Breast cancer is the most common cancer in the world, and 5-year survival rate of metastatic breast cancer is about 20%. The treatment of metastatic breast cancer is mainly chemotherapy, endocrine therapy and targeted therapy. However, after multiline treatment, patients with MBC especially the triple negative breast cancer face the problem of drug resistance. Tumor angiogenesis theory suggests that blocking angiogenesis can inhibit tumor growth and migration. Based on this, angiogenesis treatment strategy is proposed. Antiangiogenic drugs mainly include biological macromolecular drugs targeting vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) and small molecule VEGFR inhibitors. Angiogenesis is known to play a key role in the growth and metastasis of breast cancer. Therefore, anti-angiogenetic therapy has potential in metastatic breast cancer patients. Since the approval of tumor drug indications by NPMA in China is often later than the release of the latest research data, the National Health Commission issued "the guiding principles for the clinical application of new antitumor drugs" in 2020. The principle pointed out that under special circumstances such as the absence of better treatment, medical institutions should manage the usage of drugs that are not clearly defined in the instructions but have evidence-based data. Based on the latest research progress in breast cancer, the consensus writing expert group collated published reports, international academic conferences, conducted analysis, discussion and summary, collected data on the use of small molecule anti-vascular targeting drugs for advanced breast cancer, and formulated "expert consensus on the application of small molecule anti-angiogenic drugs in the treatment of advanced breast cancer" . For clinicians' reference only.
Angiogenesis Inhibitors/therapeutic use* ; Breast Neoplasms/pathology* ; Consensus ; Female ; Humans ; Neovascularization, Pathologic/pathology* ; Off-Label Use ; Vascular Endothelial Growth Factor A/metabolism*

Objective: To understand the current situation regarding pediatric off-label use of drugs recommendations in Chinese clinical practice guidelines and to make recommendations for standardized reporting format regarding off-label use of drugs for children. Methods: This cross-sectional study was carried out by systematically searching the databases for Chinese guideline consensus articles published in journals between 2018 and 2020 and extracting recommendations regarding off-label use of drugs from those articles. The essential characteristics of the included guidelines, the ranking of off-label drug types, the order of drug information, the type of off-label drug use, and the percentage of citation studies on which the recommendations were based were analyzed. Results: Among 108 studies that included Chinese off-label guidelines and consensus, 364 recommendations on pediatric off-label use of drugs were included. The Chinese Medical Association published the most, 48 out of the 108 studies (44.4%), and of those 14 studies (13.0%) were on infectious and parasitic diseases. Of the 364 recommendations on off-label use of drugs, the most commonly addressed drugs were 16 recommendations (4.4%) for cyclosporine A, 11 recommendations (3.0%) for methotrexate , and 11 recommendations (3.0%) for fentanyl. The most commonly addressed drug categories were as follows: 68 recommendations (18.6%) were immune system drugs, 66 recommendations (18.1%) were anti-infectives, and 56 recommendations (15.4%) were oncology drugs. The most commonly addressed drug information accounts were as follows: 364 recommendations (100.0%) were indications, 204 recommendations (56.0%) were dosages, and 198 recommendations (54.4%) were the route of administration. Based on the instructions approved by the Chinese Food and Drug Administration, the main forms of the off-label drug were as follows: 175 recommendations (48.1%) were unapproved indications, 127 recommendations (34.9%) were unapproved populations, and 72 recommendations (19.8%) were unapproved ages. Only 129 recommendations (35.4%) were cited, mainly including clinical guidelines (48 studies, 23.4%), reviews (22 studies, 10.7%), and pediatric randomized controlled trials (22 studies, 10.7%). Conclusions: Off-label use of drugs is commonly recommended in pediatric guidelines and consensus documents written by Chinese authors. However, the reporting of the recommendations varies widely, and the quality of the supporting evidence is poor.
Child ; China ; Consensus ; Cross-Sectional Studies ; Humans ; Off-Label Use ; Pharmaceutical Preparations

PURPOSE: Label adherence for non-vitamin K antagonist oral anticoagulants (NOACs) has not been well evaluated in Asian patients with non-valvular atrial fibrillation (AF). The present study aimed to assess label adherence for NOACs in a Korean AF population and to determine risk factors of off-label prescriptions of NOACs. MATERIALS AND METHODS: In this COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, patients with AF who were prescribed NOACs between June 2016 and May 2017 were included. Four NOAC doses were categorized as on- or off-label use according to Korea Food and Drug Regulations. RESULTS: We evaluated 3080 AF patients treated with NOACs (dabigatran 27.2%, rivaroxaban 23.9%, apixaban 36.9%, and edoxaban 12.0%). The mean age was 70.5±9.2 years; 56.0% were men; and the mean CHA₂DS₂-VASc score was 3.3±1.4. Only one-third of the patients (32.7%) was prescribed a standard dose of NOAC. More than one-third of the study population (n=1122, 36.4%) was prescribed an off-label reduced dose of NOAC. Compared to those with an on-label standard dosing, patients with an off-label reduced dose of NOAC were older (≥75 years), women, and had a lower body weight (≤60 kg), renal dysfunction (creatinine clearance ≤50 mL/min), previous stroke, previous bleeding, hypertension, concomitant dronedarone use, and anti-platelet use. CONCLUSION: In real-world practice, more than one-third of patients with NOAC prescriptions received an off-label reduced dose, which could result in an increased risk of stroke. Considering the high risk of stroke in these patients, on-label use of NOAC is recommended.
Anticoagulants ; Asian Continental Ancestry Group ; Atrial Fibrillation ; Body Weight ; Cohort Studies ; Drug and Narcotic Control ; Drug Labeling ; Female ; Hemorrhage ; Humans ; Hypertension ; Korea ; Male ; Off-Label Use ; Prescriptions ; Prospective Studies ; Risk Factors ; Rivaroxaban ; Stroke

Over the last two decades, the systemic treatment of cancer has evolved from cytotoxic chemotherapy to targeted therapy and now immunotherapy. Next-generation sequencing (NGS) is entering clinical applications for cancer treatment through the help of more powerful computational analyses. The increasing number of targeted therapies approved by regulatory authorities (RAs) with or without biomarkers necessitates the screening of multiple biomarkers using NGS, which is now approved and reimbursed by Korean RAs for some types of malignancies. However, the clinical utility of NGS remains to be established as a prerequisite for its routine incorporation into clinical practice. Currently, the best scenario of NGS use in clinics is to enroll patients into clinical trials based on the detection of biomarkers, but this is only possible in the hospitals conducting the specific trial. The other scenario is the off-label use of a targeted drug, but this requires social consensus for future implementation. The clinical applications of NGS are expanding in terms of its platforms, from targeted sequencing to whole exome and RNA sequencing, and in terms of systemic therapy, from targeted therapy to immunotherapy. Research into tumor mutational burden and neoantigens is shedding new light on the clinical use of NGS in immunotherapy.
Biomarkers ; Consensus ; Drug Therapy ; Exome ; Humans ; Immunotherapy ; Mass Screening ; Off-Label Use ; Sequence Analysis, RNA

OBJECTIVE: This study was conducted to determine the effectiveness and safety of medical treatment with sublingual misoprostol (MS) in the 1st trimester miscarriage under the approval by Health Insurance Review and Assessment Service (HIRA) for off-label usage by the single medical center in Korea. METHODS: A retrospective cohort study was performed in one institution between April 2013 and June 2016. Ninety-one patients diagnosed with miscarriage before 14 weeks of gestation and wanted to try medical treatment were included. A detailed ultrasound scan was performed to confirm the diagnosis. Patients took 600 microgram (mcg) of MS sublingually at initial dose, and repeated the same dose 4–6 hours apart. Successful medical abortion was defined as spontaneous expulsion of gestational products (including gestational sac, embryo, fetus, and placenta). If gestational products were not expelled, surgical evacuation was performed at least 24 hours later from the initial dose. Information about side effects was obtained by medical records. RESULTS: About two-thirds of patients had a successful outcome. The median interval time from pill to expulsion was 18 hours in the successful medical treatment group. There was no serious systemic side effect or massive vaginal bleeding. Presence or absence of vaginal spotting before diagnosis of miscarriage, uterine leiomyomas, subchorionic hematoma, or distorted shape of gestational sac on ultrasound scan were not statistically different between the two groups. CONCLUSION: Medical treatment with sublingual MS can be a proper option for the 1st trimester miscarriage, especially for the patient who want to avoid surgical procedure. We can reduce the unnecessary sedation or surgical intervention in the patients with the 1st trimester miscarriage.
Abortion, Incomplete ; Abortion, Missed ; Abortion, Spontaneous* ; Administration, Sublingual ; Cohort Studies ; Diagnosis ; Embryonic Structures ; Female ; Fetus ; Gestational Sac ; Hematoma ; Humans ; Insurance, Health ; Korea* ; Leiomyoma ; Medical Records ; Metrorrhagia ; Misoprostol* ; Off-Label Use* ; Pregnancy ; Retrospective Studies ; Ultrasonography ; Uterine Hemorrhage

BACKGROUND: The aim of this study was to explore the use of off-label/unlicensed drugs to confirm the safety and efficacy of their prescription in children in Korea. METHODS: In this retrospective study, we analyzed data of patients who received any of the 32 drugs between January–December 2014 in tertiary hospitals in Korea, including demographics, diagnoses, reasons for the medication, administration route, and details of adverse drug reactions. Additionally, the mortality in the cohort was assessed. The primary outcomes were efficacy and safety, including mortality, of these drugs in pediatric patients. The secondary outcomes were the current statuses of the use of off-label/unlicensed drugs in two centers. RESULTS: Totally, 5,130 prescriptions were found in 2,779 patients. Age (73.5%) and indication (11.7%) were the most frequent reasons for prescriptions being off-labeled/unlicensed. Approximately 88% of the prescriptions were effective, and 19% of the patients developed adverse drug reactions. The number of prescriptions was significantly higher in children with adverse drug reactions than it was in those without (2.8 vs. 1.5; P < 0.001). The number of prescribed off-label/unlicensed medicines and age at prescription were independently associated with adverse drug events (odds ratio, 1.55 and 1.1; P < 0.001 and 0.034, respectively). CONCLUSION: Children are still prescribed medicines that are not authorized in terms of age, weight, indications, or routes of administration. Therefore, many old products require re-assessment of authorization. More prospective clinical studies should be performed to confirm the efficacy and safety of drugs in the pediatric population.
Child* ; Cohort Studies ; Demography ; Diagnosis ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Korea ; Mortality ; Off-Label Use ; Pediatrics ; Prescriptions ; Prospective Studies ; Retrospective Studies ; Tertiary Care Centers

BACKGROUND: Everolimus-eluting stent (EES) implantations have a relatively low rate of major adverse cardiac event (MACE) and target lesion revascularization (TLR) in patients with off-label use. However, the clinical outcome in the Korean population regarding EES in patients with off-label use is not well known. OBJECTS: The aim of the current analysis was to compare the clinical outcomes of on-label and off-label EES use over a 2-year follow-up period. METHODS: Using patient-level data from a stent-specific, prospective, all-comer registry, we evaluated 987 patients (1,342 lesions) who received an EES (XIENCE V®, Abbott Vascular, Santa Clara, CA, USA) implantation between February 2009 and April 2011. The primary outcome was assessed: 2-year MACE (a composite endpoint of death from any cause, spontaneous myocardial infarction (MI), and any repeat revascularization). The clinical outcomes in the on- and off-label groups were compared at 2 years. RESULTS: The majority of patients (79.0%) were treated for ≥1 off-label indication. The median duration of the clinical follow-up in the overall population was 2.0 years (interquartile range 1.9–2.1). At 2-years after the EES implantation in the enrolled patients, MACE occurred in 71 (7.9%) patients, cardiac death in 12 (1.3%), MI in 4 (0.5%), target vessel revascularization (TVR) in 33 (3.8%), TLR in 22 (2.5%), and definite or probable stent thrombosis (ST) in 1 (0.1%). Off-label EES implantations tend to increase the risk of 2-year MACE (4.7% vs. 8.8%, p = 0.063) without statistical significance. However, the rates of TLR were higher in the off-label EES implantations (0.0% vs. 3.2%, p = 0.013). In the multivariable analysis, renal failure, previous bypass surgery, previous cerebrovascular accident, and left main lesions were associated with 2-year MACE in patients with EES implantations. CONCLUSIONS: The incidence of 2-year MACE was 7.9%, which that might be acceptable in all-comer patients treated with EES implantations. Although the off-label use of EES was not statistically associated with an increased risk of MACE, the TLR rate was higher in the off-label group, suggesting that physicians need to pay attention to high risk patients with the use of EES implantations.
Coronary Artery Disease ; Death ; Drug-Eluting Stents* ; Follow-Up Studies ; Humans ; Incidence ; Myocardial Infarction ; Off-Label Use ; Prospective Studies ; Renal Insufficiency ; Stents* ; Stroke ; Thrombosis

After new drugs are introduced into an area of medical practice through the regulatory approval process, clinicians gain further experience using the drugs and amass real-world evidence regarding their efficacy. For these reasons, drugs can be prescribed in contexts extending beyond their labeled indication, dosage, or route because of unmet needs or additional benefits, such as cost-effectiveness. Off-label drug use (OLDU) is widespread in various clinical fields, especially in pediatrics, obstetrics, psychiatry, and oncology; however, the small amount of supporting evidence associated with increased adverse drug events has emerged as an important issue regarding OLDU. Nonetheless, OLDU has officially been allowed in South Korea by an announcement of the Ministry of Health and Welfare, a public announcement of the Health Insurance Review and Assessment Service for cancer drugs, and through submissions to the Health Insurance Review and Assessment Service by hospitals after receiving institutional review board approval. Despite these systems, the proper scope of OLDU has been a topic of debate. In order to improve the appropriateness of OLDU, a transparent system for evidence-based recommendations, conditional decision-making, and monitoring of adverse drug events should be established and organized in collaboration with existing systems to promote consistent decision-making.
Cooperative Behavior ; Drug-Related Side Effects and Adverse Reactions ; Ethics Committees, Research ; Evidence-Based Medicine ; Insurance, Health ; Korea ; Obstetrics ; Off-Label Use ; Patient Safety ; Pediatrics

The introduction of intravenous nutritional therapy for cosmetic and health purposes in Korea has been controversial. Because it brings ethical problems of off-label prescribing on the basis of low level of medical evidences for claims of fatigue reduction, detoxification, anti-inflammation effect, skin whitening, antioxidant and anti-aging effects. Despite the lack of clinical studies, the verification of the efficacy and safety of intravenous nutritional therapy and the need to provide objective information to patients are prerequisite for the correct intravenous use. In addition, efforts should be made to prevent the abuse for commercial purposes.
Fatigue ; Fursultiamin ; Glutathione ; Glycyrrhizic Acid ; Humans ; Korea ; Off-Label Use ; Skin ; Thioctic Acid

Antidepressant prescription for youths has recently been on the increase. There is a growing concern over the increasing off-label usage of antidepressants. Current data on off-label antidepressant usage vary across countries and healthcare systems. Therefore, we examined the extent and pattern of antidepressant prescription for Korean children and adolescents using population-based data. Our data was retrieved from the Korean National Health Insurance Service National Sample Cohort of the year 2013. Among 0.2 million children and adolescents aged 6–18 years from the cohort, subjects who had received any antidepressant medication in the year 2013 were investigated for the prescribed medication, concomitant psychotropic medication, and the associated diagnosis. A total of 2,190 children and adolescents (boys, 55.4%) received antidepressant medication. The most common diagnosis was depressive disorders (n = 469, 21.4%), followed by attention-deficit/hyperactivity disorder (n = 442, 20.2%). Among the prescriptions (n = 3,370), escitalopram (n = 650, 24.1%) and fluoxetine (n = 553, 20.5%) were the two most frequently prescribed drugs. A majority of prescriptions (n = 2,039, 60.5%) included concomitant psychotropic agents, consisting of antipsychotics (n = 901, 26.7%), sedatives (n = 263, 26.3%), medication for attention-deficit/hyperactivity disorder (n = 822, 24.4%), and some others. Our study shows the prescription pattern of antidepressants for children and adolescents in Korea, of which a large proportion is off-label. The results call for close monitoring by clinicians treating this population.
Adolescent* ; Antidepressive Agents* ; Antipsychotic Agents ; Child* ; Citalopram ; Cohort Studies ; Delivery of Health Care ; Depressive Disorder ; Diagnosis ; Fluoxetine ; Humans ; Hypnotics and Sedatives ; Korea* ; National Health Programs ; Off-Label Use ; Prescriptions*