Clozapine-Associated Agranulocytosis Treatment With Granulocyte Colony-Stimulating Factor/Granulocyte-Macrophage Colony-Stimulating Factor

Lally, John; Malik, Steffi; Whiskey, Eromona; Taylor, David; Gaughran, Fiona; Krivoy, Amir; Flanagan, Robert J.; Mijović, Aleksandar; MacCabe, James H.

doi:10.1097/jcp.0000000000000715

Cited by 27 publications

(27 citation statements)

References 38 publications

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“…Nowadays, judicious use of cytokines, granulocyte colony stimulating factor (G-CSF, filgrastim) or granulocyte-macrophage colony stimulating factor (GM-CSF, sargramostim), is usually effective in promoting prompt return of the white cell count (WCC) to ‘safe’ values and together with antibiotic cover means that such episodes once recognized are rarely fatal. 43 Occasionally, however, there are unexpected reactions to cytokine therapy such as thrombocytosis. 44 GM-CSF may be effective if G-CSF has failed.…”

Section: Adverse Events On Clozapinementioning

confidence: 99%

“…G-CSF has been used to support clozapine rechallenge after neutropenia and indeed cytokines have been used to maintain the WCC with the aim of preventing clozapine discontinuation. 43 , 49 These compounds are given by injection, and hence are not suitable for long-term use. Oral lithium has also been used to stimulate leucocyte production, but requires careful monitoring and there are concerns such as possible masking of an impending clozapine-induced agranulocytosis and whether it is safe to discontinue lithium once the WCC has recovered.…”

Section: Adverse Events On Clozapinementioning

confidence: 99%

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Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals

Flanagan

Lally

Gee

et al. 2020

British Medical Bulletin

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Background Clozapine remains the only medication licensed for treating refractory schizophrenia. However, it remains underutilized in part due to concerns regarding adverse events. Sources of data Published literature. Areas of agreement Common adverse events during clozapine treatment include sedation, hypersalivation, postural hypotension, dysphagia, gastrointestinal hypomotility, weight gain, diabetes mellitus and dyslipidaemia. Rare but serious events include agranulocytosis, cardiomyopathy, myocarditis, pneumonia, paralytic ileus and seizure. Areas of controversy It remains unclear how best to minimize clozapine-induced morbidity/mortality (i) during dose titration, (ii) from hypersalivation and (iii) from gastrointestinal hypomotility. It is also unclear how clozapine pharmacokinetics are affected by (i) gastrointestinal hypomotility, (ii) systemic infection and (iii) passive exposure to cigarette smoke. Whether monthly haematological monitoring needs to continue after 12 months of uninterrupted therapy is also a subject of debate. Growing points There is a need for better management of serious clozapine-related adverse events in addition to agranulocytosis. There is also a need for better education of patients and carers, general practitioners, A&E and ITU staff and others of the problems posed in using clozapine safely. Areas timely for developing research There is a need for more research on assessing clozapine dosage (i) as patients get older, (ii) with respect to exposure to cigarette smoke and (iii) optimizing response if adverse events or other factors limit dosage.

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Section: Adverse Events On Clozapinementioning

confidence: 99%

Section: Adverse Events On Clozapinementioning

confidence: 99%

Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals

Flanagan

Lally

Gee

et al. 2020

British Medical Bulletin

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“…The beneficial role of G-CSF for reducing duration of clozapine-induced neutropenia is the subject of a recent systematic review (Lally et al, 2017). However, the pathophysiology of clozapine-induced neutropenia is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations

Myles

Clark

Bird

et al. 2017

Aust N Z J Psychiatry

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Background: Clozapine is the most effective medication for treatment-refractory schizophrenia; however, its use is contraindicated in people who have had previous clozapine-induced neutropenia. Co-prescription of granulocyte-colony stimulating factor may prevent recurrent neutropenia and allow continuation or rechallenge of clozapine.Objective and methods: Systematic review of literature reporting the use of granulocyte-colony stimulating factor to allow rechallenge or continuation of clozapine in people with previous episodes of clozapine-induced neutropenia. The efficacy of granulocyte-colony stimulating factor and predictors of successful rechallenge will be determined to elucidate whether evidence-based recommendations can be made regarding the use of granulocyte-colony stimulating factor in this context. Results:A total of 17 articles were identified that reported on clozapine rechallenge with granulocyte-colony stimulating factor support. In all, 76% of cases were able to continue clozapine at median follow-up of 12 months. There were no clear clinical or laboratory predictors of successful rechallenge; however, initial neutropenia was more severe in successful cases compared to unsuccessful cases. Cases co-prescribed lithium had lower success rates of rechallenge (60%) compared to those who were not prescribed lithium (81%). The most commonly reported rechallenge strategy was use of filgrastim 150-480 µg between daily to three times a week. There were no medication-specific side effects of granulocyte-colony stimulating factor reported apart from euphoria in one case. Three cases who failed granulocytecolony stimulating factor had bacterial infection at time of recurrent neutropenia. No deaths were reported. Conclusion:Preliminary data suggest granulocyte-colony stimulating factor is safe and effective in facilitating rechallenge with clozapine. Clinical recommendations for use are discussed.

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“…HGF use (in curative perspective) did not appear to alter either patient disease progression or mortality. So far, no data are available for HGF prophylaxis, except for the few published case-reports of clozapine-induced agranulocytosis [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

History and Outcome of Febrile Neutropenia Outside the Oncology Setting: A Retrospective Study of 76 Cases Related to Non-Chemotherapy Drugs

Andrès

Mourot-Cottet

Maloisel

et al. 2017

JCM

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Background: Despite major advances in its prevention and treatment, febrile neutropenia remains a most concerning complication of cancer chemotherapy. Outside the oncology setting, however, only few data are currently available on febrile neutropenia related to non-chemotherapy drugs. We report here data on 76 patients with febrile neutropenia related to non-chemotherapy drugs, followed up in a referral center within a university hospital. Patients and methods: Data from 76 patients with idiosyncratic drug-induced febrile neutropenia were retrospectively reviewed. All cases were extracted from a cohort study on agranulocytosis conducted at the Strasbourg University Hospital (Strasbourg, France). Results: Mean patient age was 52.2 years old (range: 18–93) and gender ratio (F/M) 1.6, with several comorbidities present in 86.8% of patients. The most common causative drugs were: antibiotics (37.4%), antithyroid drugs (17.2%), neuroleptic and anti-epileptic agents (13.1%), non-steroidal anti-inflammatory agents and analgesics (8%), and platelet aggregation inhibitors (8%). Main clinical presentations upon hospitalization included isolated fever (30%), sore throat, acute tonsillitis and sinusitis (18.4%), documented pneumonia (18.4%), septicemia (14.5%), and septic shock (6.6%). Mean neutrophil count at nadir was 0.13 × 10(9)/L (range: 0–0.48). While in hospital, 22 patients (28.9%) worsened clinically and required intensive care unit placement. All patients were promptly treated with broad-spectrum antibiotics, and 45 (59.2%) with hematopoietic growth factors. Mean duration of hematological recovery (neutrophil count ≥1.5 × 10(9)/L) was 7.5 days (range: 2–21), which was reduced to 0.7 days (range: 2–16) (p = 0.089) with hematopoietic growth factors. Outcome was favorable in 89.5% of patients, whereas eight died. Conclusions: Like in oncology and myelosuppressive chemotherapy settings, idiosyncratic febrile neutropenia is typically serious, about 40% of patients exhibiting severe pneumonia, septicemia, and septic shock, with a mortality rate of 10%. Like in febrile, chemotherapy-related neutropenia, modern and timely management (immediate broad spectrum antibiotherapy, hematopoietic growth factors) may reduce infection-related mortality. All practitioners should be aware of this potential side-effect that may even occur in the event of “daily medication” exposure.

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Clozapine-Associated Agranulocytosis Treatment With Granulocyte Colony-Stimulating Factor/Granulocyte-Macrophage Colony-Stimulating Factor

Cited by 27 publications

References 38 publications

Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals

Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals

Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations

History and Outcome of Febrile Neutropenia Outside the Oncology Setting: A Retrospective Study of 76 Cases Related to Non-Chemotherapy Drugs

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