Re-challenge following neutropenic episode (red result)

Market authorisation:¹

• Clozapine is contraindicated if there is a history of clozapine-induced agranulocytosis
• Individuals in whom clozapine has been discontinued as a result of either decreased white cell count or neutrophil count must not be re-exposed to clozapine

The use of clozapine after a ‘red’ result is therefore out with the marketing authorisation (or product licence) (referred to as ‘off-label’ or ‘off-licence’)

A ‘red’ alert is issued by the clozapine monitoring service when:

• WBC < 3.0 x 10⁹/L and/or neutrophil <1.5 x 10⁹/L

Clozapine- induced neutropenia is defined as any episode of neutropenia that occurred whilst a patient was treated with clozapine for which no other possible cause, such as concurrent infection or the concomitant use of medication known to have a substantial potential for causing agranulocytosis, could be given.²

Re-exposure can occur following an episode of clozapine-induced neutropenia under certain conditions and involves the consultant psychiatrist agreeing to an off-license disclaimer.

The success rate of rechallenge after agranulocytosis is reportedly much lower than after neutropenia.³

There are significant risks associated with a clozapine rechallenge after a blood dyscrasia and the response to a rechallenge is unpredictable.

Clozapine may be re-started within the conditions of the marketing authorisation if the (initial) red result was not confirmed by another abnormal result and when the following conditions are met for the individual clozapine monitoring services:

After a red result, daily blood testing should commence.

A subsequent red result on the day after the initial red result is classified as a confirmed red result.

Non-rechallengeable procedure is initiated:

• Monitoring service will submit patients details to Central Non-Rechallengeable Database (CNRD)
• Patient should not be re-exposed to clozapine

If there is a potential explanation for red result:

• Such as concurrent viral infection or concomitant use of medication known to have substantial potential for causing neutropenia
• Inform monitoring service at the earliest opportunity to allow clozapine to be re-titrated within the term of the market authorisation
• Diurnal variation can result in a lower neutrophil count in the morning in certain individuals; therefore timing of the sample may have an implication on the perceived result

In many situations, clozapine has been the most effective treatment and following a true, confirmed red result the individual may become increasingly unwell. Where it is felt that the benefits of a clozapine rechallenge in terms of the individual’s mental state are outweighed by the potential risks of a further blood dyscrasia, the clozapine monitoring service will consider accepting the individual for a rechallenge under an off-licence (or off-label) agreement.

The 3 clozapine manufacturers have different procedures for rechallenge so the clozapine monitoring service that the patient will be registered with should be contacted to confirm what process and documentation is required. 

If the first dyscrasia had the following characteristics, it is thought that the chances of a successful rechallenge are low (i.e. the likelihood of a further neutropenia is high):⁵

• The drop in neutrophils was inconsistent with previous counts and was not merely a slight drop in a patient with a pattern of repeated low WBC counts
• The neutropenia/agranulocytosis occurred in the first 18 weeks of treatment
• The drop in neutrophils was severe and fell below 0.5x10⁹/L
• The blood dyscrasia was prolonged (>10 days)
• There were no alternative explanations apart from clozapine for the first neutropenia/agranulocytosis, such as other medication or an infection

The following is recommended when considering a patient for a clozapine rechallenge following a blood dyscrasia;

• A second opinion from another consultant psychiatrist supporting the rechallenge.
• Advice from haematology regarding the dyscrasia and the likely relationship with clozapine and/or any other potential causes or relevant factors.
• Advice from a specialist mental health clinical pharmacist which may include a medication history and review supporting a rechallenge.
• Clear documentation of a discussion with the patient and/or carer regarding risks and benefits of a rechallenge and documentation of consent from the patient.
• For patients receiving treatment under the terms of the Mental Health (Care & Treatment) (Scotland) Act 2003, ensure that the statutory treatment plan includes the off-label prescribing of clozapine.
• Consider convening a case conference with relevant parties (including clozapine clinic staff) to discuss practical issues relating to increased monitoring and to ensure clear lines of responsibility.

A patient-specific treatment plan should be developed (which may involve input from haematology). This should include;

1. Increased monitoring

• First 12 weeks: twice weekly (in the event of 3 sequential falls in WBC and/or neutrophils, monitoring should be increased to three times weekly)*
• Weeks 12-18: weekly
• Weeks 18-52 fortnightly
• Thereafter: fortnightly* or monthly monitoring proposed in the 2nd year, according to further evaluation of risk.²

*It is the responsibility of the multidisciplinary team to ensure the increased blood monitoring takes place and results are uploaded to monitoring service website. It is vital to liaise with Leverndale pharmacy closely with regards to any increased monitoring frequency.

2. Avoiding the use of other medications which may have an impact on FBC results. Input from a specialist mental health clinical pharmacist is advisable in this respect.

3. Consider the timing of the sample. The potential diurnal variation in circulating neutrophils seen in certain individuals can result in a lower neutrophil count early in the morning compared to later in the day. Consider taking blood samples in late morning/ early afternoon to avoid this potential.

4. A clear action plan in the event of a further blood dyscrasia, including;

• Emergency contacts for key personnel (patient, carer, consultant psychiatrist, haematology, pharmacy)
• Actions to be taken in the event of an amber or red result.
• Altered monitoring parameters for WCC/ neutrophils (if these are to differ from standard clozapine monitoring parameters)
• If the management of the neutropenic episode is to include the use of prophylactic antibiotics and/or G-CSF (granulocyte-colony stimulating factor), the treatment plan should clearly state the thresholds for initiating this.
• Management options for treating the patient’s mental state during the neutropenic episode. (NB all antipsychotics have the potential for causing/delaying recovery from neutropenia and should ideally be avoided until 2 green results have been obtained. Antipsychotics with the lowest potential for blood dyscrasias include amisulpride, aripiprazole and haloperidol).
• The patient must be given education about the relevance of any physical changes, particularly fever, sore throat or other signs of symptoms of infection, and to whom these must be reported.

5. A copy of the treatment plan must also be shared with Leverndale pharmacy.

1. Summary of Product Characteristics, electronic Medicines Compendium (eMC). Accessed online 5/1/18

2. Recommendations for rechallenge with Zaponex (clozapine) after clozapine-induced neutropenia. Leyden Delta. Mar 2017. www.ztas.co.uk. Accessed online 5/1/18

3. Manu P, Sarpal D, Muir O, Kane J M, Correll C U. When can patients with potentially life threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr. Res 2012; 134:180–186

4. Zaponex Treatment Access System (ZTAS) Manual. Leyden Delta April 2015. www.ztas.co.uk Accessed online 5/1/18

5. Zaponex Fact Sheet- Agranulocytosis and neutropenia. www.ztas.co.uk May 2017 Accessed online 5/1/18