Patients must have a normal white blood cell (wbc) count and differential count prior to starting clozapine therapy. Subsequently, a wbc count and differential count must be carried out at least weekly for the first 26 weeks of treatment with clozapine and at least at two-week intervals thereafterı. Monitoring must continue for as long as the patient is on the drug, as well as for at least 4 weeks after the discontinuation of treatment. Furthermore, monitoring should occur at least weekly for a period of 4 weeks following discontinuation of clozapine therapy, irrespective of the cause of discontinuation.
Apo-clozapine is available only through a distribution system (Apo-Clozapine risk management program) that requires weekly or every-two-week hematological testing prior to the dispensing of the next period's supply of Apo-Clozapine (see indications).
ıThe change from a weekly to a Aonce every 2 weeks@ schedule should be evaluated on an individual patient basis after 26 weeks of treatment. This decision should be made based upon the clinical judgment of the treating physician, and if he/she deems it appropriate, a consulting hematologist, as well as the patient's willingness to pursue a given frequency of blood monitoring. In turn, the clinical evaluation should take into consideration possible factors that would place the patient in a higher risk group, as well as the hematological profile of the patient during the first 26 weeks of treatment.
Granulocytopenia (defined as a granulocyte count of less than 1.5 x 109/L) and agranulocytosis (defined as a granulocyte count of less than 0.5 x 109/L, including
polys+bands) have been estimated to occur in association with clozapine use at an incidence of 3% and 0.7%, respectively. These incidences are derived from post-marketing data as per June 1993, covering over 60 000 patients treated with clozapine for up to 3 years in the U.S., Canada and U.K. Approximately 88% of the cases of agranulocytosis have occurred during the first 26 weeks of therapy.A fatality rate of 32% for clozapine-induced agranulocytosis had been reported in association with clozapine use as of December 31, 1989. However, more than half of these deaths occurred before 1977, prior to the recognition of the risk of agranulocytosis and the need for routine blood monitoring. From February 1990 to August 21, 1997, among approximately 150 409 patients treated with clozapine in the U.S., 585 new cases of agranulocytosis have been reported, of which 19 (3.2%) had a fatal outcome.Fatalities occurring in association with clozapine-induced
granulocytopenia/agranulocytosis have generally resulted from infections due to compromised immune system responses. Therefore, patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat, flu-like complaints or any other signs of infection.All patients must be screened to ensure that they do not have a history of
neutropenia/ agranulocytosis associated with clozapine use (i.e., are not in the Non-rechallengeable databases of any of the current approved suppliers of
clozapine).
Apo-Clozapine treatment should be initiated and carried out according to the following guidelines:
Treatment should not be initiated if the WBC count is less than 3.5 x 109/L and/or the absolute neutrophil count (ANC) is less than 2.0 x 109/L, or if the patient has a history of a myeloproliferative disorder, or toxic or idiosyncratic agranulocytosis or severe granulocytopenia (with the exception of
granulocytopenia/agranulocytosis from previous
chemotherapy). Independently of their blood monitoring regimen (weekly or at 2-week intervals), patients should be evaluated immediately and WBC and differential counts checked at least twice weekly if after the initiation of
treatment: the total WBC count falls to between 2.0 x 109/L and 3.5 x
109/L, the ANC falls to between 1.5 x 109/L and 2.0 x
109/L, a single fall or sum of falls in WBC count of 3.0 x 109/L or more is measured in the last 4 weeks, reaching a value below 4.0 x
109/L a single fall or sum of falls in ANC of 1.5 x 109/L or more is measured in the last 4 weeks, reaching a value below 2.5 x 109/L,
and/or flu-like complaints or other symptoms appear which might suggest
infection.
In the event of a fall in total WBC to below 2.0 x 109/L or in ANC to below 1.5 x 109/L,
Apo-Clozapine therapy must be immediately withheld and the patient closely monitored. The patient is to be assigned a Non-Rechallengeable status upon confirmation of fall in wbc and neutrophil counts.
Apo-Clozapine therapy must not be resumed. Particular attention should be paid to any flu-like complaints or other symptoms which might suggest infection. If the patient should develop a further fall in the WBC count to below 1.0 x 109/L, or a decrease in ANC to below 0.5 x 109/L, it is recommended that patients be placed in protective isolation with close observation and be watched for signs of infection by their physician. Should evidence of infection develop, the appropriate cultures should be performed and an appropriate antibiotic regimen instituted. |
The development of granulocytopenia and agranulocytosis does not appear to be dose dependent, nor is duration of treatment a reliable predictor. Approximately 88% of the cases have occurred in the first 26 weeks of treatment, but some cases have developed after years of clozapine use. The incidence of neutropenia and agranulocytosis associated with the use of clozapine increases as a function of age. Experience in the U.S. (approximately 58 000 patients, as of June 1993) reveals that patients over 50 years old would present an approximately 2 to 3 times higher incidence of agranulocytosis when compared with the overall incidence in patients treated with clozapine.
Patients who have shown hematopoietic reactions to other medications may also be more likely to demonstrate such reactions with clozapine. A disproportionate number of the U.S. cases of agranulocytosis occurred in patients of Jewish origin compared to the overall proportion of such patients exposed to the drug in pre-marketing clinical experience in the United States.
Agranulocytosis associated with other antipsychotic drugs has been reported to occur with a greater frequency in patients who are cachectic or have a serious underlying medical illness.
Important safety information regarding a constellation of cardiovascular events reported in patients treated with clozapine:
Cardiovascular Toxicity: Analysis of safety databases suggests that the use of clozapine is associated with an increased risk of myocarditis especially during, but not limited to, the first month of therapy. Myocarditis has been reported in patients 19 years of age and older, at dosages within the approved dosage range and during titration of clozapine. In Canada, there have been 9 reported cases of
myocarditis. Of these, three have been fatal. Given the estimated 15,600 Canadian clozapine-treated patients as of August 2001, this represents an estimated incidence of 0.06% for all reports of myocarditis (or 1/1667 patients) and 0.02% for myocarditis fatalities (or 1/5200).Pericarditis, pericardial effusion and cardiomyopathy have also been reported in association with clozapine use, as have heart failure, myocardial infarction and mitral insufficiency; these reports include fatalities. In patients who develop persistent tachycardia at rest accompanied by other signs and symptoms of heart failure (e.g. chest pain, tachypnoea (shortness of breath), or arrhythmias), the possibility of
myocarditis, cardiomyopathy and/or other cardiovascular dysfunction must be considered. Other symptoms which may be present in addition to the above include fatigue, flu-like symptoms, fever that is otherwise unexplained, hypotension and/or raised jugular venous pressure.The occurrence of such signs and symptoms necessitates an urgent diagnostic evaluation for
myocarditis, cardiomyopathy and/or other cardiovascular dysfunction by a cardiologist. Patients with a family history of heart failure should have a cardiac evaluation prior to commencing treatment; clozapine is contraindicated in patients with severe cardiac disease.In patients in whom myocarditis is suspected, clozapine treatment should be promptly discontinued. Patients with clozapine-induced myocarditis should not be re-exposed to clozapine.
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Background Information For Cardiotoxicity
Boxed Warning (as of early 2002):
Myocarditis, pericarditis and pericardial effusion
Canadian Reports
In Canada, a total of 16 post-marketing surveillance spontaneous reports of
myocarditis/pericarditis/pericardial effusion have been received by Health Canada since marketing in 1991 (see also boxed warning regarding myocarditis cases). Information additional to the Boxed Warning: the age range was 19-37 years; the shortest known clozapine treatment duration was 2 weeks.
International Reports
Reporting incidences for myocarditis can be reliably calculated from the four countries with clozapine national registries (USA, United Kingdom, Canada, Australia). The lowest rate is reported in the U.S. (1/20 000 person years) and the highest in Australia (1/800 person years). Of these 81 cases, 37% were fatal, with 80% of fatal cases showing evidence of myocarditis at autopsy. When all international reports of myocarditis are included (n = 213 cases), the myocarditis rate is 1/14000 patient years; 23% of cases had a fatal outcome and 85% occurred within the first two months of initiation of clozapine therapy. Recurrences of myocarditis upon rechallenge with clozapine have been documented.
Another analysis of clozapine and myocarditis revealed that 70% of patients were under 50 years of age; thus, clozapine-associated myocarditis can occur in younger patients. Dosages were mostly in accordance with current labelled dosage recommendations, with a third of patients taking less than therapeutic doses; this likely reflects the occurrence of myocarditis during dose titration.
There are also reports of pericarditis/pericardial effusion, some of which have been fatal. Eosinophilia has been co-reported in some cases, which may indicate that the carditis is a hypersensitivity reaction to clozapine; however, it is not known whether eosinophilia is a reliable predictor of
carditis.
Cardiomyopathy/heart failure/mitral insufficiency
Canadian Reports
In Canada, seven cases of cardiomyopathy and 3 cases of heart
failure/mitral insufficiency have been reported to Health Canada, with individual cases reported to have concomitant
myo/endocarditis. The age range is 19-55 years. Two of the reports of heart failure are known to have been fatal (61y male, 46y male).
International Reports
A total of 178 cardiomyopathy reports (18% fatal), have been received by
Novartis. Analysis of the reports revealed that four times as many men as women were diagnosed with
cardiomyopathy. About 80% of the cases occurred in patients under the age of 50; the incidence rate of spontaneous reports of cardiomyopathy for this age range was greater in clozapine-treated patients than in the general population in established international market economies.
Diagnosis was confirmed (by echocardiography or autopsy) in 44% of the cases. Typically, the clozapine dose was within therapeutic range, with the duration of treatment more than 6 months in 65% of the patients. There was no other apparent cause of the cardiomyopathy in about 50% of all reported cases of cardiomyopathy and in 28% of fatalities (including history, concomitant medications,
comorbidities), with an average age of approximately 37 years. Terms most commonly co-reported with cardiomyopathy were: congestive heart failure (21%), heart rate and rhythm disorders (10%), cardiomegaly (8%). In the 4 cases where follow-up was reported after withdrawal of clozapine, there was improvement of the
cardiomyopathy.
Myocardial infarction
In Canada, 30 reports of myocardial infarction in patients receiving clozapine have been received by Health Canada with 50% of cases known to be fatal.
Other Adverse Cardiovascular and Respiratory Effects
Apo-Clozapine should be used with caution in patients with known cardiovascular and/or pulmonary disease, particularly in those with cardiac arrhythmias and conduction disturbances.
Orthostatic hypotension, with or without syncope, can occur with Apo-Clozapine
and may represent a continuing risk in some patients. Rarely (approximately 1 case per 3,000 patients in the United States), collapse can be profound and can be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation and may even occur on first dose. In one report, initial doses as low as 12.5 mg were associated with collapse and respiratory arrest. When restarting patients who have had even a brief interval of
Apo-Clozapine (clozapine), i.e. 2 days or more since the last dose, it is recommended that treatment be reinitiated with one-half of a 25 mg tablet (12.5 mg) once or twice daily (see DOSAGE AND ADMINISTRATION).
Cases of collapse/ respiratory arrest/ cardiac arrest during initial clozapine treatment occurred in patients administered clozapine by itself and in patients administered clozapine in combination with benzodiazepines or other psychotropic drugs. Although it has not been established that there is an interaction between
Apo-Clozapine (clozapine) and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.
Tachycardia, which may be sustained, has been observed in approximately 25% of patients taking
Apo-Clozapine with patients having an average increase in pulse rate of 10 to 15
bpm. The sustained tachycardia is not simply a reflex response to hypotension and is present in all positions monitored. Tachycardia may be due to the anticholinergic effect of
Apo-Clozapine and its ability to elevate plasma norepinephrine. Either tachycardia or hypotension may pose a serious risk for an individual with compromised cardiovascular function.
A minority of clozapine-treated patients experience ECG repolarization changes similar to those seen with other antipsychotic drugs, including S-T segment depression and flattening or inversion of T waves. The clinical significance of these changes is unclear. However, in clinical trials with clozapine, several patients experienced significant cardiac events, including ischemic changes, myocardial infarction, arrhythmias, and sudden death. In addition, there have been post-marketing reports of congestive heart failure. Causality assessment was difficult in many of these cases due to serious pre-existing cardiac disease and plausible alternative causes. Rare instances of sudden, unexplained death have been reported in psychiatric patients, with or without associated antipsychotic drug treatment, and the relationship of these events to antipsychotic drug use is unknown.
Caution should be used in administering Apo-Clozapine to patients having a history of seizures or other predisposing factors.
Seizures have been estimated to occur in association with clozapine use at a cumulative incidence at 1 year of approximately 5%, based on the occurrence of 1 or more seizures in the patients exposed to clozapine during clinical trials in the U.S. Dose appears to be an important predictor of seizure. At doses below 300 mg/day, seizure risk is comparable to that of other antipsychotic drugs (about 1 to 2%). At higher doses, seizure risk rises accordingly, reaching 5% at doses of 600 to 900 mg/day. Because of the risk of seizure associated with
Apo-Clozapine use, patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving, operating machinery, swimming, climbing, etc.).
A potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome
(NMS) has been reported in association with antipsychotic drugs. Cases of NMS have been reported in patients treated with clozapine, most of which have included the concomitant use of lithium or other CNS-active agents.
Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure,
tachycardia, diaphoresis and cardiac dysrhythmias). Additional signs may include elevated creatine
phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated
NMS.
If a patient requires antipsychotic drug treatment after recovery from
NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with conventional antipsychotic drugs. Although the prevalence of tardive dyskinesia with conventional antipsychotics appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the beginning of treatment, which patients are likely to develop the syndrome. Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive
dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment itself, however, may suppress (or partially suppress) the signs and symptoms of tardive dyskinesia and thereby may possibly mask the underlying process. The effect that symptom suppression has upon the long-term course of the syndrome is unknown.
There are several reasons for predicting that Apo-Clozapine may be different from other antipsychotic drugs in its potential for inducing tardive
dyskinesia. These include the preclinical finding that it has a relatively weak dopamine receptor blocking effect and the clinical finding that it is associated with a low incidence of extrapyramidal symptoms. Very rarely tardive dyskinesia has been reported in patients on clozapine who had been previously treated with the antipsychotic agents, so that a casual relationship cannot be established. Nevertheless, it cannot be concluded without more extended experience, that
Apo-Clozapine will not induce this syndrome.
Given this consideration, Apo-Clozapine should be prescribed in a manner that is most likely to minimize the risk of the occurrence of tardive
dyskinesia. As with any antipsychotic drug, chronic
Apo-Clozapine use should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically.
Patients in whom tardive dyskinesia developed with other neuroleptics have improved on clozapine.
If signs and symptoms of tardive dyskinesia appear in a patient on Apo-Clozapine, drug discontinuation should be considered. However, some patients may require treatment with
Apo-Clozapine despite the presence of the syndrome.
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