Special precautionary measure: Agranulocytosis:
Because of the association of clozapine with agranulocytosis, the following precautionary measures are mandatory: Drugs known to have a substantial potential to depress bone marrow function should not be used concurrently with clozapine. In addition, the concomitant use of long-acting depot antipsychotics should be avoided because of the impossibility of removing these medications, which may be potentially myelosuppressive, from the body rapidly in situations where this may be required, e.g. granulocytopenia.
Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to starting therapy.
Patients who have low white blood cell (WBC) counts because of benign ethnic neutropenia should be given special consideration and may be started on clozapine after agreement of a haematologist.
Clozapine (Leponex) must be dispensed under strict medical supervision in accordance with official recommendations.
White Blood Cell (WBC) counts and Absolute Neutrophil Count (ANC) monitoring:
White blood cell count (WBC) and differential blood counts must be performed within 10 days prior to starting treatment to ensure that only patients with normal leukocyte (WBC ≥3500/mm3
(≥3.5 x 109
/L)) and absolute neutrophil counts (ANC ≥2000/mm3
(≥2.0 x 109
/L)) will receive clozapine. After the start of clozapine (Leponex) treatment, regular WBC count and ANC must be performed and monitored weekly for 18 weeks, and thereafter at least every four weeks throughout treatment, and for 4 weeks after complete discontinuation.
Prescribing physicians should comply fully with the required safety measures. At each consultation, the patient should be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as, fever or sore throat and to other evidence of infection, which may be indicative of neutropenia. A differential blood count must be performed immediately if any symptoms or signs of an infection occur.
Low WBC count and/or ANC:
If during the first 18 weeks of clozapine (Leponex) therapy, the WBC count falls to between 3500/mm3
and/or the ANC falls to between 2000/mm3
, haematological evaluations must be performed at least twice weekly.
After 18 weeks of therapy, haematological evaluations should be performed at least twice weekly if the WBC count falls to between 3000/mm3
and/or the ANC falls to between 1500/mm3
In addition, if, during therapy, the WBC count is found to have dropped by a substantial amount from baseline, a repeat WBC count and a differential blood count should be performed. A substantial drop is defined as a single drop of 3000 mm3
or more in the WBC count or a cumulative drop of 3000 mm3
or more within three weeks.
Immediate discontinuation of clozapine (Leponex) is mandatory if the WBC count is less than 3000/mm3
or the ANC is less than 1500/mm3
during the first 18 weeks of therapy, or if the WBC count is less than 2500/mm3
or the ANC is less than 1000/mm3
after the first 18 weeks of therapy. WBC counts and differential blood counts should then be performed daily and patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection. Following discontinuation of treatment, haematological evaluation is required until haematological recovery has occurred.
If clozapine has been withdrawn and WBC count falls further to below 2000/mm3
and/or the ANC falls below 1000/mm3
, the management of this condition must be guided by an experienced haematologist. If possible, the patient should be referred to a specialised haematological unit, where protective isolation and the administration of GM-CSF (granulocyte-macrophage colony stimulating factor) or G-CSF (granulocyte colony stimulating factor) may be indicated. It is recommended that the colony stimulating factor therapy be discontinued when the neutrophil count has returned to a level above 1000/mm3
Patients in whom clozapine has been discontinued as a result of white blood cell deficiencies (see previously mentioned) must not be re-exposed to clozapine.
It is recommended that the haematological values be confirmed by performing two blood counts on two consecutive days; however, clozapine should be discontinued after the first blood count. (See Tables 1 and 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In the event of interruption of therapy for non-hematological reasons:
Patients who have been on clozapine (Leponex) for more than 18 weeks and have had their treatment interrupted for more than 3 days but less than 4 weeks should have their WBC count and ANC monitored weekly for an additional 6 weeks. If no hematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. If treatment has been interrupted for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment (see Dosage & Administration).
Other Precautions: Eosinophilia:
In the event of eosinophilia, discontinuation of clozapine is recommended if the eosinophil count rises above 3000/mm3
. Therapy should be re-started only after the eosinophil count has fallen below 1000/mm3
In the event of thrombocytopenia, discontinuation of clozapine is recommended if the platelet count falls below 50 000/mm3
In patients suffering from cardiovascular disorders (note: severe cardiovascular disorders are contraindications) the initial dose should be 12.5 mg given once on the first day, and dosage increase should be slow and in small increments (see Dosage & Administration).
Orthostatic hypotension, with or without syncope, can occur during clozapine treatment. Rarely (about one case per 3000-treated patients), collapse can be profound and may be accompanied by cardiac and/or respiratory arrest. Such events are more likely to occur during initial titration in association with rapid dose escalation; on very rare occasions they occurred even after the first dose. Therefore, patients commencing treatment require close medical supervision.
Myocarditis and Cardiomyopathy; Tachycardia that persists at rest, accompanied by arrhythmias, shortness of breath or signs and symptoms of heart failure, may rarely occur during the first month of treatment and very rarely thereafter. The occurrence of these signs and symptoms necessitates an urgent diagnostic evaluation for myocarditis, especially during the titration period. If the diagnosis of myocarditis is confirmed, clozapine should be discontinued. There have been postmarketing reports of myocarditis including fatal cases. Later in treatment, the same signs and symptoms may very rarely occur and may be linked to cardiomyopathy. Further investigation should be performed and if the diagnosis is confirmed, the treatment should be stopped unless the benefit clearly outweighs the risk to the patient.
In patients who are diagnosed with cardiomyopathy while on clozapine treatment, there is potential to develop mitral valve incompetence. Mitral valve incompetence has been reported in cases of cardiomyopathy related to clozapine treatment. These cases of mitral valve incompetence reported either mild or moderate mitral regurgitation on two-dimensional echocardiography (2DEcho) (see Adverse Reactions).
Monitoring of standing and supine blood pressure is necessary during the first weeks of treatment in patients with Parkinson's disease.
There have been postmarketing reports of myocardial infarction including fatal cases. Causality assessment was difficult in the majority of these cases because of serious pre-existing cardiac disease and plausible alternative causes.
QT interval prolongation:
As with other antipsychotics, caution is advised in patients with known cardiovascular disease or family history of QT prolongation.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase the QTc interval.
Cerebrovascular adverse events:
An increased risk of cerebrovascular adverse events has been seen in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Clozapine should be used with caution in patients with risk factors for stroke.
Risk of thromboembolism:
Since clozapine may cause sedation and weight gain, thereby increasing the risk of thromboembolism, immobilization of patients should be avoided.
Atypical antipsychotic drugs, including clozapine, have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.
On rare occasions, severe hyperglycemia, sometimes leading to ketoacidosis/hyperosmolar coma, has been reported during clozapine treatment in patients with no prior history of hyperglycemia. While a causal relationship to clozapine use has not been definitely established, glucose levels returned to normal in most patients after discontinuation of clozapine, and re-challenge produced a recurrence of hyperglycemia in a few cases. The effect of clozapine on glucose metabolism in patients with diabetes mellitus has not been studied. Impaired glucose tolerance, severe hyperglycemia, ketoacidosis and hyperosmolar coma have been reported in patients with no prior history of hyperglycemia. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Exacerbation should be considered in patients receiving clozapine who develop symptoms of hyperglycemia, such as polydipsia, polyuria, polyphagia or weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. In patients with significant treatment-emergent hyperglycemia, discontinuation of clozapine (Leponex) should be considered.
There is a risk of altering the metabolic balance resulting in slight impairment of glucose homeostasis and a possibility of unmasking a pre-diabetic condition or aggravating pre-existing diabetes.
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended.
Weight gain has been observed with atypical antipsychotic use, including clozapine. Clinical monitoring of weight is recommended.
Clozapine may lower seizure threshold. In patients with a history of seizures the initial dose should be 12.5 mg given once on the first day, and dosage increase should be slow and in small increments (see Dosage & Administration).
Clozapine exerts anticholinergic activity, which may produce undesirable effects throughout the body. Careful supervision is indicated in the presence of prostatic enlargement and narrow-angle glaucoma. Probably on account of its anticholinergic properties, clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction, paralytic ileus, megacolon and intestinal infarction/ischaemia (see Adverse Reactions). On rare occasions these cases have proved fatal.
During clozapine therapy, patients may experience transient temperature elevations above 38°C, with the peak incidence within the first 3 weeks of treatment. This fever is generally benign. Occasionally, it may be associated with an increase or decrease in the WBC count. Patients with fever should be carefully evaluated to rule out the possibility of an underlying infection or the development of agranulocytosis. In the presence of high fever, the possibility of neuroleptic malignant syndrome (NMS) must be considered. If the diagnosis of NMS is confirmed, clozapine should be discontinued immediately and appropriate medical measures should be administered.
Clozapine may cause seizures, somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Rebound, withdrawal Effects:
If abrupt discontinuation of clozapine treatment is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting and diarrhea.
Driving and using machines:
Owing to the ability of clozapine to cause sedation and lower the seizure threshold, activities such as driving or operating machinery should be avoided, especially during the initial weeks of treatment.
Special Populations: Hepatic impairment:
Patients with stable pre-existing liver disorders may receive clozapine, but must undergo regular liver function tests. Such tests should be performed immediately in patients who develop symptoms of possible liver dysfunction such as nausea, vomiting and/or anorexia during treatment. If the elevation of the values is clinically relevant or if symptoms of jaundice occur, treatment must be discontinued. It may be resumed (see Re-starting therapy under Dosage & Administration) only when the results of liver function tests are normal. In such cases, liver function should be closely monitored after re-introduction of clozapine.
In patients suffering from mild to moderate renal impairment, an initial dose of 12.5 mg/day (half a 25 mg tablet) is recommended (see Dosage & Administration).
Use in Elderly: Patients aged 60 years and older:
It is recommended that treatment be initiated at a particularly low dose (12.5 mg given once on the first day) and subsequent dose increments be restricted to 25 mg/day.
Clinical studies with clozapine did not include sufficient numbers of subjects aged 60 years and over to determine whether or not they respond differently from younger subjects.
Orthostatic hypotension can occur with clozapine (Leponex) treatment and there have been rare reports of tachycardia, which may be sustained. Patients aged 60 years and older, particularly those with compromised cardiovascular function, may be more susceptible to these effects.
Patients aged 60 years and older may also be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation.
Patients aged 60 years and older with Dementia-related Psychosis:
In patients aged 60 years and older with dementia-related psychosis, the efficacy and safety of clozapine has not been studied. Observational studies suggest that patients aged 60 years and older with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. In the published literature, risk factors that may predispose this patient population to increased risk of death when treated with antipsychotics include sedation, the presence of cardiac conditions (e.g. cardiac arrhythmias) or pulmonary conditions (e.g. pneumonia, with or without aspiration). Clozapine (Leponex) should be used with caution in patients aged 60 years and older with dementia.