Action And Clinical Pharmacology: Clozapine, a dibenzodiazepine derivative, is an atypical antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine-mediated behaviors differ from those exhibited by conventional antipsychotics. In contrast to conventional antipsychotics, clozapine produces little or no prolactin elevation. Clozapine exerts potent anticholinergic, adrenolytic, antihistaminic and antiserotoninergic activity.
Controlled clinical trials indicate that clozapine improves both positive and negative symptoms.
Patients on rare occasions may report an intensification of dream activity during clozapine therapy. Rapid eye movement (REM) sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.
As is true of more typical antipsychotic drugs, clinical EEG studies have shown that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs, and sharp wave activity and spike and wave complexes may also develop.
Pharmacokinetics: The absorption of orally administered clozapine is 90 to 95%. Food does not affect either the rate or the extent of absorption. Clozapine is subject to first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.
Plasma concentrations show large inter-individual differences, with peak concentrations occurring approximately 2.5 hours (range: 1 to 6 hours) after dosing. In a dose range of 37.5 mg b.i.d. to 150 mg b.i.d., the area under the curve (AUC) and the peak plasma concentration (Cmax) increase linearly in a dose-related fashion.
Clozapine is approximately 95% bound to plasma proteins. The elimination of clozapine is biphasic with a mean terminal half-life of 12 hours (range: 6 to 30 hours, calculated from 3 steady-state in vivo studies). After single doses of 75 mg, the mean terminal half-life was 7.9 hours; it increased to 14.2 hours when steady-state conditions were reached by administering daily doses of 75 mg for at least 7 days. Clozapine is almost completely metabolized prior to excretion. Only trace amounts of unchanged drug are detected in the urine and feces. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces.
Recent studies suggest that there is a significant correlation between clozapine plasma levels and clinical response. The concentrations of clozapine, and its major metabolite norclozapine, were significantly higher in responders than in nonresponders although the mean doses of clozapine did not differ between the 2 groups. Of the main metabolites, only norclozapine was found to be active. In patients who responded to treatment, plasma clozapine levels reached at least 350 to 370 ng/mL.
Indications And Clinical Uses: The management of symptoms of treatment-resistant schizophrenia. In controlled clinical trials, clozapine was found to improve both positive and negative symptoms.
Due to the significant risk of agranulocytosis and seizure associated with its use, clozapine should be limited to treatment-resistant schizophrenic patients who are non-responsive to, or intolerant of, conventional antipsychotic drugs. Non-responsiveness is defined as the lack of satisfactory clinical response, despite treatment with appropriate courses of at least 2 marketed chemically-unrelated antipsychotic drugs. Intolerance is defined as the inability to achieve adequate benefit with conventional antipsychotic drugs because of dose-limiting, intolerable adverse effects.
Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response to clozapine should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically re-evaluated.
Clozapine can be used only if regular hematological examinations can be guaranteed, as specified under Warnings and Dosage.
Clozapine is available only through a distribution system that ensures: weekly or every-2-week hematological testing prior to the delivery of the next period’s supply of medication (see Warnings); maintenance of a central national database that monitors the hematological results of all patients on clozapine and provides timely feedback to the treating physician; registration of the patient, treating physician, laboratory and dispensing pharmacist with the system.
Contra-Indications: Patients with myeloproliferative disorders, a history of toxic or idiosyncratic agranulocytosis or severe granulocytopenia (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy). Clozapine should not be used simultaneously with other agents known to suppress bone marrow function.
Clozapine is also contraindicated in patients with active liver disease associated with nausea, anorexia, or jaundice; progressive liver disease; hepatic failure.
Other contraindications include severe CNS depression or comatose states, severe renal or cardiac disease, uncontrolled epilepsy, and previous hypersensitivity to clozapine or any other components of Clozaril.
Manufacturers’ Warnings In Clinical States: Agranulocytosis: Because of the significant risk of granulocytopenia and agranulocytosis, a potentially life-threatening adverse event (see below), clozapine should be reserved for use in the treatment of schizophrenic patients who fail to show an acceptable response to adequate courses of conventional antipsychotic drug treatment, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects.
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 and at least at 2-week intervals thereafter*. 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.
*The change from a weekly to a “once 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.
Clozapine is available only through a distribution system that requires weekly or every-2-week hematological testing prior to the delivery of the next period’s supply of medication (see Indications).
Granulocytopenia (defined as a granulocyte count of less than 1.5´10L) and agranulocytosis (defined as a granulocyte count of less than 0.5´10L, 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.
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´10L and/or the absolute neutrophil count (ANC) is less than 2.0´10L, 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: i) the total WBC count falls to between 2.0´10L and 3.5´10L, ii) the ANC falls to between 1.5´10L and 2.0´10L, iii) a single fall or sum of falls in WBC count of 3.0´10L or more is measured in the last 4 weeks, reaching a value below 4.0´10L, iv) a single fall or sum of falls in ANC of 1.5´10L or more is measured in the last 4 weeks, reaching a value below 2.5´10L, and/or v) flu-like complaints or other symptoms appear which might suggest infection.
In the event of a fall in total WBC to below 2.0´10L or in ANC to below 1.5´10L, clozapine therapy must be discontinued immediately and the patient closely monitored. 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´10L, or a decrease in ANC to below 0.5´10L, 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 U.S.
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.
Seizures: Caution should be used in administering 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 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.).
Adverse Cardiovascular Effects: 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 Clozaril and may represent a continuing risk in some patients. Rarely (approximately 1 case per 3 000 patients in the U.S.), 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 the first or second day of initial dosing. Therefore, upon initiation of clozapine therapy or re-initiation of treatment in patients who have had even a brief interval off clozapine, i.e., 2 days or more since the last dose, it is recommended that treatment be re-initiated with only 12.5 mg (one half of a 25 mg tablet) once or twice daily (see Dosage).
Tachycardia, which may be sustained, has been observed in approximately 25% of patients taking 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 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. There have also been reports of ischemic changes, myocardial infarction, nonfatal arrhythmias, sudden unexplained deaths and congestive heart failure in association with clozapine use. 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.
Isolated cases of cardiac arrhythmias, pericarditis and myocarditis (with or without eosinophilia) have been reported, some of which have been fatal. Therefore, in patients on clozapine who develop non-specific cardiac disorders, the diagnosis of myocarditis should be considered.
Neuroleptic Malignant Syndrome: A potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported in association with antipsychotic drugs. There have been several reported cases of NMS 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 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.
Tardive Dyskinesia: 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 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 other antipsychotic agents, so that a causal relationship cannot be established. Nevertheless, it cannot be concluded, without more extended experience, that clozapine will not induce this syndrome.
Given this consideration, 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 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 clozapine, drug discontinuation should be considered. However, some patients may require treatment with clozapine despite the presence of the syndrome.
Precautions: Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response to clozapine should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be reassessed periodically.
Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully evaluated by a hematologist prior to starting clozapine.
Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may be started on clozapine after agreement of a hematologist.
Fever: 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 and self-limiting; however, on occasion there may be an associated increase or decrease in the white blood cell count. Patients should be carefully evaluated to rule out the possibility of an underlying infectious process or the development of blood dyscrasia. In the presence of high fever, the possibility of neuroleptic malignant syndrome must be considered (see Warnings).
Occupational Hazards: Interference with Cognitive and Motor Performance: Because of the potential for initial sedation, clozapine may impair mental and/or physical abilities especially during the first few days of therapy. The recommendation for gradual dose escalation should be carefully adhered to and patients should be cautioned about activities requiring alertness (e.g., driving, operating machinery, swimming, climbing, etc.) (see Dosage).
Drug Interactions: Clozapine may enhance the central effects of alcohol, MAO inhibitors, CNS depressants including narcotics, antihistamines and benzodiazepines, as well as the effects of anticholinergic and antihypertensive agents.
Caution is advised with patients who are receiving (or have recently received) benzodiazepines or other psychotropic drugs, as these patients may have an increased risk of circulatory collapse accompanied by respiratory and/or cardiac arrest.
Owing to its noradrenolytic action, clozapine may reduce the blood pressure increasing effect of norepinephrine or other predominantly a-adrenergic agents and reverse the pressure effect of epinephrine.
Clozapine should not be used with other agents, such as carbamazepine, having a known potential to suppress bone marrow function. In particular, the concomitant use of long-acting depot antipsychotic drugs should be avoided because these medications, which may have the potential to be myelosuppressive, cannot be rapidly removed from the body.
Concomitant use of valproic acid with clozapine may alter the plasma levels of clozapine.
Clozapine is highly bound to serum protein and should not be administered to a patient taking other drug(s) which are highly bound to protein (e.g., warfarin, digitoxin). Adverse effects may result from the displacement of protein-bound clozapine and/or the displacement of the other highly protein-bound drug(s).
Since the metabolism of clozapine is mainly mediated by cytochrome P450 1A2 and, probably to a minor extent, by cytochrome P450 2D6, the concomitant administration of drugs which possess affinity to 1 or both of these enzymes may result in an increase in the plasma levels of clozapine and/or the co-administered drug. However, with tricyclic antidepressants, phenothiazines and type Ic antiarrhythmics, which are known to bind to cytochrome P450 2D6, no clinically relevant interactions have been observed thus far. On theoretical grounds, however, it is possible that the plasma levels of such drugs are increased by clozapine.
Administration of cimetidine or erythromycin concomitantly with high-dose clozapine therapy was associated with increased plasma clozapine levels (of approximately 63%) and the occurrence of adverse effects.
Elevated serum levels of clozapine have been reported in patients receiving the drug in combination with fluvoxamine (up to 10-fold) or other selective serotonin re-uptake inhibitors such as paroxetine, sertraline or fluoxetine (up to 2-fold).
Conversely, drugs known to increase the activities of cytochrome P450 enzymes may decrease the plasma levels of clozapine. Discontinuation of the concomitant administration of carbamazepine resulted in an increase (up to 58%) of the clozapine plasma levels. The concomitant use of phenytoin has been found to decrease the clozapine plasma concentration (by 65 to 85%), resulting in reduced effectiveness of a previously effective clozapine dose.
Other Precautions: Clozapine has potent anticholinergic effects and great care should be exercised in using the drug in the presence of prostatic enlargement, narrow-angle glaucoma or paralytic ileus. Since clozapine may cause sedation and weight gain, thereby increasing the risk of thromboembolism, immobilization of patients should be avoided.
In the event of eosinophilia, it is recommended to discontinue clozapine if the eosinophil count rises above 3.0´ 10L, and to re-start therapy only after the eosinophil count has fallen below 1.0´ 10L.
In the event of thrombocytopenia, it is recommended to discontinue clozapine therapy if the patient falls below 50.0´ 10L.
Patients with stable pre-existing liver disorders may receive clozapine, but need regular liver function test monitoring. In patients in whom, during clozapine treatment, symptoms of possible liver dysfunction such as nausea, vomiting and/or anorexia develop, liver function tests should be performed immediately. If the elevation of these values is clinically relevant or if symptoms of jaundice occur, treatment with clozapine must be discontinued. It may be resumed only when the liver function tests have returned to normal values. In such cases, liver function should be closely monitored after the re-introduction of the drug.
Patients with Concomitant Illness: Clinical experience with clozapine in patients with concomitant systemic diseases is limited. Nevertheless, caution is advised when using clozapine in patients with hepatic, renal or cardiac disease. For severe cases, see Contraindications.
Pregnancy: Reproduction studies, performed in rats and rabbits at doses of approximately 2 to 4 times the human dose, have revealed no evidence of impaired fertility or harm to the fetus due to clozapine. However, there have not been any adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response and in view of the desirability of keeping the administration of all drugs to a minimum during pregnancy, clozapine should be used only if the benefits clearly outweigh the risks.
Lactation: Animal studies suggest that clozapine may be excreted in breast milk and have an effect on the nursing infant. Therefore, women receiving clozapine should not breast-feed.
Children: Safety and efficacy in children below age 16 have not been established.
Information for the Patient: Physicians are advised to discuss the following issues with patients (and/or their guardians) for whom they prescribe clozapine:
Patients who are to receive clozapine should be warned about the significant risk of developing agranulocytosis, a potentially life-threatening adverse event. They should be informed that regular blood tests are required to monitor for the occurrence of agranulocytosis, and that clozapine tablets will be made available only through a special program designed to ensure the required blood monitoring. They should also be informed that weekly blood tests will be required for the first 26 weeks of their treatment with clozapine and that, following this initial higher risk period, they could be allowed to change to a “once every 2 weeks” schedule, provided that their clinical condition is permitting such a change in monitoring regimen. Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat, malaise, mucous membrane ulceration or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection.
Patients should be informed of the significant risk of seizure during clozapine treatment and should be advised to avoid activities that require alertness (e.g., driving, operating machinery, swimming, climbing, etc.).
Â Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration.
Patients should be informed that if they stop taking clozapine for 2 days or more, they should not restart their medication at the same dosage, but should contact their physician for dosage instructions.
Patients should notify their physician if they are taking, or plan to take, any prescription or over-the-counter drugs or alcohol.
Patients should notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should not breast-feed an infant if they are taking clozapine.
Adverse Reactions: The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects and fever (see Warnings and Precautions). The most common side effects are drowsiness, hypersalivation, tachycardia and sedation.
CNS: Initially, drowsiness and sedation may be encountered, especially where relatively large doses of clozapine are given. Generally, this effect tends to subside with continued therapy or dose reduction. Clozapine may cause EEG changes, including the occurrence of spike and wave complexes and may lower the seizure threshold and may include myoclonic jerks or generalized seizures. On rare occasions it may induce episodes of delirium.
Extrapyramidal symptoms are limited mainly to tremor, akathisia and rigidity and if such effects occur, they tend to be mild and transient.
Autonomic Nervous System: Hypersalivation is a pharmacologically unexpected but common adverse reaction associated with clozapine therapy which may be profuse, especially during sleep, but may be diminished by dose reduction or the use of peripherally-acting anticholinergic medication. Dry mouth, blurred vision and an increase in body temperature may occur.
Cardiovascular: Rare cases of thromboembolism have been reported.
Endocrine: In contrast to conventional antipsychotics, clozapine produces little or no prolactin response in humans. Consequently, prolactin-dependent effects such as decreased libido, impotence, galactorrhea and amenorrhea are seldom associated with clozapine therapy. With continued treatment, considerable weight gain has been seen in some patients. Therapeutic doses of clozapine, to date, even on long-term treatment, have not been associated with symptoms of thyroid dysfunction. On rare occasions, hyperglycemia has been reported in patients on clozapine treatment.
Gastrointestinal: Constipation and nausea have been reported occasionally. Very rarely, ileus has been reported. Transient, asymptomatic elevations of liver enzymes and, rarely hepatitis and cholestatic jaundice may occur. Very rarely, fulminant hepatic necrosis has been reported. If jaundice develops, clozapine should be discontinued (see Precautions). As a rare event, clozapine treatment may be associated with dysphagia, a possible cause of aspiration. In rare cases, acute pancreatitis has been reported.
Genital: In a few cases, priapism has been reported. Isolated cases of acute interstitial nephritis have been reported in association with clozapine therapy.
Hemic/Lymphatic: Isolated cases of various types of leukemia have been reported in patients treated with clozapine. However, there is no evidence to suggest a causal relationship between the drug and any type of leukemia: the reported occurrence rate is in the range of the background incidence of these diseases in the general population.
Unexplained leukocytosis may occur, especially in the initial weeks of treatment.
Very rarely, clozapine may cause thrombocytopenia.
Respiratory: Rarely, aspiration of ingested food may occur in patients presenting with dysphagia or as a consequence of acute overdosage.
Musculoskeletal: Rarely, increases in CPK values have occurred.
Symptoms And Treatment Of Overdose: Symptoms: The signs and symptoms associated with clozapine overdose are: drowsiness, lethargy, coma, areflexia, confusion, agitation, delirium, hyper-reflexia, convulsions, hypersalivation, mydriasis, blurred vision, thermolability, tachycardia, hypotension, collapse, cardiac arrhythmias, heart block, respiratory depression or failure, hallucinations, extrapyramidal symptoms, aspiration pneumonia and dyspnea.
In cases of acute intentional or accidental clozapine overdosage, for which information on the outcome is available, to date the mortality is about 12%. Most of the fatalities were associated with cardiac failure or pneumonia caused by aspiration and occurred at doses above 2 000 mg. There have been reports of patients recovering from an overdose in excess of 10 000 mg. However, in a few adult individuals, primarily those not previously exposed to clozapine, the ingestion of doses as low as 400 mg led to life-threatening comatose conditions and, in 1 case, to death. In young children, the intake of 50 to 200 mg resulted in strong sedation or coma without being lethal.
Treatment: Establish and maintain an airway; ensure adequate oxygenation and ventilation. Perform gastric lavage and/or the administration of activated charcoal within the first 6 hours after the ingestion of the drug. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdosage. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine when treating hypotension, and quinidine and procainamide when treating cardiac arrhythmia.
There are no specific antidotes for clozapine. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
In managing overdosage, the physician should consider the possibility of multiple drug involvement.
Dosage And Administration: Clozapine treatment must be initiated on an in-patient basis or in an out-patient setting where medical supervision is available and vital signs can be monitored for a minimum of 6 to 8 hours after the initial 2 to 3 doses.
When treatment is initiated in out-patients, special caution is advised in patients who are receiving benzodiazepines or other psychotropic drugs as these patients may have an increased risk of circulatory collapse accompanied by respiratory and/or cardiac arrest (see Precautions, Drug Interactions). Extra caution is advised in patients with cardiovascular disease or a history of seizures (see Warnings).
Clozapine is restricted to patients who have a normal white blood cell (WBC) count and differential cell (DC) count and in whom a WBC count and DC count can be carried out at least weekly for the first 26 weeks of treatment and at least at 2-week intervals thereafter*. Monitoring must continue for as long as the patient is on the drug, as well as for at least 4 weeks after discontinuation of treatment.
*The change from a weekly to a “once 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. Weekly hematological testing should be resumed for an additional 6 weeks if therapy is disrupted for more than 3 days. If clozapine is interrupted for 4 weeks or longer, weekly monitoring is required for an additional 26 weeks.
Clozapine is available only through a distribution system that requires weekly or every-2-week hematological testing prior to the delivery of the next period’s supply of medication (see Indications).
The dosage of clozapine must be adjusted individually. For each patient the lowest effective dose should be used.
Initial Dose: On the first day, clozapine should be given at a 12.5 mg dose (one-half of a 25 mg tablet) once or twice, followed by one or two 25 mg tablets on the second day. If well tolerated, the dosage may be increased in daily increments of 25 to 50 mg, achieving a target dose of 300 to 450 mg/day by the end of 2 weeks. Subsequent dosage increases should be made no more than once or twice weekly, in increments not to exceed 100 mg. Cautious titration and a divided dosage schedule are necessary to minimize the risks of hypotension, seizure and sedation.
Switching from previous neuroleptics: When clozapine therapy is initiated in a patient undergoing oral neuroleptic therapy, it is generally recommended that the other neuroleptic should first be discontinued by tapering the dosage downwards. Once the neuroleptic is completely discontinued for at least 24 hours, clozapine treatment can be started as described above. It is generally recommended that clozapine should not be used in combination with other neuroleptics.
Therapeutic Dose Range: In most patients, antipsychotic efficacy can be expected within the therapeutic range of 300 to 600 mg/day in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime.
Since improvement may be gradual, continued therapeutic response can be expected beyond the first month of treatment.
Maximum Dose: Occasionally, patients may require doses higher than 600 mg/day to obtain an acceptable therapeutic response. Because of the possibility of increased adverse reactions (particularly seizures) at daily doses of 600 mg and higher, the decision to treat in the range of 600 to 900 mg/day must be taken prudently. Patients must be given adequate time to respond to a given dose level before escalation to a higher dose is contemplated. The maximum dose of 900 mg/day should not be exceeded.
Maintenance Dose: After achieving maximum therapeutic benefit, many patients can be maintained effectively at lower doses. Careful downward titration is recommended to the level of 150 to 300 mg/day in divided doses. At daily doses not exceeding 200 mg, a single administration in the evening may be appropriate.
Discontinuation of Therapy: In the event of planned termination of clozapine therapy, gradual reduction in dose is recommended over a 1 to 2 week period. However, should a patient’s medical condition require abrupt discontinuation (e.g., severe leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms.
Re-initiation of Treatment in Patients Previously Discontinued: When restarting patients who have had even a brief interval off clozapine, i.e., 2 days or more since the last dose, it is recommended that treatment be re-initiated with 12.5 mg (one half of a 25 mg tablet) once or twice on the first day. If that dose is well tolerated, it may be feasible to titrate patients back to a therapeutic dose more quickly than is recommended for initial treatment.
Certain additional precautions seem prudent when re-initiating treatment. The mechanisms underlying some of the clozapine-induced adverse reactions are unknown. It is conceivable that re-exposure of a patient might enhance the risk of an untoward event’s occurrence and increase its severity. Such phenomena, for example, occur when immune mediated mechanisms are responsible. Therefore, any patient who has previously experienced respiratory or cardiac arrest with initial dosing, but was then able to be successfully titrated to a therapeutic dose, should be re-titrated with extreme caution after even 24 hours of discontinuation.
Availability And Storage: 25 mg: Each round, pale yellow, uncoated, easy to break, scored tablet, embossed “CLOZARIL” on one side and “25 mg” on the other, contains: clozapine 25 mg. Nonmedicinal ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch and talc. Bottles of 100. Store below 30°C.
100 mg: Each round, pale yellow, uncoated, easy to break, scored tablet, embossed “CLOZARIL” on one side and “100 mg” on the other, contains: clozapine 100 mg. Nonmedicinal ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch and talc. Bottles of 100. Store below 30°C.
Clozaril is available only through a distribution system that requires weekly or every-2-week hematological testing prior to the delivery of the next period’s supply of medication (see Indications). (Shown in Product Recognition Section)
CLOZARIL® Novartis Pharmaceuticals Clozapine Antipsychotic Agent