Clozaril

Clozaril 25 mg: Circular, flat, yellow, beveled edges tablet. Approximately 6.3 mm diameter, coded CLOZ on one side, L/O and angle score on reverse.
Clozaril 100 mg: Circular, flat, yellow, beveled edges tablet. Approximately 10.0 mm diameter, coded CLOZ on one side, Z/A and angle score on the other side.
25 mg Tablet: Each tablet contains 25 mg clozapine.
100 mg Tablet: Each tablet contains 100 mg clozapine.
The scored tablets can be divided into equal halves.
Excipients/Inactive Ingredients: Clozaril tablets: Magnesium stearate; colloidal anhydrous silica; povidone; talc; maize starch; lactose monohydrate.

Pharmacotherapeutic group: Antipsychotic agent. ATC Code: N05A H02.
Pharmacology: Mechanism of action: Clozaril has been shown to be an antipsychotic agent that is different from classic antipsychotics.
In pharmacological experiments, the compound does not induce catalepsy or inhibit apomorphine- or amphetamine-induced stereotyped behavior. It has only weak dopamine receptor-blocking activity at D1, D2, D3 and D5 receptors, but shows high potency for the D4 receptor, in addition to potent anti-alpha-adrenergic, anticholinergic, antihistaminic, and arousal reaction-inhibiting effects. It has also been shown to possess antiserotoninergic properties.
Pharmacodynamics: Clinically Clozaril produces rapid and marked sedation, and exerts antipsychotic effects in patients with schizophrenia resistant to other antipsychotic agents. In such cases, Clozaril has proven effective in relieving both positive and negative schizophrenic symptoms in short- and long-term trials.
Clozaril is unique in that it produces virtually no major extrapyramidal reactions such as acute dystonia and tardive dyskinesia. Furthermore, parkinsonian-like side effects and akathisia are rare. In contrast to classical antipsychotics, clozapine produces little or no prolactin elevation, thus avoiding adverse effects such as gynecomastia, amenorrhea, galactorrhea, and impotence.
Potentially serious adverse reactions caused by Clozaril therapy are granulocytopenia and agranulocytosis occurring at an estimated incidence of 3% and 0.7% respectively (see Precautions).
Clinical Studies: Clinical studies in treatment-resistant schizophrenia (Clozapine study 16 & 30): The first study was Study 16, a randomized, double-blind, multicenter, parallel group comparative trial of clozapine versus chlorpromazine in hospitalized patients (aged 18 to 65 years and of either sex) with treatment resistant schizophrenia (DSM-II criteria). 151 such patients were randomly assigned to either clozapine (150 mg-900 mg) or chlorpromazine (300-1800 mg) for 28 days with an optional extension up to 28 days (75 in clozapine group and 76 in chlorpromazine group).Efficacy was assessed by measuring mean change from baseline in the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI) scores and the Nurses Observation Scale for Inpatient Evaluation (NOSIE-30). Throughout the study, and at endpoint, clozapine patients had a more rapid onset of action and showed significant improvement in BPRS items compared to chlorpromazine patients. At week 1, clozapine was statistically superior to CPZ in two items assessed: Motor retardation [0.67 vs. 0.12; p<0.05] and blunted affect [0.93 vs. 0.34; p<0.01].
At week 2, two more items also showed also showed statistically significant improvements in clozapine group, emotional withdrawal [1.48 vs. 0.98; p<0.01] and unusual through content [2.06 vs. 1.45; p<0.05]. At week 3, clozapine was statistically superior in 7 out of the 18 BPRS Total Score and maintained throughout the duration of study. Tests of comparative efficacy at endpoint showed clozapine to be significantly better for all five factors assessed: anxiety/depression (0.85 vs. 0.54; p<0.05), anergia (1.15 vs. 0.72; p<0.001), thought disturbance (1.80 vs. 1.28; p<0.01), activation (1.34 vs. 0.89; p<0.01) and hostile/suspiciousness (1.26 vs. 0.74; p<0.01)). At endpoint, clozapine showed statistically significant improvements in mean change in total BPRS score [22.53 vs. 14.64, p<0.001] and CGI {1.95 vs. 1.33, p<0.01]. Clozapine patients generally did better in all NOSIE factors, except for social competence. Mean change from baseline showed statistically significant differences favoring clozapine in the improvement of irritability at week 3 (6.28 vs. 0.67, p<0.01) and week 4 (6.84 vs. 1.36, p<0.05). For most of the factors, particularly, total patient assets, there was clear evidence of an early onset of therapeutic benefit with clozapine, thus corroborating BPRS data, although no statistical difference was observed. At endpoint, clozapine was superior to CPZ for the following NOSIE factors: social interest (4.14 vs. 3.24), personal neatness (3.19 vs. 2.26), irritability (3.04 vs. 0.60) and manifest psychosis (6.32 vs. 4.24) as well as total assets (20.54 vs. 16.66).
Second study was Study 30, a randomized, double-blind, multicenter, parallel group, 6-week, comparative study of clozapine versus chlorpromazine plus benztropine. The study population included 319 treatment-resistant schizophrenic patients, between the ages of 18-60 years, who met DSM-III criteria for schizophrenia, refractory to treatment. Eligible patients were randomly assigned to either clozapine (up to 900 mg/day) or chlorpromazine plus benztropine (up to 1800 mg/day of chlorpromazine, plus 6 mg/day of benztropine). Efficacy was assessed using the BPRS score, CGI scale and NOSIE-30. At the end of 6 weeks, clozapine showed a significantly superior to chlorpromazine in all POSITIVE, Negative and general symptoms of BPRS (p<0.001) except Grandiosity and BPRS total score. Clozapine showed a significantly superior change in CGI scale compared to chlorpromazine starting at week 1 (p<0.001). Clozapine was superior to chlorpromazine on all size NOSIE-30 factors and total assets starting at either week 1 or 2 (p<0.05 to 0.001). Clozapine was statistically significant in the following NOSIE factors, social competence, social interest and personal neatness, and total assets (p<0.001), as well as irritability and motor retardation (p<0.01<0.05, respectively).
Clinical study in risk of recurrent suicidal behavior (InterSePT Trial): The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT), a prospective, randomized, open label, international, parallel-group comparison of clozapine vs. olanzapine in patients with schizophrenia or schizoaffective disorder (DSM-IV) judged to be at risk for re-experiencing suicidal behavior, lasting for 24 months. A total of 956 patients were randomized to either clozapine (starting with 25 mg/day, titrated upwards to 200-900 mg/day) or olanzapine (5-20 mg/day). The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide, (2) hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized), or (3) worsening of suicidality severity as demonstrated by much worsening or very much worsening from baseline in the CGI-SS-BP scale. Clozapine showed a statistically significant overall treatment effect compared to olanzapine for the primary efficacy measure (p=0.0309). treatment effect to Type 1 events (a significant suicide attempt or hospitalization due to imminent suicide risk (including increased level of surveillance) was statistically significant in favor of clozapine (p=0.0316), with a hazard ratio [risk ratio] of 0.76 (95% C.I.: 0.58, 0.98). Similarly, the treatment effect for Type 2 events (worsening of suicidality severity as demonstrated by 7-point CGI-SS-BP change scale score of 6 or 7, or by implicit worsening of suicidality in favor of clozapine (p=0.0388), with a hazard ratio of 0.78 (95% C.I.: 0.61, 0.99). Probability (Standard Error, SE) of experiencing a Type 1 and Type 2 events was higher for olanzapine patients compared to clozapine patients at all visit. At week 104, the clozapine treatment group demonstrated a significantly lower probability of both Type 1 (24% vs. 32%; 95% C.I.; 2%, 14%) and Type 2 event (28% vs. 37%; 95% D.I.; 2%, 15%).
Pharmacokinetics: Absorption: The absorption of orally administered clozapine is 90% to 95%; neither the rate nor the extent of absorption is influenced by food.
Clozapine is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50% to 60%.
Distribution: In steady-state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range: 0.4 to 4.2 hours), and the volume of distribution is 1.6 L/kg. Clozapine is approximately 95% bound to plasma proteins.
Biotransformation/metabolism: Clozapine is almost completely metabolized before excretion by CYP1A2 and 3A4, and to some extent by CYP2C19 and 2D6. Of the main metabolites only the desmethyl metabolite was found to be active. Its pharmacological actions resemble those of clozapine, but are considerably weaker and of short duration.
Elimination: Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6 to 26 hours). 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.
Only trace amounts of unchanged drug are detected in the urine and feces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the feces.
Linearity/non-linearity: Dosage increases from 37.5 mg to 75 mg and 150 mg given twice daily were found to result during steady state in linearly dose-proportional increases in the area under the plasma concentration/time curve (AUC), and in the peak and minimum plasma concentrations.
Toxicology: Non-Clinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential (for reproductive toxicity, see Use in Pregnancy & Lactation).
Mutagenicity: Clozapine and/or its metabolites were devoid of genotoxic potential when investigated for induction of gene mutations, chromosome aberrations and primary DNA-damage in a spectrum of in vitro mutagenicity tests. Likewise, no genotoxic activity was observed in vivo (bone marrow micronucleus test in mice).
Carcinogenicity: In Sprague-Dawley (CD) rats treated in the diet for 2 years, maximum tolerated doses of 35 mg/kg per day revealed no carcinogenic potential of clozapine. Likewise, no evidence of tumorigenic effects was obtained in two 1.5-year feeding studies in Charles River (CD) mice. In the first study, oral dose levels of up to 64 mg/kg per day were administered to males, and of up to 75 mg/kg per day to females respectively. In the second study, the highest dose for both sexes was 61 mg/kg per day.
Reproductive toxicity: No embryotoxic or teratogenic potential of clozapine was observed in rats or rabbits at daily oral doses of up to 40 mg/kg. In male rats receiving the same dosages for 70 days prior to mating, fertility was unaffected.
In female rats, fertility as well as pre- and postnatal development of the offspring was not adversely affected by oral clozapine treatment prior to mating (up to 40 mg/kg per day). When rats were treated at the same dosages during the latter part of pregnancy and during lactation, survival rates of the young from lactating dams, were lowered and the young were hyperactive. However, there was no lasting effect on pup development after weaning.

Treatment-resistant schizophrenia: Clozaril is indicated in patients with treatment-resistant schizophrenia, i.e. patients with schizophrenia who are non-responsive to or intolerant of classic antipsychotics.
Non-responsiveness is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two marketed antipsychotics prescribed for adequate durations.
Intolerance is defined as the impossibility of achieving adequate clinical benefit with classic antipsychotics because of severe and untreatable neurological adverse reactions (extrapyramidal side effects or tardive dyskinesia).
Risk of recurrent suicidal behavior: Clozaril is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at high risk for death.

The dosage must be adjusted individually. For each patient the lowest effective dose should be used. Careful dose titration and a divided dosage schedule are necessary to minimize the risk of hypotension, seizure, and sedation. The total daily amount may be divided into unequal doses, the largest of which should be taken at bedtime.
The following dosages are recommended: Starting dose: 12.5 mg (half a 25 mg tablet) once or twice on the first day, followed by one or two 25 mg tablets on the second day. If well tolerated, the dose may then be increased in increments of 25-50 mg/day in order to achieve a daily dose of 300 mg within 2-3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50-100 mg at half-weekly or, preferably, weekly intervals.
Therapeutic dose range: In most patients the onset of antipsychotic effects occurs at a daily dosage of 300-450 mg, given in two to four divided doses. Some patients require lower daily doses, and others up to 600 mg.
Maximum dose: To obtain full therapeutic benefit, a few patients may require larger doses; in such cases the maximum permissible dose is 900 mg/day, with maximum individual increments of 100 mg. Increased adverse effects (in particular seizures) are possible at doses exceeding 450 mg/day.
Maintenance dose: Once the maximum therapeutic effect has been attained, many patients can be effectively maintained on a lower dose. Careful downward titration is therefore recommended. Treatment should be maintained for at least 6 months. If the daily dose does not exceed 200 mg, once-daily administration in the evening may be appropriate.
Withdrawal of treatment: In the event of planned withdrawal of Clozaril, it is recommended that the dose be reduced gradually over a period of 1-2 weeks. If abrupt discontinuation is necessary (e.g. because of leukopenia), the patient should be closely monitored for recurrence of psychosis and symptoms of cholinergic rebound (e.g. increased sweating, headache, nausea, vomiting and diarrhea).
Resumption of treatment: If more than two days have elapsed since the last dose of Clozaril, treatment should be resumed with 12.5 mg (half a 25 mg tablet) once or twice on the first day. If this dose is well tolerated, titration to the therapeutic level can then proceed more quickly than is recommended for initial treatment. However, re-titration should be carried out with extreme caution in any patient who has previously experienced respiratory or cardiac arrest with initial dosing (see Other precautions), but was then able to be successfully titrated to a therapeutic dose.
Switching from another antipsychotic therapy to Clozaril: It is generally recommended that Clozaril should not be combined with other antipsychotic agents. When Clozaril therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that if possible, the other antipsychotic agent should first be discontinued by tapering the dosage downwards over a period of about one week. Once the antipsychotic agent has been completely discontinued for at least 24 hours, Clozaril treatment can be started as described previously.
A lower starting dose and slower build-up are recommended for patients with a history of seizures or with cardiovascular, renal or hepatic disorders.
Dose adjustment is necessary in patients receiving drugs that interact with Clozaril, such as benzodiazepines, carbamazepine or selective serotonin reuptake inhibitors (see Interactions).
(Long-term) reducing the recurrent suicidal behavior in patients with schizophrenia and schizoaffective disorder: The dosage and administration guidelines described previously for the use of Clozaril in patients with treatment-resistant schizophrenia are also valid when Clozaril is used in patients with schizophrenia or schizoaffective disorder who show evidence of a long-term risk for recurrent suicidal behavior.
Special patient groups: Patients with heart disease: The starting dose should be low (1 x 12.5 mg on the first day) in patients with heart disease. It should be increased slowly and in small increments. It is contraindicated for patients with severe cardiovascular disease (see Contraindications).
Patients with renal insufficiency: The starting dose should be low (1 x 12.5 mg on the first day) in patients with mild to moderate renal insufficiency. It should be increased slowly and in small increments.
Patients with hepatic insufficiency: In patients with hepatic insufficiency, Clozaril should only be administered with care and regular monitoring (see Precautions).
Children and adolescents: There are no studies in children and adolescents on the safety and effectiveness of Clozaril.
Elderly patients: In older patients (≥60 years) initiation of treatment at a particularly low dose is recommended (12.5 mg given once on the first day), with subsequent dose increments restricted to 25 mg/day.

In cases of acute intentional or accidental Clozaril 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 2000 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 Clozaril, the ingestion of doses as low as 400 mg led to life-threatening comatose conditions and, in one case, to death. In young children, the intake of 50 mg to 200 mg resulted in strong sedation or coma without being lethal.
Signs and symptoms: Drowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extrapyramidal symptoms, hyper-reflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnea, respiratory depression or failure.
Treatment: There are no specific antidotes for Clozaril.
Gastric lavage and/or the administration of activated charcoal within the first 6 hours after Clozaril ingestion. (Peritoneal dialysis and hemodialysis are unlikely to be effective). Symptomatic treatment under continuous cardiac monitoring, surveillance of respiration, monitoring of electrolytes and acid-base balance. The use of epinephrine should be avoided in the treatment of hypotension because of the possibility of a 'reverse epinephrine' effect.
Close medical supervision is necessary for at least 5 days because of the possibility of delayed reactions.

Known hypersensitivity to clozapine or to any of the excipients of Clozaril.
Patients unable to undergo regular blood tests.
History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy).
Impaired bone marrow function.
Uncontrolled epilepsy.
Alcoholic and other toxic psychoses, drug intoxication, comatose conditions.
Circulatory collapse and/or CNS depression of any cause.
Severe renal or cardiac disorders (e.g. Myocarditis).
Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure.
Paralytic ileus.

Clozaril can cause agranulocytosis. Its use should be limited to patients: With schizophrenia who are non-responsive to or intolerant of classical antipsychotic agents, or with schizophrenia or schizoaffective disorder who are at risk of recurrent suicidal behavior (see Indications/Uses); who have initially normal leukocyte findings (white blood cell count (WBC) ≥3500/mm³ (3.5 x 10⁹/L), and absolute neutrophil counts (ANC) ≥2000/mm³ (2.0 x 10⁹/L)); and in whom regular white blood cell counts and absolute neutrophil counts can be performed as follows: Weekly during the first 18 weeks of therapy, and at least every 4 weeks thereafter throughout treatment. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Clozaril (see Precautions).
Prescribing physicians should comply fully with the required safety measures. At each consultation, a patient receiving Clozaril 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 (see Precautions).
Clozaril must be dispensed under strict medical supervision in accordance with official recommendations (see Precautions).

Special precautionary measure: Agranulocytosis: Because of the association of Clozaril 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 Clozaril. 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 hematologist prior to starting Clozaril.
Patients who have low white blood cell (WBC) counts because of benign ethnic neutropenia should be given special consideration and may be started on Clozaril after agreement of a hematologist.
Clozaril 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 Clozaril 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 Clozaril. After the start of Clozaril 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 of Clozaril.
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 Clozaril therapy, the WBC count falls to between 3500/mm³ and 3000/mm³ and/or the ANC falls to between 2000/mm³ and 1500/mm³, haematological evaluations must be performed at least twice weekly.
After 18 weeks of Clozaril therapy, haematological evaluations should be performed at least twice weekly if the WBC count falls to between 3000/mm³ and 2500/mm³ and/or the ANC falls to between 1500/mm³ and 1000/mm³.
In addition, if, during Clozaril 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 Clozaril 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 Clozaril, haematological evaluation is required until haematological recovery has occurred.
If Clozaril 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 specialized 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 Clozaril has been discontinued as a result of white blood cell deficiencies (see previously mentioned) must not be re-exposed to Clozaril.
It is recommended that the haematological values be confirmed by performing two blood counts on two consecutive days; however, Clozaril should be discontinued after the first blood count. (See Tables 1 and 2.)

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Click on icon to see table/diagram/image

In the event of interruption of therapy for non-hematological reasons: Patients who have been on Clozaril 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 Clozaril treatment has been interrupted for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment (see Dosage & Administration).
In the event of eosinophilia, discontinuation of Clozaril is recommended if the eosinophil count rises above 300/mm³. Therapy should be re-started only after the eosinophil count has fallen below 1000/mm³.
Thrombocytopenia: In the event of thrombocytopenia, discontinuation of Clozaril is recommended if the platelet count falls below 50,000/mm³.
Cardiovascular disorders: 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 Clozaril treatment. Rarely (about one case per 3000 Clozaril-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 Clozaril treatment require close medical supervision. 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, Clozaril should be discontinued. 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 Clozaril treatment, there is potential to develop mitral valve incompetence. Mitral valve incompetence has been reported in cases of cardiomyopathy related to Clozaril treatment. These cases of mitral valve incompetence reported either mild or moderate mitral regurgitation on two-dimensional echocardiography (2DEcho) (see Adverse Reactions).
Myocardial infarction: In addition, there have been post marketing reports of myocardial infarction which may be fatal. 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 Clozaril 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. Clozaril should be used with caution in patients with risk factors for stroke.
Risk of thromboembolism: Since Clozaril may cause sedation and weight gain, thereby increasing the risk of thromboembolism, immobilization of patients should be avoided.
Metabolic changes: Atypical antipsychotic drugs, including Clozaril, 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.
Hyperglycemia and Diabetes Mellitus: On rare occasions, severe hyperglycemia, sometimes leading to ketoacidosis/hyperosmolar coma, has been reported during Clozaril treatment in patients with no prior history of hyperglycemia. While a causal relationship to Clozaril use has not been definitely established, glucose levels returned to normal in most patients after discontinuation of Clozaril, and re-challenge produced a recurrence of hyperglycemia in a few cases. The effect of Clozaril 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 Clozaril 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 Clozaril 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.
Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including Clozaril. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended.
Weight gain: Weight gain has been observed with atypical antipsychotic use, including Clozaril. Clinical monitoring of weight is recommended.
Seizures: Clozaril 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).
Anticholinergic effects: Clozapine exerts anticholinergic activity, which may produce undesirable effects throughout the body. Probably on account of its anticholinergic properties, Clozaril has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction, paralytic ileus, megacolon and intestinal infraction/ischaemia. On rare occasions these cases have proved fatal. Careful monitoring during treatment with Clozaril to identify early, the onset of constipation, followed by effective management of constipation are recommended to prevent complications. Careful supervision is indicated in the presence of prostatic enlargement and narrow-angle glaucoma.
Fever: During Clozaril 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, Clozaril should be discontinued immediately, and appropriate medical measures should be administered.
Special populations: Hepatic impairment: Patients with stable pre-existing liver disorders may receive Clozaril, 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 Clozaril treatment. If the elevation of the values is clinically relevant or if symptoms of jaundice occur, treatment with Clozaril 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 Clozaril.
Renal impairment: 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).
Rebound, withdrawal effects: If abrupt discontinuation of Clozaril 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 diarrhoea.
Driving and using machines: Owing to the ability of Clozaril 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.
Use in the 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 Clozaril 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 Clozaril treatment and there have been rare reports of tachycardia, which may be sustained, in patients taking Clozaril. 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). Clozaril should be used with caution in patients aged 60 years and older with dementia.

Women of child-bearing potential and contraceptive measures: Some female patients treated with antipsychotics other than Clozaril may become amenorrheic. A return to normal menstruation may occur as a result of switching from other antipsychotics to Clozaril. Adequate contraceptive measures must therefore be ensured in women of childbearing potential.
Pregnancy: Reproduction studies in animals have revealed no evidence of impaired fertility or harm to the fetus due to clozapine. However, the safe use of Clozaril in pregnant women has not been established. Therefore, Clozaril should be used in pregnancy only if the expected benefit clearly outweighs any potential risk.
Non-teratogenic effects: Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Antipsychotic drugs, including Clozaril, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Breast-feeding: Animal studies suggest that clozapine is excreted in breast milk and has an effect in the suckling offspring. Therefore, mothers receiving Leponex/Clozaril should not breast-feed.

Summary of the safety profile: The adverse effects of clozapine are most often predictable based on its pharmacological properties with the exception of agranulocytosis (see Warnings and Precautions).
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/sedation, dizziness, tachycardia, constipation, and hypersalivation.
Data from the clinical trials experience showed that a varying proportion of clozapine-treated patients (from 7.1 to 15.6%) were discontinued due to an adverse event, including only those that could be reasonably attributed to clozapine. The more common events considered to be causes of discontinuation were leukopenia; somnolence; dizziness (excluding vertigo); and psychotic disorder.
Adverse drug reactions (ADRs) are listed by MedDRA system organ class (see Table 3). Within each system organ class, the adverse reactions are ranked by frequency, using the following convention: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000) including isolated reports. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. (See Table 3.)

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Very rare events of ventricular tachycardia, cardiac arrest and QT prolongation which may be associated with Torsades De Pointes have been observed although there is no conclusive causal relationship to the use of this medicine.
Adverse drug reactions from spontaneous reports and literature (frequency not known): The following adverse drug reactions (ADRs) were derived from post-marketing experience with Clozaril via spontaneous case reports and literature cases and have been categorized according to MedDRA system organ class (see Table 4). Because these reactions have been reported voluntarily from a population of uncertain size and are subject to confounding factors, these post-marketing ADRs have been categorized with a frequency of "not known" since it is not possible to reliably estimate their frequency. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. (See Table 4.)

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Pharmacodynamic-related interactions: Anticipated pharmacodynamic interactions resulting in concomitant use not being recommended: Medicinal products known to have a substantial potential to depress bone marrow function should not be used concurrently with Clozaril (see Warnings and Precautions).
As with other antipsychotics, caution should be exercised when Clozaril is prescribed with medicines known to increase the QTc interval, or causing electrolyte imbalance.
Observed pharmacodynamic interactions to be considered: Particular caution is recommended when Clozaril therapy is initiated in patients who are receiving (or have recently received) a benzodiazepine or any other psychotropic agent, as these patients may have an increased risk of circulatory collapse, which, on rare occasions, can be profound and may lead to cardiac and/or respiratory arrest.
Concomitant use of lithium or other CNS-active agents may increase the risk of development of neuroleptic malignant syndrome (NMS).
Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Clozaril was co-administered with valproic acid have been reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not been determined.
Anticipated pharmacodynamic interactions to be considered: Clozapine may enhance the central effects of alcohol, MAO inhibitors and CNS depressants such as narcotics, antihistamines, and benzodiazepines.
Because of the possibility of additive effects, caution is essential when substances possessing anticholinergic, hypotensive, or respiratory depressant effects are given concomitantly.
Owing to its anti-alpha-adrenergic properties, clozapine may reduce the blood pressure-increasing effect of norepinephrine or other predominantly alpha-adrenergic agents and reverse the pressor effect of epinephrine.
Pharmacokinetic-related interactions: Clozapine is a substrate for many CYP 450 isoenzymes, in particular 1A2 and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution is called for in patients receiving concomitant treatment with other substances that are either inhibitors or inducers of these enzymes.
No clinically relevant interactions have been observed thus far with tricyclic antidepressants, phenothiazines or type 1_C anti-arrhythmics, which are known to bind to cytochrome P450 2D6.
Observed pharmacokinetic interactions to be considered: Concomitant administration of substances known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine.
Substances known to induce the activity of 3A4 and with reported interactions with clozapine include, for instance, carbamazepine, phenytoin and rifampicin.
Concomitant administration of substances known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine.
Substances known to inhibit the activity of the major isozymes involved in the metabolism of clozapine and with reported interactions include, for instance, cimetidine, erythromycin (3A4), fluvoxamine (1A2), perazine (1A2), ciprofloxacin (1A2) and oral contraceptives (1A2, 3A4, 2C19).
The plasma concentration of clozapine is increased by caffeine (1A2) intake and decreased by nearly 50% following a 5-day caffeine-free period. Elevated clozapine plasma concentrations also have been reported in patients receiving the substances in combination with selective serotonin re-uptake inhibitors (SSRIs) such as paroxetine (1A2), sertraline, fluoxetine or citalopram.
Anticipated pharmacokinetic interactions to be considered: Concomitant administration of substances known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine.
Known inducers of 1A2 include, for instance, omeprazole and tobacco smoke. In cases of sudden cessation of tobacco smoking, the plasma clozapine concentration may be increased, thus leading to an increase in adverse effects.
Concomitant administration of substances known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine.
Potent inhibitors of CYP3A, such as azole antimycotics and protease inhibitors, could potentially also increase clozapine plasma concentrations; no interactions have been reported to date, however.

Incompatibilities: Not applicable.
Instruction for Use and Handling: Any unused product or waste material should be disposed of in accordance with local requirements.

Do not store above 30°C.

Antipsychotics

N05AH02 - clozapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics.

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