Published: 9 June 2020
Revised: 29 July 2020

Safety Information

Alert Communication

Important updates to clozapine data sheets and monitoring during covid-19 pandemic


9 June 2020

Clozapine monitoring during the covid-19 pandemic
Updates to clozapine data sheets
Advice for consumers and caregivers
Information for healthcare professionals
Products affected
Further information
Useful links

Clozapine monitoring during the covid-19 pandemic

International consensus [1] is that on a case by case basis it may be appropriate to relax monitoring requirements for patients who meet ALL the following criteria:

  • Continuous clozapine treatment for longer than 12 months
  • Never had an ANC (absolute neutrophil count) < 2000/mm³ (< 2.0 x 109/L) ( or < 1500/mm³ (< 1.5 x 109/L) with history of benign ethic neutropenia)
  • No safe or practical access to testing

Please contact your local public health unit for advice on the local case numbers of covid-19 infections.

All other patients should continue with weekly/monthly monitoring.

Please contact the company to update the patient status in the monitoring database for patients returning to monthly blood testing.

Updates to clozapine data sheets

The data sheets for clozapine products in NZ have been updated. The changes include:

Dose

The expected therapeutic dose range has been adjusted from 300 - 450 mg/day to 200 - 450mg/day. After maximum therapeutic benefit has been achieved, patients should have their dose slowly reduced to the lowest effective dose.

Blood monitoring

Monitoring threshold levels for white cell counts and absolute neutrophil count have been aligned with international standards.

Constipation

The warning regarding the risk of constipation has been strengthened.

Smoking

Information on dose adjustments for patients changing their smoking habits has been added.

Advice for consumers and caregivers

  • Do not stop taking clozapine without first talking to your doctor
  • Contact your doctor immediately if you experience any of the following symptoms
    • flu-like symptoms
    • fever
    • fast and/or irregular heartbeat even at rest
    • palpitations
    • breathing problems
    • chest pain
    • unexplained tiredness
    • fewer bowel movements than normal
    • hard or dry stools, or difficulty passing gas
    • nausea or vomiting
    • bloating, belly swelling or belly pain
  • Tell your doctor if you are starting or stopping smoking

Information for healthcare professionals

  • The dose range where antipsychotic efficacy is described to be expected has been extended to 200-450 mg/day.
  • The threshold levels of WBC (white blood cell count) and ANC have been updated so there is no change after the first 18 weeks of treatment. This change in the clozapine patient monitoring systems comes into effect on 31 October 2020.
  • Continue to closely monitor for constipation, actively question patients about their bowel habits and avoid co-prescribing clozapine with other medicines that can cause gastrointestinal hypomotility.
  • Consider prophylactic use of laxatives when starting clozapine in patients at high risk of experiencing constipation.
  • Remember to adjust the clozapine dose for patients changing their smoking habits.

Products affected

Product name Sponsor
Clozaril Mylan New Zealand Ltd
Clopine Douglas Pharmaceuticals Ltd

Further information

Clozapine is used to treat schizophrenia when other antipsychotic medicines either have been ineffective or have caused severe side effects. Clozapine has a number of significant side effects and patients need to be closely monitored whilst on treatment.

Data from CARM shows that while the frequency of cases of neutropenia is higher in patients that have been treated for less than one year, cases are also reported after longer periods of treatment.

In the five years to end March 2020, a total of 86 cases of neutropenia were reported to CARM and 29 of these were described as severe. The reaction occurred during the first month of treatment in 8 cases, between 1 and 12 months of treatment in 18 cases and in 44 cases the patient had been treated for more than 5 years. Last year (April 2019 to end of March 2020) 14 cases were reported, 4 of these occurred within the first year of treatment and in 7 cases the patient had been treated for more than 5 years.

Dose

Many of the side effects of clozapine are dose related. The recent review of the New Zealand data sheets highlighted that the expected therapeutic dose range provided in the New Zealand data sheet was higher than for product information in other countries. The dose range has therefore been adjusted from 300- 450 mg/day to 200-450 mg/day.

To obtain full therapeutic benefit, a few patients may require larger doses than 450 mg/day. After achieving maximum therapeutic benefit however, patients can usually be maintained effectively on lower doses. The maintenance dose should be the lowest effective dose for the individual patient. If the daily dose is 200 mg or lower, once daily administration in the evening may be appropriate.

Blood monitoring

The monitoring threshold levels for WBC and ANC have been updated, see summary of changes in the tables below:

Threshold for monitoring twice a week:
  Changed from Changed to
WBC/mm³ First 18 weeks: 3000 - 3500 After 18 weeks: 2500 - 3000 Between ≥ 3000 and < 3500
ANC/mm³ First 18 weeks: 1500 - 2000 After 18 weeks: 1000 - 1500 Between ≥ 1500 and < 2000
Threshold for immediate discontinuation:
  Changed from Changed to
WBC/mm³ First 18 weeks: ≤ 3000 After 18 weeks: < 2500 < 3000
ANC/mm³ First 18 weeks: ≤ 1500 After 18 weeks: < 1000 < 1500


These changes will come into effect in the company databases on 31 October 2020. Note that patients who would technically fall into red range on this date (i.e. those with ANC between 1000 to <1500/mm³) are to be managed based on the previous blood thresholds until resolution of that event. Only out-of-range blood results identified after 31 October will be based on the updated blood thresholds.

Constipation

The data sheets have been updated to strengthen the advice about constipation. The risk of constipation is greater with clozapine than other medicines used to treat schizophrenia [2].

Severe, sometimes fatal complications of constipation have been associated with delayed diagnosis.

It is essential to question patients about bowel habits, for example whenever a prescription is to be issued. A patient may not feel or be aware of constipation symptoms, which include fewer bowel movements than normal, especially if less than three times a week, hard or dry stools, or difficulty passing gas. Symptoms associated with serious bowel problems include nausea, bloating or belly swelling, belly pain, and vomiting. Action may need to be taken urgently, do not wait to see if symptoms settle without the use of a laxative.

Smoking

Starting or stopping smoking (but not nicotine replacement therapy or vaping) affects the level of clozapine in the blood and the dose may have to be adjusted. The data sheet has been updated to provide further advice.

In cases of sudden cessation of tobacco smoking, the plasma clozapine concentration may be increased, which may result in an increased risk of adverse drug reactions. Dose reduction is strongly recommended in the first week with therapeutic monitoring and further adjustment over the next four weeks. A dose increase may be required for patients starting smoking.

Useful links

References

  1. Siskind D, Honer WG, Clark S, et al. 2020. Consensus statement of the use of clozapine during the COVID-19 pandemic. J Psychiatry Neurosci 45(4):45-4-20061. URL: http://jpn.ca/45-4-200061/ (accessed 9 June 2020).
  2. Every-Palmer S, Nowitz M, Stanley J, et al. 2016. Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: A cross sectional study. EBioMedicine 5:125‐34. URL: https://www.sciencedirect.com/science/article/pii/S2352396416300536?via%3Dihub (accessed 9 June 2020).
Hide menus
Show menus
0 1 2 4 5 6 7 9 [ /