10.21.2025

Clozapine Therapy: Overview and Place in Hospice & Palliative Care

Recently, the U.S. Food and Drug Administration (FDA) removed the Risk Evaluation and Mitigation Strategies (REMS)1 program for clozapine (Clozaril® tablets, Fazaclo® orally disintegrating tablets, Versacloz® oral suspension), stating the REMS is no longer necessary and citing prescribing information as sufficient to mitigate clozapine risks and ensure the benefits.2,3 The removed REMS required enrollment of prescribers, pharmacies, and patients in a restricted distribution program and reporting of the level of certain white blood cells to mitigate the risk of severe neutropenia (absolute neutrophil count (ANC) less than 500/microL).2,4

Despite relief from the administrative burden associated with clozapine REMS and the resulting improved access, the risk of neutropenia and other serious adverse effects remain. Clozapine remains the only FDA approved medication for treatment-resistant schizophrenia (TRS).5 It is a vital psychiatric medication that serves a medically vulnerable population, and it is important to consider continuing this therapy in advanced disease when feasible. This article will serve as an overview of clozapine and its place in hospice and palliative care.

INTRODUCTION TO CLOZAPINE

Clozapine was the first of the second-generation (i.e., atypical) antipsychotics (SGAs). Originally developed in 1958, patient deaths from agranulocytosis (the most severe form of neutropenia (ANC < 200/microL)) halted further U.S. clinical trials until the 1980s. Clozapine was FDA-approved in 1989 for treatment-resistant schizophrenia (TRS) and later for suicidal behavior in schizophrenia (i.e., schizoaffective disorder).3,6,7

SGAs are associated with a lower risk of extrapyramidal symptoms and tardive dyskinesia compared with first-generation antipsychotics (FGAs) like haloperidol (Haldol®) and chlorpromazine (Thorazine®). Since 1989, thirteen SGAs have been FDA-approved for various conditions. These newer SGAs are not associated with severe neutropenia like clozapine and have comparably fewer adverse effects. FGAs and SGAs remain comparable in their clinical efficacy, except for clozapine which provides superior efficacy for TRS.8

Clozapine is an antagonist at all dopamine receptors (D1 through D5), with lower affinity for D1 and D2 receptors and a high affinity for D4 receptors, resulting in greater activity at limbic versus striatal dopamine receptors compared to other SGAs. This profile is thought to explain its superior antipsychotic efficacy, the virtual absence of extrapyramidal effects,4 and support its off-label use for behavioral disturbances in patients with dementia with Lewy bodies and psychosis in Parkinson’s disease.4,9

Postural dizziness, sedation, and increased appetite may reflect actions of clozapine at alpha-1, H1, and 5-HT2c receptors, respectively. Actions at the 5-HT2A and M1 receptors may support the reduction of movement-related side effects.10 Table 1 provides an overview of clozapine’s receptor activity compared to a selection of SGAs.

Table 1: Receptor Activity Profile of Select Atypical Antipsychotics4

The Clozapine REMS Program was approved in 2015 and ensured optimal patient monitoring for and management of clozapine-induced severe neutropenia, providing a centralized system for prescribers and pharmacists in managing patient risk. Prior to the approval of the Clozapine REMS Program, individual clozapine manufacturers operated separate patient registries.11 These former registry requirements, in addition to the introduction of newer SGAs to the market with less adverse effects, limited the use of clozapine, firmly affixing its place in therapy as last line, for refractory cases.

Clozapine remains underutilized despite its superior efficacy for TRS.7,12 Schizophrenia is considered treatment-resistant when a patient has failed at least two adequate courses of antipsychotic medication (an adequate course of treatment is considered ≥ 6 weeks of therapeutic dosing with at least 80% adherence).12 Healthcare providers are urged to be proactive in diagnosing TRS, as early administration of clozapine is likely to positively impact patient outcomes.13

Clozapine prescribing considerations to be covered in the remaining sections include:8

  • Adverse effects including neutropenia, cardiovascular effects, seizures, orthostatic hypotension, and anticholinergic effects (constipation, urinary retention)
  • Drug and smoked tobacco interactions
  • Interruption of therapy ≥ 48 hours requires restarting at initial dose
  • Monitoring associated with adverse effects, including laboratory work

ADVERSE EFFECTS

Neutrophils (white blood cells) are an essential part of the human immune system, helping the body remove invading fungi, viruses, and bacteria.14 Neutropenia is a medical condition characterized by inadequate neutrophils circulating in the blood stream. It is medically defined as an absolute neutrophil count (ANC) of <1500 neutrophils per microliter of blood. Severe neutropenia is defined as ANC < 500/microL with the most severe cases, referred to as agranulocytosis, at ANC <200/microL.15 When suffering from neutropenia, patients are at heightened risk of infections that can be life-threatening.14

Boxed warnings (formerly known as “Black Box Warnings”) are the highest medication safety-related warnings assigned by the FDA. These warnings are intended to bring attention to the major risks of the drug.16 Clozapine has boxed warnings for:

  • Severe neutropenia (associated with an increased risk of serious and fatal infections)
  • Orthostatic hypotension, bradycardia, and syncope (dose-related)
  • Seizure (dose-related)
  • Myocarditis, pericarditis, cardiomyopathy and mitral valve incompetence
  • Increased mortality in elderly patients with dementia-related psychosis

Additionally, clozapine labeling warns of the following adverse effects: 3

  • Severe gastrointestinal hypomotility (which can lead to constipation, obstruction, or impaction)
  • Eosinophilia
  • QT interval prolongation
  • Metabolic changes (e.g., hyperglycemia, dyslipidemia, weight gain)
  • Neuroleptic malignant syndrome
  • Hepatotoxicity
  • Fever
  • Pulmonary embolism
  • Anticholinergic toxicity (e.g., constipation, urinary retention)
  • Interference with cognitive motor performance

It deserves restating that the benefits of treatment for TRS often outweigh the potential for significant side effects. Slow titration of clozapine combined with close monitoring for, and management of, adverse reactions can help increase tolerability.10

MEDICATION AND SMOKED TOBACCO INTERACTIONS

Current medications and social history must be considered in patients taking clozapine. Guidance on how to anticipate and manage interactions includes:3

  • Reducing clozapine doses to one-third of the usual dose when administered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin)
  • Avoiding concomitant use of strong CYP3A4 inducers (e.g., rifampin, phenytoin)
  • Reducing clozapine doses when CYP1A2 inducers, like tobacco smoking, or CYP3A4 inducers, like carbamazepine, are discontinued
    • There are case reports of clozapine toxicity associated with abrupt tobacco smoking cessation or a significant decrease in number of cigarettes per day.17,18 Note that the interaction is associated with tobacco smoking only and not nicotine use from other sources (e.g., smokeless tobacco, nicotine-containing smoking cessation therapies).
    • Be mindful of smoking history for patients that are admitted to facilities where access to cigarettes is limited or in those patients who otherwise have limited capability to smoke

DOSING CONSIDERATIONS

Conservative initiation and titration are the keys to increased tolerability:3,10

  • The recommended starting dose of clozapine is 12.5mg once or twice daily
  • If it is well tolerated (monitor for side effects like hypotension, excessive sedation), increase in increments of 25mg to 50mg daily to achieve a target dose of 150mg to 225mg twice daily at the end of a two-week titration
  • Maximum daily dosing is 450mg twice a day

When restarting clozapine after an interruption of therapy, proactively lower the dose to minimize risk of hypotension, bradycardia, and syncope. A temporary dose reduction is necessary to safely resume therapy.3,10

  • If 1 day of dosing is missed – resume treatment at 40 to 50% of the established dose3,10
  • If 2 days of dosing are missed – resume dose at 25% of the established dose3,10
  • For interruptions > 2 days – restart therapy at 12.5mg once or twice daily. For patients that are being reinitiated due to an interruption of therapy, it is not necessary to taper as slowly as with the first titration; dosing should be modified based on patient symptoms. 3,10

MONITORING

There is discussion in professional communities that blood count monitoring recommendations for clozapine should be reassessed, especially after two years of therapy.12 The drug labeling in the U.S., however, has not been revised to reflect this recommendation. Current labeling recommends monitoring white blood cell counts (i.e., CBC with differential): 3,10

  • At baseline to establish the presence of a normal neutrophil count
  • Weekly for the first 6 months of therapy (i.e., day 1 to month 6)
  • Every 2 weeks for the next 6 months of therapy (i.e., month 7 to month 12)
  • Every 4 weeks thereafter for the duration of therapy (i.e., month 13 and thereafter)

Risk of agranulocytosis is highest in the first 6 months of therapy and is estimated to occur at a rate of 0.8%:3

  • Mild neutropenia (ANC between 1000 to 1499/microL) does not require dose adjustment; increased blood monitoring to 3 times weekly is recommended until ANC levels are above 1500/microL
  • Moderate neutropenia (ANC between 500 to 999/microL) warrants holding clozapine therapy and daily monitoring until the ANC is ≥ 1000/microL, at which point clozapine can be restarted
  • Severe neutropenia (< 500/microL) warrants discontinuation of clozapine therapy. Rechallenge should only occur if the benefits outweigh the risks. (See “Dosing Considerations” above)

QT prolongation: Obtain an electrocardiogram (ECG) prior to starting clozapine and repeat once the patient is on maintenance dosing. Seek a cardiology consultation in patients who develop tachycardia and a QTc >500 msec while on clozapine.10

Myocarditis: Individuals with preexisting heart disease are at greater risk of morbidity from clozapine-induced myocarditis—initiate clozapine in these patients only in an inpatient setting with cardiac monitoring. For others, monitor weekly for first 8 weeks of treatment for symptoms of myocarditis including malaise, chest pain, and shortness of breath.10

CONSIDERATIONS FOR HOSPICE CARE

Initiating Clozapine Therapy

Due to the complexity of initiating clozapine therapy, careful consideration is recommended before initiating in patients electing hospice care. Time to initial response can vary with some symptoms showing improvement in weeks (e.g., hallucinations, disorganized thinking, delusions) however the full therapeutic effect of clozapine may not manifest for months, limiting its utility in patients with a limited prognosis.19,20

Maintaining Clozapine Therapy

Patients entering hospice care already maintained on and tolerating clozapine should be maintained on the medication for as long as medically reasonable. For patients stable on therapy, it is reasonable to discontinue routine blood monitoring and focus on palliating signs and symptoms of neutropenia (e.g., fever, mouth sores) and managing preventable adverse effects, like constipation and hypotension.15

According to clozapine prescribing information, ANC should still be monitored at baseline and ongoing.5 However, under the former Clozapine REMS, an exception existed for hospice, allowing the reduction of ANC monitoring frequency to every 6 months.21 While mandatory reporting is no longer necessary, it set a precedent that end-of-life care providers can justify modifying standard monitoring protocols.

Clozapine discontinuation is associated with significant withdrawal symptoms (e.g., psychosis, agitation, clonus, cholinergic symptoms like nausea, insomnia, delirium, and withdrawal associated catatonia).22 If therapy needs to be stopped in patients with a normal ANC, it is recommended to taper clozapine doses; however, an optimal regimen is not defined.15 Prescribing information suggests gradually reducing doses over several weeks.3

When patients with a history of treatment resistant conditions become stabilized on clozapine and then elect hospice care, it is important to maintain therapy to prevent relapse, when feasible. Clozapine is typically reserved for treatment resistant conditions—patients typically have a history of relapse and failed several courses and dose titrations of other antipsychotics. Switching from clozapine to another antipsychotic after a first relapse in a patient with schizophrenia more than doubles the risk of a second relapse.23 This complicates therapeutic interchange when considering discontinuation strictly for formulary adherence.

Clozapine therapy truly embodies the healthcare philosophy of weighing medication risk vs. benefit. For patients burdened with treatment-resistant schizophrenia, clozapine can be a life-changing medication and deserves thoughtful consideration of continued use during hospice care to prevent relapses and optimize patient comfort.

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References

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