Adverse Event Reporting System (KIDS-KAERS) database, a nationwide database of adverse events reports, between January 2008 and December 2017 to investigate the reporting count of all drug eruptions and calculated the ratio of DRESS/SJS/TEN reports for each AED.RESULTS: Among a total of 2,942 reports, most were of rash/urticaria (2,702, 91.8%), followed by those of DRESS (109, 3.7%), SJS (106, 3.6%), and TEN (25, 0.85%). The common causative AEDs were lamotrigine (699, 23.8%), valproic acid (677, 23%), carbamazepine (512, 17.4%), oxcarbazepine (320, 10.9%), levetiracetam (181, 6.2%), and phenytoin (158, 5.4%). In limited to severe drug eruptions (DRESS, SJS, and TEN; total 241 reports), the causative AEDs were carbamazepine (117, 48.8%), lamotrigine (57, 23.8%), valproic acid (20, 8.3%), phenytoin (15, 6.3%), and oxcarbazepine (10, 4.2%). When comparing aromatic AED with non-aromatic AED, aromatic AEDs were more likely to be associated with severe drug eruption (aromatic AEDs: 204/1,793 versus non-aromatic AEDs: 37/1,149; OR, 3.86; 95% CI, 2.7–5.5). Death was reported in 7 cases; DRESS was the most commonly reported adverse event (n = 5), and lamotrigine was the most common causative AED (n = 5).CONCLUSION: Although most cutaneous drug eruptions in this study were rash or urticaria, approximately 8% of reports were of severe or life-threatening adverse drug reactions, such as SJS, TEN, or DRESS. When hypersensitivity skin reactions occurred, aromatic AEDs were associated with 4 fold the risk of SJS/TEN/DRESS compared with non-aromatic AEDs. Our findings further emphasize that high risk AEDs should be prescribed under careful monitoring, and early detection and prompt interventions are needed to prevent severe complications.]]>
Anticonvulsants ; Carbamazepine ; Drug Eruptions ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions ; Exanthema ; Hypersensitivity ; Korea ; Pharmacovigilance ; Phenytoin ; Risk Management ; Skin ; Stevens-Johnson Syndrome ; Urticaria ; Valproic Acid

PURPOSE: Despite morbidities and fatalities, nationwide epidemiologic data for severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), are not widely available. We aimed to investigate SCAR epidemiology over the last two decades in Korea. MATERIALS AND METHODS: We analyzed individual case safety reports (ICSRs) of SCARs in the Korea Adverse Event Reporting System from 1988 to 2013. Administered drugs, demographic profiles, and causality assessment according to the World Health Organization-Uppsala Monitoring Center system were analyzed. RESULTS: A total of 755 SCAR cases (508 SJS/TEN, 247 DRESS) were reported. The number of SCAR ICSRs has been increasing with increasing ICSRs for overall adverse drug events. Since 2010, the number of SCAR ICSRs has increased up to 100 cases/year. Allopurinol was the most common causative drug (SJS/TEN: 10.2%; DRESS: 11.3%; SCAR ICSRs: 10.6%), followed by carbamazepine (SJS/TEN: 8.7%; DRESS: 9.7%; SCAR ICSRs: 8.6%). Regarding drug groups, antiepileptics (19.5%) and antibiotics for systemic use (12.7%) were common causative drug groups. Twenty SCAR-related deaths were recorded. Antibacterials were the most common causes of deaths (8 cases), followed by antiepileptics (5 cases). The potential risk of SCARs was not specified in the drug information leaflet for 40.2% of drugs causing SJS/TEN and 82.5% causing DRESS syndrome in Korea. CONCLUSION: The number of SCAR ICSRs has increased rapidly with recent active pharmacovigilance programs in Korea. Allopurinol and antiepileptics are the most common individual and categorical causative agents, respectively.
Allopurinol ; Anti-Bacterial Agents ; Anticonvulsants ; Carbamazepine ; Cause of Death ; Cicatrix ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions ; Epidemiology ; Global Health ; Korea ; Pharmacovigilance ; Stevens-Johnson Syndrome

Adverse drug reactions can cause considerable discomfort. They can be life-threatening in severe cases, requiring or prolonging hospitalization, impeding proper treatment, and increasing treatment costs considerably. Although the incidence of severe cutaneous adverse reactions (SCARs) is low, they can be serious, have permanent sequelae, or lead to death. A recent pharmacogenomic study confirmed that genetic factors can predispose an individual to SCARs. Genetic markers enable not only elucidation of the pathogenesis of SCARs, but also screening of susceptible subjects. The human leukocyte antigen (HLA) genotypes associated with SCARs include HLA-B*57:01 for abacavir (Caucasians), HLA-B*58:01 for allopurinol (Asians), HLA-B*15:02 (Han Chinese) and HLA-A*31:01 (Europeans and Koreans) for carbamazepine, HLA-B*59:01 for methazolamide (Koreans and Japanese), and HLA-B*13:01 for dapsone (Asians). Therefore, prescreening genetic testing could prevent severe drug hypersensitivity reactions. Large-scale epidemiologic studies are required to demonstrate the usefulness and cost-effectiveness of screening tests because their efficacy is affected by the genetic differences among ethnicities.
Allopurinol ; Carbamazepine ; Cicatrix ; Dapsone ; Drug Hypersensitivity ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions ; Epidemiologic Studies ; Genetic Markers* ; Genetic Testing ; Genotype ; Health Care Costs ; HLA Antigens ; Hospitalization ; Humans ; Incidence ; Leukocytes ; Mass Screening ; Methazolamide ; Pharmacogenetics ; Stevens-Johnson Syndrome

PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea. MATERIALS AND METHODS: We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01. RESULTS: HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03. CONCLUSION: HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN.
Adult ; Aged ; *Alleles ; Allopurinol/adverse effects/*pharmacology ; Anticonvulsants/*adverse effects ; Asian Continental Ancestry Group/*genetics ; Carbamazepine/adverse effects/*pharmacology ; Case-Control Studies ; Drug-Related Side Effects and Adverse Reactions/*genetics/immunology ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; HLA-B Antigens/*genetics ; Humans ; Male ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Stevens-Johnson Syndrome/ethnology/etiology/*genetics ; Triazines/adverse effects/*pharmacology

Ataxia ; Carbamazepine ; analogs & derivatives ; therapeutic use ; Carcinoma ; Central Nervous System ; pathology ; Diagnosis, Differential ; Female ; Gait ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Nasopharyngeal Neoplasms ; complications ; radiotherapy ; Nervous System Diseases ; complications ; diagnosis ; Radiotherapy ; adverse effects ; Seizures ; complications ; diagnosis ; Siderosis

Oxcarbazepine is a new antiepileptic drug. The results of clinical trials suggest that oxcarbazepine is well tolerated and has less drug interactions. It is being used more and more widely in clinical practice, but its adverse effects should not be ignored. The most common adverse effects of oxcarbazepine are usually related to the central nervous system and digestive system, including fatigue, drowsiness, diplopia, dizziness, nausea and vomit. The common skin adverse reaction is rash. Long-term use of oxcarbazepine may also cause hyponatremia. This article reviews the literature from China and overseas about the adverse effets of oxcarbazepine over the last 10 years in order to find information about rational clinical use of oxcarbazepine.
Anticonvulsants ; adverse effects ; Carbamazepine ; adverse effects ; analogs & derivatives ; Exanthema ; chemically induced ; Humans ; Hyponatremia ; chemically induced

BACKGROUND: In Vietnam, we observed a high incidence of carbamazepine (CBZ)-induced severe cutaneous adverse drug reactions (SCARs)-Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity rash with eosinophilia and systemic symptoms (DRESS). In other Asian countries, HLA-B*1502 is an established risk factor for SCARs. OBJECTIVE: The aim of our study was to determine the frequency of HLA-B*1502 in SCARs patients at a large University Medical Center in Hanoi, Vietnam. METHODS: Thirty-eight cases of SCARs caused by CBZ and 25 patients with epilepsy tolerating CBZ were enrolled in a case-controlled study. Clinical manifestations and laboratory findings were recorded for each subject. Genomic DNA was isolated using the QIAamp DNA purification system. The combination of polymerase chain reaction and sequence specific oligonucleotide probes with the Luminex 100×MAP flow cytometry dual laser system was then used to quantitate fluorescently labelled oligonucleotides attached to colour-coded microbeads. RESULTS: Cases comprised 20 SJS (52.6%), 7 TEN (18.4%), 8 overlap syndrome (21.1%), and 3 DRESS patients (7.9%). A strong association between HLA B*1502 and bullous skin reactions such as SJS/TEN and overlap was confirmed with an odds ratio (OR) of 33.78 (95% confidence interval [CI], 7.55-151.03), p < 0.0001, Sensitivity 91.4%, Specificity 76.0%, positive predictive value 84.2%, and negative predictive value 86.4%. We did not, however, observe any correlation between the presence of this allele and CBZ-induced nonbullous skin reactions (DRESS) (OR, 6.33; 95% CI, 0.48-82.74; p = 0.1592). CONCLUSION: Our results indicate the presence of HLA-B*1502 in Vietnamese is a pharmacogenetic risk factor for developing CBZ-induced SJS/TEN.
Academic Medical Centers ; Alleles ; Asian Continental Ancestry Group ; Carbamazepine ; Case-Control Studies ; Cicatrix ; DNA ; Drug-Related Side Effects and Adverse Reactions ; Eosinophilia ; Epilepsy ; Exanthema ; Flow Cytometry ; HLA-B Antigens ; Humans ; Hypersensitivity ; Incidence ; Microspheres ; Odds Ratio ; Oligonucleotide Probes ; Oligonucleotides ; Pharmacogenetics ; Polymerase Chain Reaction ; Risk Factors ; Sensitivity and Specificity ; Skin ; Vietnam

BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous adverse reactions (SCARs) that also affect the internal organs with high mortality. However, there has been no previous nationwide study of SCARs in Korea. METHODS: Cases of SCARs were recruited from the nationwide Korean Pharmacovigilance Research Network database, collected from June 2009 to December 2010, by a spontaneous reporting system. We analyzed age, gender, route of administration and the causative agents. We also reviewed previously published cases of SCARs in Korea. RESULTS: In total, 100 cases of SJS (66 cases), TEN (7 cases), and DRESS (27 cases) were reported. The mean age of the patients was 54.1 +/- 19.8 years and the proportion of males to females was 1:0.88. In total, 81 drugs were reported as causative agents: SJS (61 drugs), TEN (15 drugs), and DRESS (29 drugs). The most commonly reported causative drug was allopurinol (12 cases). Allopurinol (8 cases) and levofloxacin (2 cases) were the most commonly reported causative drugs for SJS and TEN, respectively. In DRESS, allopurinol (4 cases) and vancomycin (4 cases) were the two most common causative drugs. Anti-infective drugs were the most common drug category (75 cases). Carbamazepine was the most commonly reported causative drug according to published cases in Korea. CONCLUSIONS: Allopurinol in the spontaneous reporting system and carbamazepine in the published cases were the most common single causative drugs in SCARs in Korea. Anti-infectives were the most common drug category in the spontaneous reporting system.
Allopurinol ; Carbamazepine ; Cicatrix ; Drug Hypersensitivity ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions* ; Eosinophilia ; Female ; Humans ; Korea ; Levofloxacin ; Male ; Mortality ; Pharmacovigilance ; Stevens-Johnson Syndrome ; Vancomycin

Nefopam (NFP) is a non-opioid, non-steroidal, centrally acting analgesic drug that is derivative of the non-sedative benzoxazocine, developed and known in 1960s as fenazocine. Although the mechanisms of analgesic action of NFP are not well understood, they are similar to those of triple neurotransmitter (serotonin, norepinephrine, and dopamine) reuptake inhibitors and anticonvulsants. It has been used mainly as an analgesic drug for nociceptive pain, as well as a treatment for the prevention of postoperative shivering and hiccups. Based on NFP's mechanisms of analgesic action, it is more suitable for the treatment of neuropathic pain. Intravenous administration of NFP should be given in single doses of 20 mg slowly over 15-20 min or with continuous infusion of 60-120 mg/d to minimize adverse effects, such as nausea, cold sweating, dizziness, tachycardia, or drowsiness. The usual dose of oral administration is three to six times per day totaling 90-180 mg. The ceiling effect of its analgesia is uncertain depending on the mechanism of pain relief. In conclusion, the recently discovered dual analgesic mechanisms of action, namely, a) descending pain modulation by triple neurotransmitter reuptake inhibition similar to antidepressants, and b) inhibition of long-term potentiation mediated by NMDA from the inhibition of calcium influx like gabapentinoid anticonvulsants or blockade of voltage-sensitive sodium channels like carbamazepine, enable NFP to be used as a therapeutic agent to treat neuropathic pain.
Administration, Intravenous ; Administration, Oral ; Analgesia ; Analgesics, Non-Narcotic ; Anticonvulsants ; Antidepressive Agents ; Calcium ; Carbamazepine ; Dizziness ; Drug-Related Side Effects and Adverse Reactions ; Hiccup ; Long-Term Potentiation ; Molecular Mechanisms of Pharmacological Action ; N-Methylaspartate ; Nausea ; Nefopam* ; Neuralgia* ; Neurotransmitter Agents ; Nociceptive Pain ; Norepinephrine ; Shivering ; Sleep Stages ; Sodium Channels ; Sweat ; Sweating ; Tachycardia

Drug allergy exhibits a wide range of clinical features that partly reflect the diversity of the underlying responsible mechanisms. These range from non-immunologic idiosyncratic reactions to Gell and Coombs type 1, 2, 3, and 4 reactions. Consequently, a drug allergy may be difficult to differentiate from an adverse drug reaction. The prevalence of drug allergy varies but is assumed to account for 30% of all adverse drug reactions. In the U.S., 3.1-6.2% of all ward patients are admitted because of adverse drug reactions, and 5-10% of all out-patients or ward patients have suffered an adverse drug reaction. Nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and radiocontrast media are the most common causes of drug allergy, but with the recent introduction of molecular anti-cancer agents, the number of drug allergy cases by these agents is soaring. Drug allergy is an important cause of mortality in admitted patients, and 1 out of every 10,000 admitted patients will die because of a drug allergy. Approximately 30% of adverse drug reactions can be prevented if previous reactions have been monitored and managed adequately. In 2006, a regional pharmacovigilance program was launched in Korea. In addition, the Korean Institute of Drug Safety and Risk Management plans to develop a nationwide drug utilization review program to monitor adverse drug reactions and to provide relevant information from the program to health professionals working in hospitals and clinics, with the aim of preventing drug allergies. Recent studies have shown a strong association between human leukocyte antigen genotypes and the severe cutaneous adverse reactions (SCARs) induced by certain drugs. Genotype prescreening may contribute to the prevention of SCARs induced by culprit drugs such as carbamazepine, allopurinol, and abacavir.
Allopurinol ; Anti-Bacterial Agents ; Carbamazepine ; Cicatrix ; Contrast Media ; Drug Hypersensitivity* ; Drug Utilization Review ; Drug-Related Side Effects and Adverse Reactions ; Genotype ; Health Occupations ; Humans ; Korea ; Leukocytes ; Mortality ; Outpatients ; Pharmacovigilance ; Prevalence ; Risk Management