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

Abstract

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.

How and when to use clozapine

“…Prescribers in countries without local monitoring guidelines should refer to schedules recommended by the registries of countries with similar ethnic composition, given the differences between ethnicities in monitoring requirements. In the event of decreasing absolute neutrophil counts, local registry guidelines as to the threshold for which holding clozapine is required should be followed, and if appropriate, the use of lithium or granulocyte colony‐stimulating factor , both of which stimulate the generation of granulocytes in the bone marrow, should be considered. Persistence or progression of low neutrophil after interruption of clozapine treatment should prompt a hematology consult.…”

Need to bleed? Clozapine haematological monitoring approaches a time for change

“…Two strategies commonly employed to manage clozapine-associated neutropenia are the use of lithium (Paton and Esop, 2005) and Granulocyte Colony-Stimulating Factor (G-CSF) (Lally et al, 2017;Myles et al, 2017). These strategies are not without risks.…”

Late-Onset Neutropenia in Long-Term Clozapine Use and Its Management Utilizing Prophylactic G-CSF

“…Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine-induced neutropenia [ 12 ]. Filgrastim works most effectively when prescribed prophylactically [ 12 ].…”

“…Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine-induced neutropenia [ 12 ]. Filgrastim works most effectively when prescribed prophylactically [ 12 ]. It is important that hematology specialists are involved, patient education is advocated, and blood monitoring is adhered to in utilizing such strategies to avoid neutropenia [ 12 ].…”

“…Filgrastim works most effectively when prescribed prophylactically [ 12 ]. It is important that hematology specialists are involved, patient education is advocated, and blood monitoring is adhered to in utilizing such strategies to avoid neutropenia [ 12 ]. There has been limited published data on the use of regular dosing of filgrastim in the management of clozapine-induced neutropenia in Ireland to date.…”