Clozapine

Indications

Clozapine is an antipsychotic that should be offered to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least 2 different antipsychotic drugs (i.e. treatment resistant schizophrenia).

Also, it is used to treat psychosis associated with Parkinson's disease.



Initiation Schedule

Start treatment at a low dose and to increase dosage slowly.

  • Many of the adverse effects of clozapine are dose-dependent and associated with speed of titration.
  • Adverse effects (e.g. sedation, hypersalivation and hypotension) also tend to be more common and severe at the beginning of therapy.

Taken at night.

  • Blood pressure should be monitored hourly for 6 hours because of the hypotensive effect of clozapine.
  • This monitoring is not usually necessary if the first dose is given at night.



Missed Doses

If, for any reason, a patient misses <2 days' clozapine, restart at the dose prescribed before the event. Do not administer extra tablets to catch up.

If >2 days are missed, restart at 12.5 mg daily and increase slowly.

NOTE: If clozapine treatment is stopped abruptly, there is a need to monitor for symptoms of cholinergic rebound, such as nausea, vomiting, diarrhoea, sweating and headache,as well as the possible emergence of dystonias, dyskinesias and catatonic symptoms.



Mandatory Blood Monitoring

Baseline and regular blood monitoring (white blood cells, absolute neutrophils, eosinophils and platelets) must be carried out before medication is supplied.

  • Weekly for the first 18 weeks of treatment
  • Fortnightly for the next 34 weeks of treatment
  • At 4-week intervals thereafter.

This is because neutropenia, leading to agranulocytosis, is a known adverse reaction to clozapine.

  • FDA recommends that treatment with clozapine to be stopped when neutrophils fall below 1000/mm3 (compared with UK recommendations for cessation if ANC < 1500/mm3).
  • Benign ethnic neutropenia (BEN) is a widely recognised, hereditary condition in which the neutrophil count is relatively low. People of African or Middle Eastern descent have a higher prevalence. Many countries allow registration of BEN status whereby different (lower) limits are set for neutrophil counts in these patients.

NOTE: The use of iatrogenic agents to elevate white cell count (e.g. lithium and granulocyte-colony stimulating factor) in patients with clear prior clozapine-induced neutropenia is not recommended.

Patients should be reminded to contact their doctor immediately if any kind of infection, fever, sore throat or other flu-like symptoms develop.

  • Differential blood counts must be performed immediately if any symptoms or signs of an infection occur.



Serious Cardiac Adverse Effects

Fatal myocarditis (most commonly in first 2 months) and cardiomyopathy reported.

  • Advise patients to inform staff if they experience persistent tachycardia (although commonly benign), palpitations, shortness of breath, fever, arrhythmia, symptoms mimicking myocardial infarction, chest pain and other unexplained symptoms of heart failure.



Intestinal Obstruction

Impairment of intestinal peristalsis, including constipation, intestinal obstruction, faecal impaction, and paralytic ileus, (including fatal cases) reported.

  • Clozapine should be used with caution in patients receiving drugs that may cause constipation (e.g. antimuscarinic drugs) or in those with a history of colonic disease or lower abdominal surgery.

Effective treatment or prevention of constipation is essential as death my result.

  • Stimulant laxatives (senna) are first-line treatments, adding emollients (docusate) and/or osmotics (macrogols) if needed.
  • Bulk-forming laxatives should usually be avoided as the underlying cause is gastric hypomotility.



Weight Gain

Weight gain is common and often profound (4.5 kg in the first 10 weeks).

  • Dietary counselling is essential.



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