome. Methylprednisolone, cefoxitin, omeprazole, and other drugs, external skin care measures such as wet compress of the affected area with furacilin solution and keeping the skin moist were given. After 15 days of treatments, the patient′s hands and feet symptoms were improved. Then doxorubicin hydrochloride liposomes injection were stopped and replaced by docetaxel, and hand and foot symptoms in the patient did not recur.
  • Chen Hongxu, Wu Qing
    Adverse Drug Reactions Journal. 2022, 24(7): 384-387.
    A 44-year-old female patient was treated with docetaxel and carboplatin chemotherapy for cervical cancer and dexamethasone 7.5-mg twice daily was given the day before and on days 1 and 2 of chemotherapy. No adverse reactions occurred in the first 3 courses. No abnormality was found in laboratory tests, color Doppler echocardiography, or CT examination of chest and abdomen before the 4th chemotherapy. On day 3 and 4 of the 4th chemotherapy, the patient felt mild nausea, which was relieved after intravenous injection of metoclopramide; on day 5, she suffered sudden upper abdominal distension, pain, and discomfort, accompanied by nausea and vomiting. Chest and abdominal CT examination indicated a large amount of peritoneal effusion. Renal function tests showed blood urea 10.29-mmol/L and blood creatinine 215-μmol/L. Tumor peritoneal metastasis, acute abdomen, cardiac insufficiency, hypoproteinemia and other reasons were excluded, and the peritoneal effusion caused by docetaxel was considered, which then induced prerenal acute kidney injury. Peritoneal effusion was extracted through peritoneal puncture and glucocorticoid and diuretic therapy were given. On day 8 of chemotherapy, renal function of the patient was normal; on day 9, her abdominal distention and pain were obviously relieved; on day 11, abdominal ultrasonography showed no obvious mass or liquid dark area. After that, the patient received traditional Chinese medicine for cervical cancer and chest and abdomen CT examination was repeated every 3-6 months. Blood routine examination and liver and kidney function showed no abnormality in subsequent tests.
  • Tong Yuanxu, Li Yan, Wei Yali, Qi Lu, Liu Chen, Li Shuang, Wang Xinghe
    Adverse Drug Reactions Journal. 2022, 24(6): 308-313.
    Objective To compare the safety of the generic and the original regorafenib tablets. Methods Two single center, randomized, open-label, 2-period self-crossover phase I clinical trials (single dose) were conducted under fasting condition and with low-fat meal respectively in healthy adult volunteers. The test preparation (T) of regorafenib was produced by Beijing Sl Pharmaceutical Co.,Ltd. and the reference preparation (R) was produced by Bayer HealthCare Pharmaceuticals Inc. In the 2 trials, male healthy subjects were randomly divided into 2 groups, respectively, and took 2 times of the preparations with different order in each group, which were R-T group (subjects took R on day 1 and then T on day 13) and T-R group (subjects took T on day 1 and then R on day 13). The subjects took drugs under fasting condition and with low-fat meal in the 2 trials respectively. After medication, vital signs detection, electrocardiogram, general physical examination, blood routine, blood biochemical, coagulation function, and other tests were performed regularly, and the occurrence of adverse events (AEs) were recorded and the severity of AEs was assessed. Results Sixty-four subjects were enrolled in the trial under fasting condition, including 32 in the T-R group and 32 in the R-T group, and the safety data was obtained from 61 and 57-subjects taking T and R, respectively. Seventy-six subjects were included in the postprandial trial, including 38 in the T-R group and 38 in the R-T group, and the safety data was obtained from 74-subjects taking T and R, respectively. In the 2 trials, there was no significant difference in the incidence of AEs between subjects taking T and those taking R [41.0% (25/61) vs. 31.6% (18/57), χ2=1.125, P=0.289; 56.8% (42/74) vs. 45.9% (34/74), χ2=0.183, P=0.188]. A total of 230 AEs occurred in the 2 trials, of which 228 cases were grade 1 (99.1%, 131 and 97 AEs occurred in subjects taking T and R, respectively), 2 cases were grade 2 (0.9%, 1 AE occurred in subjects taking T and R, respectively), and no grade ≥ 3 AEs occurred. The types of AEs occurred in the 2 trials were the same, of which bradycardia was the most common, followed by prolonged QT interval of ECG. All ECG abnormalities were found during routine examinations, and no subjects had obvious clinical symptoms. Conclusion The safety of the generic and the original regorafenib tablets was consistent after a single dose administration under fasting condition and with low-fat meal.
  • Liu Tong, Su Su, Zhang Yangxin, Yu Siqi, Yan Suying
    Adverse Drug Reactions Journal. 2022, 24(11): 584-590.
    Objective To understand the prescription medications that may cause or exacerbate heart failure (HF-CEPMs) in elderly outpatients with HF and analyze its influencing factors. Methods Prescriptions for elderly patients with HF in clinic of Xuanwu Hospital, Capital Medical University between January 2016 and August 2020 were collected. According to the list of HF-CEPMs published by the American Heart Association in 2016, HF-CEPMs in prescriptions were identified. The patient′s gender, age, disease diagnosis, medical insurance, therapeutic drugs, visiting departments, physician titles, and other information are extracted from the prescription, and the use of HF-CEPMs in the prescription was descriptively analyzed. The patients were divided into HF-CEPMs group and non-HF-CEPMs group according to whether the prescription included at least one drug in the list of HF-CEPMs. The clinical characteristics, number of drugs, medical insurance, visiting departments, and professional titles of prescription physicians in patients in the 2 groups were compared, and the influencing factors of prescription containing HF-CEPMs were analyzed by multivariate logistic regression. Results A total of 2-418 patients were enrolled, including 1-264 males (52.27%) and 1-154 females (47.73%), with a median age of 80 (65, 99) years and a median number of comorbidities 1 (0, 5). The top 3 comorbidities requiring long-term medication were hypertension (1-233 patients, 50.99%), bronchial asthma (448 patients, 18.53%) and diabetes mellitus (385 patients, 15.92%), and the median number of drugs was 5 (1, 16). Among the 2-418 patients, 254 (10.50%) used HF-CEPMs, including 142 (55.91%) males and 112 (44.09%) females. Two hundred and twenty-four patients (88.19%), 26 patients (10.24%), and 4 patients (1.57%) were treated with 1, 2, and 3 kinds of HF-CEPMs, respectively. The top 5 HF-CEPMs in drug use rates were antihypertensive drugs [4.47% (108/2 418)], pulmonary drugs [2.52% (61/2 418)], antidiabetic drugs [1.99% (48/2 418)], urological drugs [1.12% (27/2 418)], antipyretic and analgesic drugs [1.03% (25/2 418)]. Multiple logistic regression analysis showed that the number of comorbidities ≥1 (1 kind of disease: OR=3.732, 95%CI: 2.246-6.623, P<0.001; more than 2 kinds of diseases: OR=6.054, 95%CI: 3.624-10.788, P<0.001) and the number of prescribed drugs ≥5 (OR=4.003, 95%CI: 2.874-5.693, P<0.001) were independent influencing factors for prescribing HF-CEPMs. Conclusions Antihypertensive drugs, pulmonary drugs, antidiabetic drugs, urological drugs, and antipyretic and analgesics drugs were the most common HF-CEPMs in outpatient prescriptions of elderly HF patients. The number of comorbidities and polypharmacy therapy in elderly outpatients with HF were independent influencing factors for prescribing HF-CEPMs.
  • Ma Lulu, Zhang Xiuhua
    Adverse Drug Reactions Journal. 2022, 24(8): 393-395.
    The rational application of analgesics to control postoperative pain is an important measure to improve the efficacy of surgical treatment and the quality of life and prognosis of patient.The multi-mode analgesia, preventive analgesia, and the perioperative goal-oriented whole process analgesia management were recommended to control postoperative pain in relevant guidelines at home and abroad. However, irrational use of modes of analgesia and/or analgesics is still common and some patients are not satisfied with postoperative pain management. It is of high clinical significance to provide patient education with analgesic method and drug use before operation, enhance the continued medical education about postopera- tive pain management for doctors in related clinical departments, set up acute pain service management group at the hospital level for improvement of the satisfaction of postoperative analgesia, rational use of analgesics, and the prognosis of patients.
  • Rui Min, Zhu Zhonghua
    Adverse Drug Reactions Journal. 2023, 25(1): 53-55.
    A 73-year-old male patient with metastatic sarcomatoid carcinoma of lymph node received an IV infusion of tirelizumab 200-mg on day 1, and 3 weeks was 1 cycle. After 10 cycles of treatment, the patient developed dizziness, chest tightness, nausea, and vomiting. Laboratory tasts showed random blood glucose 99.1-mmol/L, serum creatinine (Scr) 260 μ mo/L, blood potassium 5.8-mmo/L, blood sodium 129-mmol/L, and blood osmotic pressure 368 mOsm/(kg·H2O). Blood gas analysis showed pH 7.1 and lactic acid 2.8-mmol/L. Ketoacidosis was considered and treatments such as rehydration, hypoglycemic with insulin, and electrolyte supplement were given. After 5 days of treatments, the patient′s symptoms were improved, and laboratory tests showed blood potassium 4.4-mmol/L, blood sodium 134-mmol/L, carbon dioxide binding capacity 17.0-mmol/L, and fasting C-peptide 0.02-nmol/L. Seven days later, laboratory tests showed fasting C-peptide 0 and 2 h post-prandial C-peptide 0. The patient was diagnosed with fulminant type 1 diabetes mellitus, which was considered to be related to tirelizumab. After 19 days of treatments, laboratory tests showed fasting blood glucose 5.8-mmol/L, blood glucose at 2 hours after meal 19-mmol/L, Scr 102-μmol/L, blood sodium 139-mmol/L, blood chlorine 108-mmol/L, and blood potassium 3.9-mmol/L.
  • Liu Jinchun, Zhang Fan
    Adverse Drug Reactions Journal. 2023, 25(2): 114-116.
    Two patients (patient 1, a 49-year-old female; patient 2, a 51-year-old female) took Anshen Bunao liquid 10-ml twice daily orally by themselves because of poor sleep. None of the 2 patients had concomitant medications. Patient 1 and patient 2 developed fatigue and poor appetite after 7 and 10 days of Anshen Bunao liquid treatment, respectively. Laboratory tests showed that alanine aminotransferase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were 1-147-U/L, 1-271-U/L, 215-U/L and 805-U/L, 333-U/L, 227-U/L, respectively. Then Anshen Bunao liquid was stopped and hepatoprotective therapy was given. Seven days later, symptoms of fatigue and poor appetite in the 2 patients were improved, amd laboratory tests showed that the levels of ALT, AST, ALP decreased to 222-U/L, 396-U/L, 122-U/L and 85-U/L, 23-U/L, 129-U/L, respectively. Patient 1 took Anshen Bunao liquid again. Two days later, she developed abdominal discomfort with vomiting, ALT was 409-U/L, and AST was 339-U/L. After stopping the drug and giving liver-protective treatments for nearly 4 months, ALT was 32-U/L, AST was 22-U/L, and ALP was 89-U/L. Patient 2 did not take the drug again. Re-examination after 138 days after discharge, ALT was 39-U/L, AST was 28-U/L, and ALP was 130-U/L.
  • Cong Duanduan, Xue Wei, Liu Xiaohui, Li Kexin, Hu Xin
    Adverse Drug Reactions Journal. 2022, 24(6): 281-283.
    Since healthy volunteers usually have no expected direct clinical benefits in clinical trial, it is particularly important to fully assess the risks and carry out safety monitoring in all links of the trial in combination with their group characteristics. The risk points for healthy volunteers to participate in clinical trials lie in the aspects of trial drugs, clinical trial design, and trial implementation process. The safety and rights of healthy volunteers should be better protected by implementing the Good Pharmacovigilance Practices, improving the level of risk management, enhancing the transparency of clinical trial results, and carrying out relevant risk management research.
  • Chen Xiaolin, Li Haixi, Yang Jie, Yang Hai
    Adverse Drug Reactions Journal. 2022, 24(7): 371-373.
    A 64-year-old female patient with paraganglioma received intramuscular injection of metoclopramide hydrochloride injection 10-mg to prevent chemotherapy-induced vomiting. Five minutes later, he developed palpitation, sweating, headache, limb weakness, and other discomfort symptoms, and the blood pressure increased to 214/101 mmHg. Hypertensive crisis was diagnosed. Urapidil 25-mg was given intravenously, and the blood pressure in the patient was continuously monitored. About 12-hours later, the patient′s symptoms were improved and the blood pressure gradually returned to normal. It is suggested in the label that metoclopramide should not be used in patients with pheochromocytoma and paraganglioma. The patient suffered from hypertension crisis due to the use of the drug, and the hospital stay was prolonged, so it was grade F medication error.
  • Lu Meizhi, Li Wenhao, Yang Shen, Yan Wensheng, Zhang Yunfang
    Adverse Drug Reactions Journal. 2022, 24(11): 606-608.
    A 62-year-old male patient received aspirin, clopidogrel, and atorvastatin calcium after percutaneous coronary intervention for coronary atherosclerotic heart disease. One week later, the patient received anti-Helicobacter pylori (Hp) therapy with amoxicillin capsules, clarithromycin tablets, bismuth tartrate capsules, and pantoprazole sodium enteric coated tablets due to Hp infection, and two to three days after taking the drugs, the patient developed systemic fatigue, nausea, joint discomfort and muscle soreness, which were gradually aggravated. Laboratory tests showed muscle hemoglobin (MYO)>1-000-μg/L, serum creatinine (Scr) 69-mmol/L, urea nitrogen (BUN) 3.5-mmol/L, alkaline phosphatase (ALP) 148-U/L, alanine aminotransferase (ALT) 750-U/L, aspartate aminotransferase (AST) 850-U/L, g-glutamyl tran- speptidase (γ-GT) 181-U/L, lactate dehydrogenase (LDH) 1-177-U/L, creatine kinase (CK) 8-144-U/L, CK-MB 255-U/L. Atorvastatin calcium was stopped, and symptomatic and supportive treatments such as alkalized urine and fluid replacement were given, and anti-Hp treatments were continued. However, the CK level was continued to increase. CK reached 15-794-U/L 4 days after atorvastatin calcium discontinuation. It was considered that the patient′s rhabdomyolysis might be related to interaction between atorvastatin calcium and clarithromycin. Then the anti-Hp drugs were discontinued. On the 2nd of drug withdrawal, the patients′ muscle soreness was alleviated than before; on the 4th day, CK and other serum enzymology indexes began to decline; on the 8th day, the patient′s fatigue and muscle soreness completely disappeared, with CK 908-U/L; on the 15th day, ALT was 105-U/L, AST was 42-U/L, γ-GT was 107-U/L, CK was 143-U/L, CK-MB was 29-U/L, and LDH was 339-U/L; 5 weeks later, the patient took atorvastatin again, myalgia and fatigue did not recur, and no abnormality was found in blood biochemical indexes.
  • Wang Yanling, Zhang Qingxia
    Adverse Drug Reactions Journal. 2022, 24(7): 341-346.
    Objective To understand and analyze the occurrence of medication error (ME) on warfarin and their related factors in order to avoid or reduce adverse events. Methods All ME reports in the National Monitoring Network for Clinical Safe Medication (monitoring network) from January 1, 2016 to December 31, 2020 were collected and warfarin ME reports were selected. The grading and contents of warfarin MEs, the persons who caused and found the errors, and the factors that triggered the errors were analyzed. Results During the set period, a total of 59-987 ME reports from 30-hospitals in 13 provinces and municipalities in China were collected in the monitoring network, which included 149 ME reports (0.3%) of warfarin, involving 149 patients. Among the 149 patients, 94 were male (63.1%) and 55 were female (36.9%), aged 2-87 years. The indications of warfarin were atrial fibrillation in 78 patients, mechanical valve replacement in 47 patients, thrombosis in 10 patients, pulmonary embolism in 10 patients, and congenital heart defect in 4 patients. One hundred and thirty-two MEs (88.6%) were mild and 17 (11.4%) were severe, of which 1 caused patient death. Among the warfarin MEs, dose errors ranked the first, accounting for 29.5% (44/149), followed by medication frequency error (26.2%, 39/149) and wrong drug class (22.2%, 33/149). Among the 149 MEs, 102 (68.5%) were triggered by doctors, 25 (16.8%) were by pharmacists, and 22 (14.8%) were by patients/family members. In the 102 MEs triggered by doctors, 94 were intercepted by pharmacists or nurses and 8 were not intercepted, which were all severe MEs [7 were drug selection errors (drugs were not selected based on drug interaction) and 1 were wrong dose]. In the 25 MEs triggered by pharmacists, 24 were intercepted by pharmacists, nurses, or patients/family members and 1 was not intercepted, which was dose error(severe); the patient involved in the severe ME was treated with combined anticoagulant therapy and no thromboembolic events occurred. In the 22 MEs caused by patients/family members, 14 were intercepted by doctors, nurses, or pharmacists and 8 were not intercepted, which were severe MEs, including 1 dose error (causing patient death), 2 frequency errors, and 5 drug class errors. A total of 132 MEs were found in time and successfully intercepted. Among the persons who found the MEs, 61 were pharmacists, accounting for 46.2%; 53 were nurses, accounting for 40.1%; 10 were doctors, accounting for 7.6%; 8 were patients/family members, accounting for 6.1%. The main factors causing MEs were lack of knowledge(accounting for 57.1%, 85/149), fatigue, misreading, and machine fault (accounting for 22.8%, 34/149), and unskilled technology (accounting for 13.4%, 20/149) in order. Conclusions In the content of warfarin MEs, dose error ranks the first, and drug class errors and drug selection errors usually cause severe MEs. Pharmacists play an important role in discovering and intercepting the warfarin MEs. Lack of knowledge is the primary factor causing MEs.
  • Ding Zheng, Zheng Yingli
    Adverse Drug Reactions Journal. 2022, 24(7): 337-340.
    Direct oral anticoagulants (DOACs) are recommended as first-line therapy in patients with atrial fibrillation and venous thromboembolic diseases in relevant guidelines at home and abroad. Compared with warfarin, DOACs have relatively fixed dose, fewer drug interactions, and no need of routine therapeutic drug monitoring in clinic. DOACs bring much convenience to anticoagulant therapy, but they also raise a series of new medication safety challenges. Pharmacists should ensure the safe use of DOAC through improving corresponding pharmaceutical care mechanism, such as assisting doctors to improve the suitability of dose in prescription, standardizing laboratory monitoring process, setting up early warning of potential drug interaction, and strengthening anticoagulant conversion and perioperative anticoagulant therapy management. In the post-coronavirus disease 2019 era, incorporating DOACs into the standardized management at anticoagulation clinics is an important work extension of the traditional anticoagulation clinics and may reduce the risk of exposure to the novel coronavirus. In addition, considering the limit in labour and work energy of clinical pharmacists, the application of DOAC-related clinical decision support system may help improve the appropriateness of prescription and reduce the adverse drug events.
  • Ren Xiuhua, Yu Hengyi, Fang Yinian, Zhang Donglin, Chen Qian,
    Adverse Drug Reactions Journal. 2022, 24(6): 300-307.
    Objective To compare the pharmacokinetics and safety of single intravenous injection of the generic bevacizumab injection WBP264 and the original bevacizumab injection Avastin- in healthy male volunteers. Methods The study was designed as a randomized, double-blind, single dose, parallel, and controlled phase I clinical trial. Healthy male volunteers who were recruited publicly were randomized into the trial group (intravenous infusion of WBP264) and the control group (intravenous infusion of Avastin-), and the dose was 3-mg/kg. Peripheral venous blood was collected within 30-minutes before administration, 45-minutes after onset of the administration, immediately after finishing the administration, 2.5, 3.5, 5.5, 9.5, 13.5, 24, 48-hours and on the 5th, 8th, 15th, 22nd, 29th, 36th, 43rd, 57th, 71st, 85th, and 99th days after the administration. The plasma concentration was measured by enzyme-linked immunosorbent assay, the plasma concentration-time curve and its semilogarithmic plot were plotted, and the pharmacokinetic parameters such as the area under the plasma concentration-time curve [including AUC from time zero to the time of the last quantifiable concentration (AUC0-t) and AUC from time zero to infinity (AUC0-∞)], peak concentration (Cmax), time to peak (Tmax), plasma elimination half-life (t1/2), clearance rate (CL), and apparent volume of distribution (Vd) were calculated. When the 90% confidence intervals (CI) of the geometric mean ratio of AUC0-t, AUC0-∞, and Cmax between the trial group and the control group were between 0.80-1.25, it indicated that pharmacokinetics of WBP264 and Avastin- were similar. The physical examination, vital signs detection, electrocardiogram, and laboratory tests were performed on the subjects, the occurrence of adverse events (AEs) and the severity classification were recorded, and correlation between the AEs and the trial drug was evaluated. The anti-drug antibody and its neutralizing antibody were detected before administration and on the 8th, 15th, 29th, 43rd, 71st, and 99th days after administration to evaluate the immunogenicity of the drug. Results A total of 78-subjects were recruited, 39 in the trial group and 39 in the control group. In the trial group, 2 cases withdrew from the trial (1 case did not take the drug and 1 case withdrew for personal reason after taking the drug). Seventy-seven cases were in the safety analysis set and 76 cases in the pharmacokinetic analysis set. The differences in age, height, weight, and body mass index between the 2 groups were not significant (all P>0.05). The plasma concentration-time curves of bevacizumab between the trial group and the control group were similar. The geometric mean ratios (90%CI) of AUC0-t, AUC0-∞, and Cmax were 1.04 (0.98-1.10), 1.03 (0.98-1.10), and 1.09 (1.03-1.14), respectively. The differences in the incidence of overall AEs [89.5% (34/38) vs. 87.2% (34/39)] and the incidence of AEs possibly related to the trial drug [86.8% (33/38) vs. 79.5% (31/39)] between the trial group and the control group were not significant (all P>0.05). Only one case of AE in the trial group was grade 3 in severity and was assessed as being not related to the drug, and the rest were grade 1-2, with grade 1 AEs accounting for the vast majority. The difference in the positive rate of anti-drug antibody between the trial group and the control group was not significant [10.5% (4/38) vs. 10.3% (4/39), P>0.05]. The neutralizing antibody test was negative in the patients with positive anti-drug antibody. Conclusion The pharmacokinetics and safety of WBP264 and Avastin- are similar.
  • Liu Chen, Zhao Hao, Wang Ning, Li Jingjie, Chu Yanqi, Yan Suying
    Adverse Drug Reactions Journal. 2022, 24(8): 404-409.
    Objective To evaluate the efficacy and safety of sodium valproate in the prevention of epileptic seizure during the perioperative period in neurosurgical patients. Methods The medical records in patients, who were treated with sodium valproate during perioperative period in Neurosurgery Department of Xuanwu Hospital, Capital Medical University from March to June 2021, were collected and data including the basic information in patients, use of sodium valproate and the combination drugs, valproic acid blood concentration (reference range: 50-100-mg/L), and adverse reactions was recorded. The effects of the first intravenous dose of valproate and the combination drugs on the blood concentration of valproic acid and the efficacy and safety of sodium valproate in preventing epileptic seizure were analyzed. Results A total of 107 patients were enrolled, including 48 males and 59 females, aged (54±13) years. The median total dose of sodium valproate administered intravenously was 5-600-mg (range: 800-17-600-mg), the median duration of intravenous therapy was 3 days (range: 1-10 days), and the blood concentration of valproic acid was (53.5±19.6) mg/L. The median hospital stay was 16 days (range: 6-49 days) and no patients had seizures during hospitalization. The first intravenous dose of sodium valproate was insufficient in 38.3% (41/107) of the patients and the valproic acid blood concentration and its compliance rate to the reference range in these patients were significantly lower than those in the patients with appropriate first intravenous dose [(43±21)mg/L vs. (60±16)mg/L, P<0.001; 22.0%(9/41) vs. 78.5% (51/65), P<0.001]. Carbapenems was used for 1 day in combination with sodium valproate in 6 patients, 3 of whom had the blood concentration that was lower than the reference range. However the difference in the blood concentration of valproic acid between patients with and without carbapenems use was not statistically significant[(43±26) mg/L vs. (54±19) mg/L, P=0.187]. In the 107 patients, a total of 60 adverse events occurred in 49 patients (45.8%), including hyperammonemia in 33 patients (30.8%) , elevated activated partial thromboplastin time in 12 patients (11.7%), hypofibrino- genemia in 3 patients (2.9%), hyponatremia in 6 patients (5.6%), liver injury in 4 patients (3.7%), and kidney injury and thrombocytopenia in 1 patient (0.9%) each. The severity of adverse reactions was grade 1, 3, and 4 in 39, 9, and 1 patient, respectively. The incidence of serious adverse reactions of grade 3 and above was 9.3% (10/107). Of the 10 patients with serious adverse events, 7 had hyperammonemic encephalopathy, 2 had liver injury, and 1 had hyperammonemic encephalopathy and liver injury. One patient who developed grade 3 adverse reaction died due to primary disease (brain tumor with stroke). Conclusions The use of sodium valproate during perioperative period in neurosurgery patients to prevent epileptic seizures is safe and effective in general, but adverse reactions such as elevated blood ammonia, liver injury, and coagulation dysfunction may occur. Insufficient first intravenous dose and concomitant use of carbapenems may affect the blood concentration of valproic acid, which should be paid attention to.
  • Liu Yumeng, Zhu Baoqiang, Bian Yuan, Long Enwu, Wang Guojun, Hu Jiaqiang
    Adverse Drug Reactions Journal. 2022, 24(12): 617-623.
    Objective To understand the clinical characteristics of rivaroxban- related adverse events (AE) in perioperative patients. Methods The relevant databases at home and abroad (as of April 20, 2020) were searched and the case reports of AE associated with rivaroxban used during perioperative period were collected. Relevant information in patients (nationality, gender, age, medical history, application of rivaroxaban, combined drugs, and the occurrence, treatment, and outcome of AE, etc.) was extracted and analyzed descriptively. Results A total of 42 case reports of AE caused by rivaroxban during perioperative period were collected, involving 46 patients from 11 countries. Of the 46 patients,25 (54.3%) were male and 21 (45.7%) were female with an age of 16-96 years. In terms of the reasons for medication, 34 patients used rivaroxban before operation for prevention of postoperative venous thrombosis, 7 used rivaroxban after operation for prevention atrial fibrillation, stroke, or systemic thrombosis after operation, 4 discontinued rivaroxban during perioperative period, and 1 did not explain the reason for using rivaroxban. Past medical history were described in 21 patients, including hypertension, hyperlipidemia, and diabetes, etc. Combined medication was described in 22 patients, including antibiotics, non-steroidal anti-inflammatory drugs, analgesics, cardiovascular and cerebrovascular drugs, etc. The onset time of AE was recorded in 31 patients, which was 2 hours to 2 months after medication and most within 1 month. AE associated with rivaroxban were bleeding in 29 patients, liver injury in 7 patients, anaphylaxis in 6 patients, kidney injury in 3 patients, thrombosis in 3 patients, thrombocythemia in 2 patients, thrombocytopenia, pulmonary embolism, acute attack of coronary atherosclerotic heart disease, and visual loss in 1 patient each. After the occurrence of AE, 31 patients were improved after rivaroxban withdrawn, switching to other anticoagulants, and receiving symptomatic treatment; 1 patient improved after changing concomitant medications as well as reducing the dose of rivaroxban; 2 patients did not stop the drug in time and developed new allergic reaction; 2 patients were improved after using rivaroxban again; 1 patient died of hemorrhagic shock due to gastrointestinal bleeding; 9 patients′ outcome were unknown. Among the 46 patients, 18-had medication errors, of which 16-had dose error and 2 had compatibility errors. Conclusions Hemorrhage is the most common AE related to rivaroxban in the perioperative use of rivaroxban, which mainly occurs within 1 month after medication. The overall prognosis is good after rivaroxban withdrawal, switching to other anticoagulants, and symptomatic treatment. Medication error is one of the causes of AE related to rivaroxban in perioperative period.
  • Zheng Feilang
    Adverse Drug Reactions Journal. 2023, 25(2): 120-122.
    A 75-year-old male patient with lung cancer received intravenous infusion of sintilimab 200-mg on day 1, 21 days as one cycle. Three days after the 5th cycles of treatment, the patient developed edema of lower limbs and yellowish skin on whole body. Laboratory tests showed alanine aminotransferase (ALT) 914-U/L, aspartate aminotransferase (AST) 622-U/L, alkaline phosphatase (ALP) 385-U/L, total bilirubin (TBil) 152.6-μmo1/L, direct bilirubin (DBil) 87.9-μmol/L, indirect bilirubin (IBil) 64.7-μmol/L and total bile acid (TBA) 25.8-μmol/L. The liver injury caused by other reasons was excluded by laboratory and auxiliary examination, and it was diagnosed as drug-induced liver injury, which was considered to be related to sintilimab. Drugs such as reduced glutathione, compound glycyrrhizin, ademetio- nine, polyene phosphatidylcholine, magnesium isoglycyrrhizinate, and ursodeoxycholic acid successively were given. The patient′s edema of lower limbs and yellowish skin gradually subsided. After 25 days of treatments, laboratory tests showed ALT 33-U/L, AST 33-U/L, ALP 92-U/L, TBil 18.2-μmol/L, DBil 5.2-μmol/L, IBil 13.0-μmol/L, and TBA 7.4-μmol/L.
  • Chen Yanhao, Zhou Xiaobin, Fan Shuang, Wang Xiaodong, Duan Liwei
    Adverse Drug Reactions Journal. 2022, 24(9): 490-491.
    A 62-year-old female osteoporosis patient received alendronate sodium 70-mg orally once a week (taking the drug 30-minutes before breakfast with plenty of water and keeping upright during and after taking drug for a while). After taking the drug for 3 times, the patient developed retrosternal pain on swallowing with occasional acid aversion and epigastric dull pain. Gastroscopy showed multiple shallow ulcers, with yellow and white fur on the surface, in the esophagus 20-cm to 37-cm from the incisors. Esophagitis was considered, which might be related to alendronate sodium. Alendronate was stopped, and the treatments of acid suppression, mucosal repair, proper rehydration, and total liquid intake were given. Two days later, the stabbing pain behind the sternum was relieved; 7 days later, the pain was obviously relieved and symptoms of the acid aversion and epigastric dull pain disappeared; 1 month later, the retrosternal pain on swallowing disappeared.
  • Zhang Lina, Fang Wei, Li Jinfeng, Gao Jian, Wang Bing
    Adverse Drug Reactions Journal. 2022, 24(9): 492-494.
    A 78-year-old female patient was treated with orelabrutinib 100-mg once daily orally due to recurrence of lymphoma. On the 2nd day of treatment, the patient′s fecal occult blood was weakly positive. Three days later, fibrinogen was 0.61-g/L. After intravenous infusion of cryoprecipitated coagulation factor and frozen plasma, the fibrinogen level rose slightly. The patient did not follow the doctor′s advice and took orelabrutinib irregularly, and her fibrinogen level recovered to 1.71-g/L. After further regular treatment with orelabrutinib, her fibrinogen decreased to 0.74-g/L and irregular skin ecchymosis and bleeding spots appeared in the inner side skin of both lower limbs. The fibrinogen in the patient returned to 2.17-g/L after temporary suspension of orelabrutinib and receiving 2 times of intravenous infusion of cold precipitated coagulation factor 10 U, then decreased to 0.94 g/L after reuse of orelabrutinib, and finally recovered to 3.82-g/L after 3 times of intermittent infusion of cold precipitated coagulation factor. It is considered that the hypofibrinogenemia in the patient was caused by orelabrutinib.