From the FDA Drug Label
For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≥1500/μL and for BEN patients until their ANC is ≥1000/μL or above their baseline. Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101. 3°F, or greater) during the 2 weeks after discontinuation [see Warnings and Precautions (5.1)].
If a patient on long-term clozapine becomes septic, the decision to discontinue clozapine should be made with caution.
- The primary concern is the potential for neutropenia to worsen, which could exacerbate the patient's condition.
- However, abrupt discontinuation of clozapine may also lead to recurrence of psychotic symptoms and cholinergic rebound.
- Given the potential risks, it is recommended to reduce the dose gradually over a period of 1 to 2 weeks if termination of clozapine therapy is planned, unless there is evidence of moderate to severe neutropenia.
- In the case of sepsis, it may be necessary to discontinue clozapine abruptly, but this should be done under close medical supervision, with careful monitoring of the patient's ANC and clinical condition 1.
- Close monitoring of the patient's ANC and clinical condition is essential during this period.
From the Research
Clozapine should generally be discontinued in patients with sepsis to avoid worsening neutropenia, as the risk of severe neutropenia and its potential to compromise the patient's immune response to infection outweighs the benefits of continuing the medication. Sepsis itself can cause neutropenia, and clozapine carries a significant risk of agranulocytosis, which could compound this problem and further compromise the patient's immune response to infection 2. During sepsis treatment, the patient's absolute neutrophil count (ANC) should be closely monitored. If the ANC falls below 1500/mm³, clozapine should be stopped immediately.
The decision to restart clozapine after resolution of sepsis should be made carefully, with gradual reintroduction and more frequent blood monitoring (twice weekly for at least 4 weeks). While discontinuing clozapine, alternative antipsychotic coverage may be necessary, though no other antipsychotic has equivalent efficacy for treatment-resistant schizophrenia. The risk of psychiatric decompensation must be balanced against the risk of severe neutropenia, but in acute sepsis, treating the life-threatening infection takes priority. Once the infection resolves and neutrophil counts stabilize, the treatment team should reassess the risk-benefit ratio of restarting clozapine.
Some studies suggest that the risk of neutropenia associated with clozapine may not be significantly higher than with other antipsychotic medications 2, but in the context of sepsis, the potential for worsening neutropenia and its consequences on the patient's immune response cannot be ignored. Therefore, a cautious approach is warranted, and discontinuation of clozapine is recommended in patients with sepsis.
Key considerations in managing patients on clozapine who develop sepsis include:
- Close monitoring of ANC during sepsis treatment
- Discontinuation of clozapine if ANC falls below 1500/mm³
- Alternative antipsychotic coverage as needed
- Gradual reintroduction of clozapine after resolution of sepsis, with frequent blood monitoring
- Reassessment of the risk-benefit ratio of restarting clozapine once the infection resolves and neutrophil counts stabilize.