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Atencion Primaria 2021To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and...
OBJECTIVE
To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and metamizole contains accurate and necessary information to protect patients from the presentation of this adverse reaction (AR) and if the official documentation of medicines containing metamizole for doctors, pharmacists and the general population conforms to the guidelines of the AEMPS to reduce this risk.
SETTING AND PARTICIPANTS
Drug safety update, bibliographic search, information at the European Medicines Agency on metamizole drugs marketed in Spain, technical datasheets, leaflets, Bot PLUS Health Information Database and Catalog of Pharmaceutical Specialties. Notification of 4cases of agranulocytosis due to metamizole after the drug safety update was issued.
MAIN INTERVENTIONS AND MEASUREMENTS
Comparison of the key points of the drug safety update and official documents on metamizole with the bibliography. Description of the 4cases of agranulocytosis due to metamizole and application of the causality and severity algorithm.
RESULTS
The drug safety update contains omissions and contradiction in respect to the bibliography and the actual use of metamizole in healthcare practice. The official documents show a lack of updating, unapproved indications and doses higher than those recommended. The drug safety update has not stopped the presentation of cases of agranulocytosis due to metamizole.
CONCLUSIONS
The AEMPS drug safety update can be improved and it is necessary to update the official information documents on metamizole for health professionals and patients in order to decrease the risk of agranulocytosis.
Topics: Agranulocytosis; Anti-Inflammatory Agents, Non-Steroidal; Databases, Factual; Dipyrone; Humans; Spain
PubMed: 33823317
DOI: 10.1016/j.aprim.2021.102047 -
British Journal of Pharmacology Jun 2022Chemotherapy-induced immune-suppression is a common, but potential detrimental, adverse reaction in patients undergoing treatment for cancer and strategies with capacity... (Review)
Review
Chemotherapy-induced immune-suppression is a common, but potential detrimental, adverse reaction in patients undergoing treatment for cancer and strategies with capacity to boost the immune cell populations are needed. Physical exercise training is a potent regulator of immune cell viability and function and may serve as a viable, non-pharmacological prophylactic strategy in addition to the current pharmacological management by, for example, granulocyte-colony stimulating factor (G-CSF). Here, we review the mechanistic evidence linking exercise training to haematopoietic function and subsequent possible amelioration of chemotherapy-related neutropenia. First, we briefly describe neutrophil regulation and management of neutropenia in cancer patients. Second, we summarize the effect of acute and chronic exercise training on neutrophils and their progenitors, and finally, we outline the current clinical evidence of exercise interventions in ongoing anti-cancer treatment in regard to neutropenia incidence, treatment tolerance and related outcomes. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.
Topics: Exercise; Humans; Neutropenia
PubMed: 32449810
DOI: 10.1111/bph.15141 -
The Lancet. Psychiatry May 2022Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of...
Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland.
BACKGROUND
Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics.
METHODS
We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions.
FINDINGS
For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis.
INTERPRETATION
Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine.
FUNDING
The Finnish Ministry of Social Affairs and Health and Academy of Finland.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Agranulocytosis; Antipsychotic Agents; Case-Control Studies; Clozapine; Cohort Studies; Female; Finland; Hematologic Neoplasms; Humans; Leukemia; Male; Middle Aged; Schizophrenia; Young Adult
PubMed: 35334224
DOI: 10.1016/S2215-0366(22)00044-X -
Nederlands Tijdschrift Voor Geneeskunde Jan 2022Metamizole is a non-selective NSAID with a strong analgesic and spasmolytic effect. In the late 1970s, metamizole has been withdrawn from the market in many...
Metamizole is a non-selective NSAID with a strong analgesic and spasmolytic effect. In the late 1970s, metamizole has been withdrawn from the market in many industrialized countries because of an allegedly unacceptable high risk of agranulocytosis. The absolute risk of metamizole-related agranulocytosis is estimated to be less than 1 per million daily doses. The incidence of agranulocytosis may be reduced by short-term use and careful consideration when prescribing to specific patient categories. Metamizole has a relatively favorable safety profile with respect to morbidity and mortality compared to other NSAIDs. In the Netherlands the official registration of metamizole has been limited for years to intravenous and postoperative use. In March 2021, the Dutch Medicine Assessment Board certified one oral formulation of metamizol under strict conditions. The debate about the wider application of (oral) metamizole in the Netherlands should be re-opened.
Topics: Agranulocytosis; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Dipyrone; Humans; Netherlands
PubMed: 35138735
DOI: No ID Found -
Tijdschrift Voor Psychiatrie 2023Clozapine is the most effective treatment for people with treatment-resistant schizophrenia. However, it is prescribed less often than guidelines indicate. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Clozapine is the most effective treatment for people with treatment-resistant schizophrenia. However, it is prescribed less often than guidelines indicate.
AIM
To personalize clozapine treatment, we investigated the efficacy of clozapine as first- or second-line treatment and investigated whether there are factors that were associated with efficacy and side effects.
METHOD
We collected a unique cohort of over 800 clozapine users diagnosed with a schizophrenia spectrum disorder. We meta-analyzed factors that were associated with response during clozapine treatment. Additionally, we conducted genetic association analyses to investigate the relations between side effects and symptom severity during clozapinetreatment.
RESULTS
From our meta-analyses, we found that clozapine was more effective when used as a first- or second-line treatment. Furthermore, we found that younger age, less negative symptoms and the paranoid subtype of schizophreniawere associated with a better clozapine response. Several specific locations on genes (loci) were associated with clozapine-induced agranulocytosis and neutropenia, while polygenic risk scores were associated with symptom severity.
CONCLUSION
We found that clozapine could be effective earlier in treatment and identified factors that could aid the prediction of< response to clozapine treatment in the future. These finding could contribute to the start of a personalized clozapine treatment.
Topics: Humans; Antipsychotic Agents; Clozapine; Neutropenia; Precision Medicine; Schizophrenia
PubMed: 36912056
DOI: No ID Found -
Multiple Sclerosis (Houndmills,... Jan 2024Late-onset neutropenia (LON), defined as an absolute neutrophil count (ANC) < 1500/mm that develops between 4 weeks and 6 months after the last drug administration, is a...
BACKGROUND
Late-onset neutropenia (LON), defined as an absolute neutrophil count (ANC) < 1500/mm that develops between 4 weeks and 6 months after the last drug administration, is a rare side effect of anti-CD20 drugs including ocrelizumab. Although continuation of ocrelizumab after LON is not contraindicated, the risk of LON recurrence is not well known.
CASES
We report three cases of recurrent symptomatic agranulocytosis (ANC < 500/mm) occurring under ocrelizumab.
CONCLUSION
Given the risk of recurrence of symptomatic agranulocytosis and the availability of other treatments, a therapeutic switch may be discussed after the first episode of LON.
Topics: Humans; Rituximab; Neutropenia; Antibodies, Monoclonal, Humanized; Leukocyte Count
PubMed: 37888775
DOI: 10.1177/13524585231206218 -
Annals of the American Thoracic Society Nov 2022
Topics: Humans; Neutropenia; Pleural Effusion
PubMed: 35960258
DOI: 10.1513/AnnalsATS.202204-331RL -
The Journal of Emergency Medicine Nov 2019Cancer is associated with a variety of complications, including neutropenic fever, which can result in severe morbidity and mortality. This oncologic emergency requires... (Review)
Review
BACKGROUND
Cancer is associated with a variety of complications, including neutropenic fever, which can result in severe morbidity and mortality. This oncologic emergency requires ED management.
OBJECTIVE
This narrative review provides focused updates for emergency clinicians regarding neutropenic fever.
DISCUSSION
Neutropenic fever is defined by fever with oral temperature >38.3°C or temperature >38.0°C for 1 hour with an absolute neutrophil count (ANC) < 1000 cells/microL. Patients who have received chemotherapy within 6 weeks of presentation are at high risk for neutropenia. While most patients with neutropenic fever do not have an identifiable bacterial source of fever, clinicians should treat patients for bacterial infection. Rapid assessment and management are vital to improving outcomes in patients with suspected or confirmed neutropenic fever. History and examination should focus on the most common sites of infection: the gastrointestinal tract, blood, skin, lung, and urinary tract. However, physical examination and laboratory or imaging assessment may not display classic signs of infection. Blood cultures should be obtained, and broad-spectrum antibiotics are recommended. Oncology consultation is an integral component in the care of these patients. Several risk scores can assist in stratifying patients who may be appropriate for discharge home and follow-up.
CONCLUSIONS
Neutropenic fever is an oncologic emergency. Rapid diagnosis and care of patients with neutropenic fever can improve outcomes, along with oncology consultation.
Topics: Adult; Blood Cell Count; Drug Therapy; Female; Fever; Humans; Middle Aged; Neoplasms; Neutropenia
PubMed: 31635928
DOI: 10.1016/j.jemermed.2019.08.009 -
Journal of Clinical Immunology May 2023
Topics: Humans; Neutropenia; Syndrome
PubMed: 37010672
DOI: 10.1007/s10875-023-01446-2 -
EMBO Molecular Medicine Jan 2024Elevated peripheral blood and tumor-infiltrating neutrophils are often associated with a poor patient prognosis. However, therapeutic strategies to target these cells...
Elevated peripheral blood and tumor-infiltrating neutrophils are often associated with a poor patient prognosis. However, therapeutic strategies to target these cells are difficult to implement due to the life-threatening risk of neutropenia. In a genetically engineered mouse model of lung adenocarcinoma, tumor-associated neutrophils (TAN) demonstrate tumor-supportive capacities and have a prolonged lifespan compared to circulating neutrophils. Here, we show that tumor cell-derived GM-CSF triggers the expression of the anti-apoptotic Bcl-xL protein and enhances neutrophil survival through JAK/STAT signaling. Targeting Bcl-xL activity with a specific BH3 mimetic, A-1331852, blocked the induced neutrophil survival without impacting their normal lifespan. Specifically, oral administration with A-1331852 decreased TAN survival and abundance, and reduced tumor growth without causing neutropenia. We also show that G-CSF, a drug used to combat neutropenia in patients receiving chemotherapy, increased the proportion of young TANs and augmented the anti-tumor effect resulting from Bcl-xL blockade. Finally, our human tumor data indicate the same role for Bcl-xL on pro-tumoral neutrophil survival. These results altogether provide preclinical evidence for safe neutrophil targeting based on their aberrant intra-tumor longevity.
Topics: Animals; Humans; Mice; Aging; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Cell Line, Tumor; Lung Neoplasms; Neutropenia; Neutrophils
PubMed: 38177532
DOI: 10.1038/s44321-023-00013-x