Clozapine-Associated Agranulocytosis: A Systematic Review. Is It Really So Frighteningly Common?

BACKGROUND: Clozapine is a very effective therapeutic option for schizophrenic disorders that have been refractory to most other therapies. This extremely positive aspect clashes easily with an adverse effect of the drug that is deemed to be a very dangerous one: agranulocytosis. We asked whether the mandatory strict hematological follow-up prescribed in the black box warning of clozapine's label is proportioned to the actual incidence of agranulocytosis, considering that is the main reason that such a drug is often used only late in the treatment course. METHODS: We carried out a systematic review of reports examining clozapine administration and agranulocytosis incidence. We specifically selected those where mild and moderate neutropenia was not used as a trigger to stop administration of clozapine, to better estimate the sheer incidence of agranulocytosis when clozapine was continued even with mild hematological effect, where detected. We used PubMed, MEDLINE, EMBASE, Cochrane, and ScienceDirect databases to identify clinical studies conducted between January 1975 and April 2023. RESULTS: We included 14 studies, mostly retrospective ones, that examined the incidence of hematological adverse effects in patients using clozapine. A total of 2354 subjects were included. The mean age of the subjects was 33.5 years. The mean duration of observation of subjects who took clozapine was 800 days, with a mean daily dose of 319.5 mg per day. Of the 2354 subjects examined, we found that 11 of them experienced agranulocytosis (0.47%). CONCLUSIONS: These results suggest the evidence of a lower incidence of agranulocytosis than previously estimated and are in line with more recent meta-analyses. We may therefore think that clinical practice may demand a revision of the approach that both psychiatrists and supervising organizations often take when talking about clozapine.

Characterizing Granulocytopenia Associated with Thiamazole in Patients with Hyperthyroidism Based on Real-World Data from the MID-NET in Japan.

Despite the requirement of routine blood tests during thiamazole treatment in Japan, granulocytopenia among patients treated with thiamazole has been occasionally reported to the Pharmaceuticals and Medical Devices Agency (PMDA). To characterize granulocytopenia in patients with thiamazole in Japan, the effects of routine blood tests were examined in a cohort of new users of thiamazole or propylthiouracil utilizing the MID-NET. The occurrence of granulocytopenia (neutrophil count ≤ 1,500/µL) in a given period was compared between patients with and without blood test results prior to the period. The trend in neutrophil count during thiamazole treatment was also compared between patients with and without granulocytopenia. A nested case-control study based on the cohort was conducted to identify potential risk factors for granulocytopenia during thiamazole treatment. In the new user cohort including 4,371 patients treated with thiamazole, the occurrence of granulocytopenia in patients who had undergone blood tests at all previous periods was similar or higher than that among those who had not undergone blood test in all previous periods (e.g., adjusted odds ratio in period 2 was 1.63). The neutrophil count was relatively lower in the group of patients with granulocytopenia even before the occurrence of granulocytopenia. In a nested case-control study, an upward tendency of the risk was observed when a patient was co-prescribed anti-arrhythmic drugs or antiulcer drugs with thiamazole. The characteristics of granulocytopenia during thiamazole treatment elucidated in this study should be recognized in clinical practice for the proper use of thiamazole.

Detection of drug safety signal of drug-induced neutropenia and agranulocytosis in all-aged patients using electronic medical records.

PURPOSE: We explored the adverse drug reaction signals of drug-induced neutropenia (DIN) and drug-induced agranulocytosis (DIA) in hospitalized patients and evaluated the novelty of these correlations. METHOD: A two-step method was established to identify the relationship between drugs and DIN or DIA using 5-year electronic medical records (EMRs) obtained from 242 000 patients at Qilu Hospital of Shandong University. First, the drugs suspected to induce DIN or DIA were selected. The associations between suspected drugs and DIN or DIA were evaluated by a retrospective cohort study using unconditional logistic regression analysis and multiple linear regression model. RESULTS: Twelve suspected drugs (vancomycin, meropenem, voriconazole, acyclovir, ganciclovir, fluconazole, oseltamivir, linezolid, compound borax solution, palonosetron, polyene phosphatidylcholine, and sulfamethoxazole) were associated with DIN, and six suspected drugs (vancomycin, voriconazole, acyclovir, ganciclovir, fluconazole, and oseltamivir) were associated with DIA. The multivariate linear regression model revealed that nine drugs (vancomycin, meropenem, voriconazole, ganciclovir, fluconazole, oseltamivir, compound borax solution, palonosetron, and polyene phosphatidylcholine) and four drugs (vancomycin, voriconazole, ganciclovir, and fluconazole) were found to be associated with DIN and DIA, respectively. While logistic regression analysis revealed that palonosetron and ganciclovir were associated with DIN and DIA, respectively. CONCLUSION: Palonosetron and ganciclovir were found to be correlated with drug-induced granulocytopenia. The results of this study provide an early warning of drug safety signals for drug-induced granulocytopenia, facilitating a quick and appropriate response for clinicians.

Thionamide-induced Agranulocytosis: A Retrospective Analysis of 36 Patients With Hyperthyroidism.

OBJECTIVE: Agranulocytosis is a rare but serious adverse drug reaction (ADR) of thionamide antithyroid drugs (ATDs). We explored the characteristics of ADRs in patients with hyperthyroidism. METHODS: This retrospective study included 3558 inpatients with Graves disease treated in a Class A Grade 3 hospital between 2015 and 2019. The clinical presentation and laboratory workup of patients with antithyroid drug (ATD)-induced agranulocytosis was analyzed. RESULTS: Agranulocytosis was thought to be caused by ATDs in 36 patients. The hospital length of stay was 12 (10-16) days, and hospitalization costs were approximately $2810.89 ($2156.50-$4164.67). The median duration of ATD therapy prior to agranulocytosis development was 30 (20-40) days. Fever (83.33%) and sore throat (75%) were the most common symptoms as early signs of agranulocytosis. The lowest neutrophil counts were 0.01 (0.00-0.03) × 109/L and 0.14 (0.02-0.29) × 109/L in the methimazole and propylthiouracil groups, respectively (P = .037). The recovery times of agranulocytosis were 9.32 ± 2.89 days and 5.60 ± 4.10 days in the methimazole and propylthiouracil groups, respectively (P = .016). Patients with severe agranulocytosis required a longer time to recover (P < .001) and had closer to normal serum thyroxine and triiodothyronine levels. The interval between the first symptom of agranulocytosis and ATD withdrawal was 1 (0-3) day. CONCLUSIONS: Patients with agranulocytosis needed a long hospital length of stay and incurred high costs. Methimazole was prone to causing a more serious agranulocytosis than propylthiouracil. High thyroid hormone was unlikely to play a role in adverse drug reactions. Patient education is important.

Silent existence of eosinopenia in sepsis: a systematic review and meta-analysis.

BACKGROUND: Sepsis is a life-threatening and time-critical medical emergency; therefore, the early diagnosis of sepsis is essential to timely treatment and favorable outcomes for patients susceptible to sepsis. Eosinopenia has been identified as a potential biomarker of sepsis in the past decade. However, its clinical application progress is slow and its recognition is low. Recent studies have again focused on the potential association between Eosinopenia and severe infections. This study analyzed the efficacy of Eosinopenia as a biomarker for diagnosis of sepsis and its correlation with pathophysiology of sepsis. METHOD: The protocol for this meta-analysis is available in PROSPERO (CRD42020197664). We searched PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials CENTRAL databases to identify studies that met the inclusion criteria. Two authors performed data extraction independently. The pooled outcomes were calculated by TP (true positive), FP (false positive), FN (false negative), TN (true negative) by using bivariate meta-analysis model in STATA 14.0 software. Meanwhile, possible mechanisms of sepsis induced Eosinopenia was also analyzed. RESULTS: Seven studies were included in the present study with a total number of 3842 subjects. The incidence of Eosinopenia based on the enrolled studies varied from 23.2 to 92.7%. For diagnosis of sepsis, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of Eosinopenia were 0.66 (95%CI [0.53-0.77]), 0.68 (95%CI [0.56-0.79]), 2.09 (95%CI [1.44-3.02]), 0.49 (95%CI [0.34-0.71]) and 4.23 (95%CI [2.15-8.31]), respectively. The area under the summary receiver operator characteristic curve (SROC) was 0.73 (95%CI [0.68-0.76]). Meta-regression analysis revealed that no single parameter accounted for the heterogeneity of pooled outcomes. For each subgroup of different eosinopenia cutoff values (50, 40, ≤25, 100), the sensitivity was 0.61, 0.79, 0.57, 0.54, and the specificity was 0.61, 0.75, 0.83, 0.51, respectively. CONCLUSIONS: Our findings suggested that Eosinopenia has a high incidence in sepsis but has no superiority in comparison with conventional biomarkers for diagnosis of sepsis. However, eosinopenia can still be used in clinical diagnosis for sepsis as a simple, convenient, fast and inexpensive biomarker. Therefore, further large clinical trials are still needed to re-evaluate eosinopenia as a biomarker of sepsis.

Clozapine-Associated Leukopenia and Agranulocytosis in Western Cape, South Africa: A 3-Year Retrospective Cohort Study.

BACKGROUND: Clozapine may cause life-threatening hematological side effects (HSEs). Hematological side effect incidence data from Sub-Saharan Africa are lacking. Furthermore, clozapine reduces cellular immunity, and it is unknown whether clozapine is a risk factor for tuberculosis or whether HIV is a risk factor for developing HSEs. We assessed the incidence of HSEs in South Africans from the Western Cape Province on clozapine, and the secondary objective was to determine the association of HIV and tuberculosis with clozapine exposure. METHODS: We conducted a 24-week retrospective descriptive study of patients initiated on clozapine between January 2015 and December 2017 using anonymized data from the Provincial Health Data Centre. A control group of patients initiated on risperidone was selected. RESULTS: We identified 23,328 patients and included 5213 who had white blood cell monitoring (n = 1047 clozapine, n = 4166 risperidone). The incidence of leukopenia in patients on clozapine was 0.38% (95% confidence interval [CI], 0.01%-0.76%) measured over a 24-week period and was 0.41% in patients on risperidone (95% CI, 0.21%-0.6%) (P = 0.91). The incidence of agranulocytosis in patients on clozapine was 0.19% (95% CI, 0.00%-0.46%) measured over a 24-week period and was 0.24% in patients on risperidone (95% CI, 0.09%-0.39%) (P = 0.266). HIV-infected patients had a 7.46 times increased risk of developing leukopenia (95% CI, 3.37-16.48; P < 0.01). Patients who developed leukopenia had a 6.24 times increased risk of contracting tuberculosis (95% CI, 1.84-21.11; P < 0.01). CONCLUSIONS: Our incidence of clozapine-induced HSEs was lower than previously reported and not significantly different compared with risperidone. HIV infection was associated with HSEs. Patients with HSEs had an increased risk of developing tuberculosis.

No adverse events were observed in clozapine-treated patients on extended hematologic monitoring intervals during the coronavirus pandemic in four psychiatric centers in Japan.

AIM: As an emergency measure during the coronavirus disease pandemic, the monitoring interval for clozapine use was temporarily extended beyond the regulatory requirement in Japan, which is the safest monitoring interval worldwide. In this study, we aimed to explore the effect of this measure on patients undergoing clozapine treatment. METHODS: This retrospective chart review study included patients with treatment-resistant schizophrenia (TRS) who were undergoing clozapine treatment at four psychiatric institutions in Japan. Demographic characteristics and clinical information of these patients were collected on April 27, 2020, when Japanese psychiatrists were virtually allowed to prescribe clozapine beyond the regulatory requirement. Furthermore, information of adverse events related to the emergency measure was collected and analyzed. RESULTS: Of the 41 patients with TRS included in this study, 19 patients underwent extended hematological monitoring during clozapine treatment. No psychiatric or hematological adverse events were observed in the patients during the extended monitoring interval. CONCLUSION: This study suggested that there were few adverse events of clozapine-treated patients related to emergency measures in Japan. However, hematological monitoring intervals during clozapine treatment have been emergently extended worldwide; hence, it is necessary to verify the results of these measures.

Austrian syndrome, ceftriaxone-induced agranulocytosis and COVID-19.

We present a case of a 75-year-old woman with Austrian syndrome: pneumonia, meningitis and endocarditis all due to Streptococcus pneumoniae Transoesophageal echocardiogram demonstrated a large mitral valve vegetation with severe mitral regurgitation. She was treated with intravenous ceftriaxone and listed for surgical repair of her mitral valve. Preoperatively, she developed an idiosyncratic drug-induced agranulocytosis secondary to ceftriaxone, which resolved on cessation of the medication. However, while awaiting neutrophil recovery, she developed an acute deterioration, becoming critically unwell. This deterioration was multifactorial, with acute decompensated heart failure alongside COVID-19. After multidisciplinary discussion, she was considered too unwell for surgery and palliated.

Association of MICA gene polymorphisms with thionamide-induced agranulocytosis.

BACKGROUND: Thionamide-induced agranulocytosis (TIA), namely antithyroid drug (ATD)-induced agranulocytosis, is one of the most feared adverse effect of ATDs. It is defined as a granulocyte count of less than 0.5 × 109/L after ATD administration. Several studies reported that TIA is associated with human leukocyte antigen (HLA) and nearby genes. Our previous study found that the susceptibility genes of TIA are similar in north China and European populations. METHODS: We evaluated the associations of 23 candidate single nucleotide polymorphisms (SNPs) in 37 patients with TIA and 254 patients with Graves' disease (GD) as controls by iPLEX MassARRAY system. RESULTS: Five SNPs in the MHC class I polypeptide-related sequence A(MICA) genes [rs4349859 (p = 1.43E-7); rs145575084 (p = 5.79E-6); rs116135464 (p = 3.70E-5); rs148015908 (p = 3.79E-5) and rs189600525 (p = 2.15E-4)] were found to be significantly associated with TIA after Bonferroni correction. After combining with previous data of rs4349859 and HLA-B*27:05, the haplotype analysis showed that patients carrying P-A-C-A-T-T-A haplotype have a higher risk of TIA (p = 9.76E-7; OR = 14.85, 95% CI 3.63-60.77). CONCLUSION: Our findings suggest that five high linked SNPs of MICA gene are significantly associated with susceptibility to TIA.

Clozapine-induced agranulocytosis in Japan: Changes in leukocyte/neutrophil counts before and after discontinuation of clozapine.

OBJECTIVE: To determine the prevalence, background factors, and progression of and recovery from clozapine-induced agranulocytosis in Japan. METHODS: Data on treatment-resistant schizophrenia patients registered with the Clozaril Patient Monitoring Service (CPMS) between July 29, 2009 and January 20, 2016 were extracted. Patients with a neutrophil count <500/mm3 were defined as having agranulocytosis, and those with a leukocyte count <3,000/mm3 or a neutrophil count <1,500/mm3 but not meeting the criteria for agranulocytosis were defined as having leukopenia/neutropenia. RESULTS: Of 3,746 patients, agranulocytosis and leukopenia/neutropenia were observed in 38 (1.0%) and 182 (4.9%) patients, respectively. Age was significantly higher in the agranulocytosis group (p < .001). Decreased leukocyte counts 1 week prior to discontinuation were observed only in the agranulocytosis group. The median number of days to recovery from agranulocytosis and leukopenia/neutropenia was 10 and 4, respectively, with more variation in the latter. CONCLUSIONS: Although some patients with leukopenia/neutropenia might carry less pathologic significance, the results of this study reconfirmed the importance of regular blood monitoring for preventing agranulocytosis.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

[Idiosyncratic drug-induced agranulocytosis: 7 year-analysis in a French university hospital]. / Agranulocytoses médicamenteuses idiosyncrasiques : analyse de 7 ans dans un hôpital universitaire français.

INTRODUCTION: Idiosyncratic drug-induced agranulocytosis is a rare but potentially serious haematological disorder. The pathophysiological mechanisms are complex and poorly understood. We aimed at investigating agranulocytosis drug related causes from the myelograms with "myeloid maturation arrest" performed in our university hospital over the last seven years. METHODS: A retrospective analysis of myelograms collected for agranulocytosis was performed from 1st January 2010 to 31th December 2016. We used the method of Bégaud et al. for drug causality assessment. RESULTS: Among the 104 myelograms analysed, 41 agranulocytosis were drug-induced, whose 28 were idiosyncratic. Among these 28 cases, 26 different drugs were involved. Agranulocytosis was a known adverse reaction in the summary of the product characteristics for 24 drugs, mainly associated with undetermined frequency (n=7). Mean onset latency was 38.1 days after starting the drug (calculated for n=23 cases) and granulocyte growth factors were used in 50% of cases without shortening the mean delay of blood count recovery. Bone marrow presented hypereosinophilia in 29% of cases. Pharmacovigilance reporting rate was 48%. CONCLUSION: A "maturation arrest" in the myelogram is not pathognomonic for idiosyncratic drug-induced agranulocytosis. This rare event require multidisciplinary care involving haematologists, biologists and pharmacovigilance experts. Agranulocytosis reporting rate was high compared with usual adverse drug reaction reporting rate (5 to 10%), probably related to the potential severity of this event.

Agranulocytosis attributed to metamizole: An analysis of spontaneous reports in EudraVigilance 1985-2017.

Despite ongoing debates about its safety, the use of metamizole (dipyrone) is still increasing in many countries. In this study, we analysed spontaneous reports of suspected metamizole-associated agranulocytosis recorded in EudraVigilance database from 1985 to 2017 with regard to patient and treatment characteristics as well as fatal vs non-fatal outcomes and compared these findings among countries. A total of 1448 reports from 31 different countries were included (Germany 42.0%; Spain 29.6%; Switzerland 13.1%; other countries 15.3%). Mean age of patients was 53.6 years (63.4% females). Differences among countries were observed, for example with respect to patient age, route of administration and daily doses. Overall, median time between starting metamizole and developing an agranulocytosis was 13 days with 34.7% of cases occurring up to 7 days. This time was much shorter in patients who had already received metamizole before (median: 6 vs 15 days). About 16% of cases ended fatally. Patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes. When adjusting for age and sex in a multivariable logistic regression, methotrexate was associated with an increased risk of fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78). In conclusion, metamizole-associated agranulocytosis is still a life-threatening condition, especially in the elderly and those also receiving methotrexate. As agranulocytosis can develop weeks after last administration and independently of dose and duration of treatment, prescribers and patients should be aware of its signs and symptoms.

The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies.

BACKGROUND: Clozapine treatment increases the risk of agranulocytosis, but findings on the epidemiology of agranulocytosis have been inconsistent. This meta-analysis examined the prevalence of agranulocytosis and related death in clozapine-treated patients. METHODS: A literature search in the international (PubMed, PsycINFO, and EMBASE) and Chinese (WanFang, Chinese National Knowledge Infrastructure, and Sinomed) databases was conducted. Prevalence estimates of agranulocytosis and related death in clozapine-treated patients were synthesized with the Comprehensive Meta-Analysis program using the random-effects model. RESULTS: Thirty-six studies with 260 948 clozapine-treated patients published between 1984 and 2018 were included in the meta-analysis. The overall prevalence of agranulocytosis and death caused by agranulocytosis were 0.4% (95% CI 0.3-0.6%) and 0.05% (95% CI 0.03-0.09%), respectively. The prevalence of agranulocytosis was moderated by sample size, study quality, year of publication, and that of data collection. CONCLUSIONS: The prevalence of clozapine-associated agranulocytosis is low. Agranulocytosis-related death appears rare.

Neutropenia and Life-threatening Agranulocytosis Among Children With ß-Thalassemia Treated With Oral Iron Chelators in a Community With Background of Ethnic Neutropenia.

INTRODUCTION: Neutropenia and agranulocytosis are rare side effects of deferiprone (DFP) in patients treated for iron overload. Unfortunately, no study directly addressed special risks in countries with a background of ethnic neutropenia, such as Oman. AIM: The aim of this study was to report the incidence of neutropenia in Omani children with ß-thalassemia treated with different iron chelators. METHODS/DESIGN: This was a retrospective study that included 179 Omani pediatric patients. For patients who developed neutropenia, demographic data, iron-chelating agent, clinical presentation, management, and outcome were recorded. Detailed clinical, laboratory±radiologic information was added for patients with agranulocytosis. RESULTS: Neutropenia was encountered in 43.6% of patients: severe neutropenia in 10 patients, moderate in 29, and mild in 69 patients. Severe and moderate neutropenia had similar incidence among DFP-exposed and DFP-naive patients (P=0.515 and 0.421, respectively), while mild neutropenia was common among DFP-naive patients (P=0.0001). A higher incidence of DFP-related agranulocytosis (4.1%) was noted compared with previous reports, but none had a fatal outcome. CONCLUSIONS: In a community with ethnic neutropenia, mild to moderate neutropenia is common. Higher incidence of severe neutropenia and agranulocytosis mandates careful monitoring and rational modification of iron-chelating agents to avoid life-threatening complications.

Inappropriate use of ritodrine hydrochloride for threatened preterm birth in Japan: a retrospective cohort study using a national inpatient database.

BACKGROUND: No study has revealed the effectiveness of long-term tocolysis for patients diagnosed with threatened preterm birth, and the use of betamimetics in these patients has not been recommended in the United States or Europe because of the potential for severe maternal adverse effects. However, long-term tocolysis with intravenous infusion of ritodrine hydrochloride, a betamimetic, can be selected as the first-line tocolytic treatment in Japan. This study was performed to (i) examine the current status of long-term tocolytic treatment, particularly with intravenous infusion of betamimetics, for threatened preterm birth in Japan and (ii) clarify the association between long-term tocolytic treatment and maternal adverse effects. METHODS: This retrospective cohort study was conducted using a national inpatient database for acute-care inpatients in Japan. Among all pregnant women who were diagnosed with threatened preterm birth and admitted to the hospital from July 2010 to March 2016, we identified 134,959 eligible patients. The primary outcome was maternal serious adverse effects during hospitalization. A multivariable logistic regression analysis was performed to evaluate factors associated with maternal adverse effects. RESULTS: Among all patients, 17.2% received intravenous infusion of ritodrine hydrochloride for ≤48 h and 28.7% received this treatment for ≥28 days. The proportion of maternal adverse effects was significantly higher among patients treated for ≥28 days than ≤48 h. A longer duration of tocolysis was significantly associated with increased maternal adverse effects. CONCLUSIONS: Long-term tocolysis was associated with an increased incidence of maternal adverse effects in the current study using real-world data. Japanese clinicians should adjust their tocolytic treatment practices in accordance with the latest scientific evidence or make efforts to verify the effectiveness and safety of long-term tocolysis.

Off-Label Use of Clozapine in Children and Adolescents-A Literature Review.

BACKGROUND: Clozapine is a second-generation antipsychotic typically used for refractory schizophrenia or otherwise psychotic pathology. There are no FDA or manufacturer guidelines for use of clozapine in pediatric population. We investigated the current state of research concerning the use of clozapine in pediatric patients. AREAS OF UNCERTAINTY: We describe consistent calls for more research into the long-term and short-term effects of clozapine use in a young patient population. Despite the strongly supported efficacy, questions concerning clear indications for use and risk-benefit analysis persist. We acknowledge that a more comprehensive meta-analysis would greatly benefit the field. However, this is the first article of its kind for clozapine in recent history, and therefore, serves as a focus and reference point for future, more in-depth analyses. DATA SOURCES: We conducted a search of PubMed, ClinicalKey, PsycINFO, and MEDLINE databases. Keywords used included, in varying combinations: clozapine, off-label, indications, children and adolescent, pediatric, behavioral, suicidality, psychosis, early and very-early onset schizophrenia, side-effect profile, and long-term use. Further criteria and selection are described in Methods below. RESULTS: We describe the documented efficacy of clozapine for the management of refractory psychotic and nonpsychotic symptoms in the pediatric population. The authors highlight the risk of unmanaged early-onset schizophrenia, aggressive or suicidal behavior, and severe nonpsychotic pathology. Unfortunately, these studies are generally small. There is little consistency in when clozapine is prescribed, how long it is administered, and how long patients are followed. Despite the lack of FDA and manufacturer guidelines, clozapine continues to be used for the benefit of young patients. CONCLUSIONS: Indications for prescription of clozapine should be revisited, given the data presented in this manuscript of a low risk-benefit ratio for properly chosen patients. Larger studies should be conducted to provide more statistical power and determine clear guidelines for use, risk of side effects, and long-term adverse events that may arise.

Pediatric drug safety signal detection of non-chemotherapy drug-induced neutropenia and agranulocytosis using electronic healthcare records.

Objectives: This study aimed to develop a procedure to explore the adverse drug reaction signals of drug-induced neutropenia (DIN) or drug-induced agranulocytosis (DIA) in children using an electronic health records (EHRs) database. Methods: A two-stage design was presented. First, the suspected drugs to induce DIN or DIA were selected. Second, the associations were evaluated by a retrospective cohort study. Results: Ten and five drugs were potentially identified to be associated with DIN and DIA, respectively. Finally, five (oseltamivir, chlorpheniramine, vancomycin, meropenem, and ganciclovir) and two (chlorpheniramine, and vancomycin) drugs were found to be associated with DIN and DIA, respectively. Of these, the association between oseltamivir and neutropenia (P = 9.83 × 10-9; OR, 2.10; 95% CI, 1.62-2.69) was considered as a new signal for both adults and children. Chlorpheniramine-induced neutropenia (P = 3.01 × 10-8; OR, 1.59; 95% CI, 1.35-1.87) and agranulocytosis (P = 3.16 × 10-7; OR, 3.76; 95% CI, 2.25-6.26) were considered as new signals in children. Other drugs associated with DIN or DIA were confirmed by previous studies. Conclusion: A method to detect signals for DIN and DIA has been described. Several pediatric drugs were found to be associated with DIN or DIA.

Clozapine-induced agranulocytosis and leukopenia: Incidence, associated factors, and rate of hematologic adverse-effects monitoring in psychiatric out-patient services in Thailand.

The present study aimed to investigate the incidence of agranulocytosis and leukopenia and its associated factors in Thai schizophrenia patients treated with clozapine and the rate of hematologic adverse events monitored in clinical practice. Data were collected from the medical records of 641 outpatients at two hospitals. The results showed no cases of agranulocytosis and 20 cases of leukopenia (3.1%), 85% of which were observed after 1 year of prescription. The associated factors were female (p = 0.019) and duration of clozapine prescription (p = 0.026). According to the guideline for safety monitoring, 23.6% of cases had neutrophils count monitoring.

Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective.

Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1, HLA-B and SLCO1B3/SLCO1B7. We describe recent findings relating to the Duffy-null genotype and its association with benign neutropenia in individuals with African ancestry. Further advances will come from sequencing studies, large, cross-population studies and in understanding the molecular mechanisms underlying these associations.