Treatment management

Agranulocytosis

Although it has been noted, agranulocytosis is uncommon in patients on clozapine treatment, and it should not be a barrier to prescribing it for patients with TRS who may benefit significantly from it.

In two clinical studies with a total of 250 patients treated with clozapine, four patients developed agranulocytosis (1.6%), all of whom recovered after withdrawal from treatment.1,2

As part of the Clozaril® Connect programme, Viatris offer several support services including the UK Clozaril® Patient Monitoring Service (CPMS). The CPMS monitors patients’ white blood cell counts and ANC and is a vital resource for maintaining patient safety while on Clozaril®. Although mortality rates due to agranulocytosis are low (estimated at 0.3%)3 when a monitoring service is not used, regular blood monitoring by the CPMS can markedly reduce mortality risk due to agranulocytosis to 0.01%,4 an absolute risk reduction of 0.29%.

Weight gain

Weight gain with Clozaril® is no more common than with other antipsychotics so should not be a barrier to prescribing it.

Two systematic reviews – one comparing clozapine with typical antipsychotics and one comparing clozapine with typical and atypical antipsychotics – found that weight gain occurred at a similar frequency in patients on clozapine and on typical/atypical antipsychotics.5, 6

In a clinical study, weight gain while on clozapine therapy has been shown to be less than, or similar to, that for patients on the atypical antipsychotics olanzapine, risperidone, and quetiapine.2

Other adverse events (AEs)

Adverse events with Clozaril® are similar to those experienced on other antipsychotics

Clinical studies and meta-analyses indicate that adverse events (AEs) associated with Clozaril® are generally similar to those of other typical and atypical antipsychotics including chlorpromazine, haloperidol, risperidone and olanzapine. These include hypotension, seizures, sedation, and weight gain.5, 7, 8

Dizziness, salivation, and nausea have been noted more frequently for clozapine compared with the typical antipsychotics haloperidol and chlorpromazine, whereas dry mouth and extrapyramidal symptoms have been reported more frequently with the latter.8-11

A summary of the main AE findings in clinical studies and meta-analyses is given in Table 2.

Table 2. Adverse events findings in clinical studies and meta-analyses comparing Clozaril® and other antipsychotics

Study

Clozaril® comparator

Main AEs findings

Kane, et al. 2001 Clinical, 71 patients

Haloperidol

  • At week 5, no differences between treatments were observed for occurrence of 12 of the 17 AEs listed under the Treatment Emergent Symptoms Scale.

Azorin, et al. 2001 Clinical, 273 patients

Risperidone

  • Of the 15 different AEs occurring in at least 5% of patients, no difference in incidence was observed between treatments were observed for eight of them.

McEvoy, et al. 2006 Clinical, 99 patients

Olanzapine (n=19) Quetiapine (n=15) Risperidone (n=16)

  • The proportion of patients experiencing any moderate or severe AEs was not significantly different between treatments.

  • Of the 10 categories of AE identified, no significant differences in incidence between treatments were observed for seven of them

Wahlbeck, et al. 1999 Meta-analysis

Typical antipsychotics

  • No difference was found between treatments for hypotension/dizziness, seizures, or weight gain.

  • Clozaril® caused more hypersalivation, temperature increase, and sedation but less dry mouth and extrapyramidal symptoms.

Essali, et al. 2009 Cochrane meta-analysis

Typical antipsychotics

  • No significant differences between treatments were found in the incidences of low blood pressure/dizziness.

  • Dry mouth occurred more frequently in the typical antipsychotic group.

  • Clozaril® caused more salivation and weight gain.

Chakos, et al. 2001 Meta-analysis

Olanzapine
Risperidone
Haloperidol
Chlorpromazine

  • Clozaril® was associated with similar frequencies of hypotension to olanzapine and risperidone; sedation to haloperidol and olanzapine, and concentration problems to chlorpromazine.

For full details of adverse events associated with Clozaril®, please refer to the Clozaril - Summary of Product characteristics UK or Clozaril - Summary of Product Characteristics Ireland.4

Regular monitoring of patients’ health while on Clozaril®

TRS patients on Clozaril® can sometimes suffer general health problems that can become serious if they are not addressed quickly. While patients are taking Clozaril®, it is recommended that they undergo regular health checks to monitor the following:1

  • Smoking

  • Weight

  • Blood glucose control

  • Blood lipids

  • Blood pressure

Addressing barriers to prescribing Clozaril®

  • Poor adherence to Clozaril® treatment

    Poor adherence to Clozaril® treatment

    If patients are not given adequate information about their condition and their medication, they may fail to see the real value in adhering to their treatment. Poor adherence to therapy may lead to suboptimal outcomes.

    • Only 4 in 10 (41%) schizophrenia patients feel adequately involved in decisions regarding their drug prescriptions (NAS, 2014)12

    • Only 4 in 10 (39%) schizophrenia patients are given information about their medication in a form they can easily understand (NAS, 2014)12

    Solution Giving patients more information about their schizophrenia and their drug prescriptions in an accessible form can help to build trust between the patient and the HCP. Greater trust in the doctor/patient relationship may improve adherence to therapy and hence outcomes.

  • Lack of access to point-of care testing

    Lack of access to point-of care testing

    In the past, access to a point-of-care (POC) testing device was linked to a number of Clozaril® patients for blood monitoring while on treatment.

    Solution As part of Viatris's endeavour to improve access to Clozapine for TRS patients, Viatris can provide a POC device and training to any sites with the required resources, enabling patients' bloods to be tested locally.

  • Nursing staff for patient physical health monitoring

    Nursing staff for patient physical health monitoring

    Nursing staff are required to monitor the physical health of patients on Clozaril® (i.e., smoking, weight, blood glucose control, blood lipids, blood pressure)

  • HCP and patient information on Clozaril®

    HCP and patient information on Clozaril®

    You may be concerned that you do not have adequate information on Clozaril® for HCPs and patients.

    SolutionAs part of Viatris’s Clozaril® Connect programme, we are producing HCP and patient materials, an education programme for HCPs, and two websites, one each for HCPs and patients.

  • Therapists to deliver Cognitive Behavioural Therapy (CBT)

    Therapists to deliver Cognitive Behavioural Therapy (CBT)

    Therapists are required to deliver CBT to some patients who may need it in addition to Clozaril®.

References

  1. Rosenheck R, Cramer J, Xu W, Thomas J, Henderson W, Frisman L, et al for the Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med 1997; 337: 809-15.
  2. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163: 600-10.
  3. de la Chapelle A, Kari C, Nurminen M, Hernberg S. Clozapine-induced agranulocytosis. A genetic and epidemiologic study. Hum Genet 1977; 37: 183-94.
  4. Clozaril® Summary of Product Characteristics (SmPC). Available at www.medicines.org.uk/emc/ (UK) or www.medicines.ie (Ireland) (last accessed July 2021).
  5. Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry 1999; 156: 990-9.
  6. Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry 2016; 209: 385-92.
  7. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001; 158: 518-26.
  8. Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009 Jan 21; (1): CD000059.pub2.
  9. Kane J, Marder S, Schooler N, Wirshing W, Umbricht D, Baker R, et al. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized double-blind comparison. Arch Gen Psychiatry 2001; 58: 965-72.
  10. Azorin JM, Spiegel R, Remington G, Vanelle JM, Pere JJ, Giguere M, et al. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry 2001; 158: 1305-13.
  11. Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT. Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry 1998; 155: 751-60.
  12. National Audit of Schizophrenia (NAS). Second National Audit of Schizophrenia: What you need to know. The Royal College of Psychiatrists, 2014.

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