Appendix 16: Protocol* for First Re-Exposure to Clozapine After a Blood Dyscrasia Requiring
Appendix 16: Protocol* for First Re-Exposure to Clozapine after a Blood Dyscrasia Requiring Discontinuation
Clozapine prescribing is strictly controlled by the Summary of Product Characteristics (SPCs) requiring regular blood monitoring throughout treatment. The SPCs state that clozapine prescribing is contra-indicated in someone with a history of clozapine-induced agranulocytosis, and once therapy has been discontinued for haematological reasons, patients must not be re-exposed to clozapine.
Reuse of clozapine after a “red” result is thus unlicensed. All manufacturers have a form that allows re-exposure but it is the Consultant’s “decision and clinical responsibility alone” and includes the disclaimer that “I waive any rights I or the hospital may have against” the suppliers.
Clozapine can be a life-changing therapy and re-exposure to clozapine can both improve mental state and not necessarily lead on to a second dyscrasia.
Incidence of recurrence on first rechallenge
A review of 53 patients rechallenged with clozapine after a leucopenia or neutropenia, showed 38% had a further dyscrasia and in most it was more severe, longer-lasting and occurred more quickly. Of the 53, 55% were rechallenged successfully and remained in treatment1. A second dyscrasia incidence peaks at 5.5 weeks (range up to 150 days). A recent review has stated that “Uncertainty over the likely cause of blood dyscrasia in people taking clozapine, coupled with uncertainty over the mechanism by which clozapine causes both neutropenia and agranulocytosis, makes any attempt to restart clozapine a high-risk venture requiring the utmost caution.”2
Protocol for re-exposure following a previous dyscrasia
A protocol is a detailed plan that must be followed for a course of medical treatment. This is a protocol*. The Trust will not support anyone acting outside this protocol. This is in recognition that the mechanism for clozapine-induced neutropenia or agranulocytosis is unknown, nor the extraneous factors involved, and so extreme caution must be exercised if re-exposing someone to clozapine after a dyscrasia.
In exceptional circumstances, the Trust supports re-exposure to clozapine after agranulocytosis as follows:
The Consultant must obtain in writing:
1. A second opinion supporting the need for clozapine
2. Advice from a haematologist regarding the dyscrasia and its likely relationship with clozapine, possible other causes and any other relevant factors and a care plan put in place
3. Advice from the relevant senior specialist clinical pharmacist
4. Informed consent from the patient, including the risks (1 in 3 chance of a repeat dyscrasia) and benefits, assuring that the patient is able to retain this information. The person's capacity to consent should be considered and documented. If patient lacks capacity the Mental Capacity Act should be followed.
· This should be in collaboration with any relatives or an advocate. However, since in law no one person can give consent for another, it should be made clear he or she will be advising relatives/advocates but that they cannot consent.
If clozapine is re-prescribed:
1. Minimise the potential from contributing drugs e.g. any that might have been implicated in the original dyscrasia, any other drugs associated with blood dyscrasias.
2. Increase blood monitoring frequency and alertness, and document clear actions to be taken. The minimum should be:
· Twice weekly for the first ten weeks, then weekly to 18 weeks, then fortnightly to one year plus TWO samples before re-starting to establish an adequate baseline
· This should be more frequent (eg 3 times a week) should 3 falls in a row occur or if there is any suspicion of a dyscrasia developing
· A slightly slower dose escalation should be considered, although there is little evidence as to whether this reduces the risk or not.
3. Clear action plan made in the notes and copied to pharmacy should a dyscrasia recur:
· Emergency contacts 24/7 (patient, carer, RMO, pharmacy) haematologist
· Discontinuing therapy plan
· Replacement therapies or management options
· The patient must be an inpatient.
4. Service user educated about the relevance of any physical changes, particularly fever, sore throat or other signs or symptoms of infection, and to whom these must be reported and information leaflet given.
Second rechallenge to clozapine
Personal communication with Novartis CPMS (Feb 2011)
· 3 patients have been rechallenged with clozapine for the second time.1 is still continuing with green blood results
· It was difficult to identify the patients on clozapine and GCSF. It appears that6 patientsare continuing with green results due to GCSF. It is not clear if these patients have had one or two clozapine rechallenges.
· No deaths haveoccurred.
No information available from manufacturers of generic clozapine .
References
1. Rechallenge with clozapine following leucopenia or neutropenia during previous therapy. Dunk, Annan and Andrews, Br J Psychiatry 2006;188:255-63.
2. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities.
Whiskey and Taylor, CNS Drugs 2007;21:25-35.
Checklist for clozapine re-challenge
The following checklist should be completed, retained in the notes and a copy sent to pharmacy. The re-supply of clozapine will not occur unless all of the below has been completed and approved in pharmacy and this form is signed and dated.
Action / Yes/No * / NotesHas a written report been obtained from a second opinion supporting the need for clozapine re-challenge? / YES/NO / This must/should be a Consultant Psychiatrist from the same speciality and not a member of another profession (as in ‘second opinion’ under MHA).
Name:
Has advice been sought from a consultant haematologist regarding the dyscrasia, other causes and relevant factors and a written report obtained? / YES/NO / Please state name of haematologist and date of contact:
Has the advice been documented and incorporated into care plan for dyscrasia.? / YES/NO / Include emergency contact names and numbers (including out of hours )
Advice from specialist clinical pharmacist has been sought and received / YES/NO / Clinical Pharmacists should review notes and enter any relevant comments in them. eg confounding factors for dyscrasias
Name of Pharmacist:
Written, informed consent obtained, discussion to include
· Risk of repeat dyscrasia (1 in 3
· Assessment as to capacity to consent considered and documented.
OR
· MHA commissioners contacted / YES/NO / If unable to consent, MHA commissioners should be contacted.
Should include written information to the service user about what physical changes to report, particularly fever, sore throat or other signs or symptoms of infection
Discussion with relatives and carers or advocate as to the nature of the treatment and relative risks / YES/NO / Cannot consent for patient. They can only advise (see note above)
Discussion and understanding of the commitment to increased blood test frequency / YES/NO / Twice weekly for 10 weeks
Weekly from weeks 11 to 18 (inclusive)
Fortnightly to week 52 (inclusive)
Then monthly ongoing
Clear direction in notes for increased blood test monitoring if falls in WBC counts occur three times in a row / YES/NO / Should 3 falls in WBC occur then frequency of testing should increase to 3 times per week at minimum.
Action plan completed with input from the haematologist and placed in notes and pharmacy should a dyscrasia occur / YES/NO / See attached “Action plan after re-occurrence of blood dyscrasia after clozapine re-challenge.”
* If answering “no” to any of these questions refer to pharmacy.
Consultant’s Name and Signature.
Dated:
Action plan should there be a re-occurrence of blood dyscrasia after clozapine re-challenge
This form should be retained in the notes and a copy sent to pharmacy.
Emergency Contacts:
Doctor to complete details.
Patient / Carer/ nearestrelative / RMO (within hours) / Pharmacy
(within hours) / Out of Hours phone (if applicable)
Name:
Address:
Post Code
Home Phone No.
Mobile Phone No.
Discontinuation Advice:
Replacement therapy and management options should blood dyscrasia recur.
Consultant Psychiatrist signature: / Consultant Haematologist signature:Date: / Date: