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50 X 25 mg
50 X 100 mg
The dosage must be adjusted individually. For each patient the lowest effective dose should be used. Cautious titration and a divided dosage schedule are necessary to minimize the risks of hypotension, seizure, and sedation. Initiation of Leponex treatment must be restricted to those patients with a WBC count ≥ 3500/mm³ (3.5 x 10^9/L) and a ANC ≥ 2000/mm³ (2.0 x 10^9/L), and within standardised normal limits. Dose adjustment is indicated in patients who are also receiving medicinal products that have pharmacokinetic interactions with clozapine, such as benzodiazepines or selective serotonin re-uptake inhibitors
Method of Administration: Leponex is administered orally.
Switching from a previous antipsychotic therapy to Leponex: It is generally recommended that Leponex should not be used in combination with other antipsychotics. When Leponex therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the dosage of other antipsychotics be reduced or discontinued by gradually tapering it downwards. Based on the clinical circumstances, the prescribing physician should judge whether or not to discontinue the other antipsychotic therapy before initiating treatment with Leponex.
Starting therapy: Leponex should be started with 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 daily dose may then be increased slowly in increments of 25 mg to 50 mg in order to achieve a dose level of up to 300 mg/day within 2 to 3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 mg to 100 mg at half-weekly or, preferably, weekly intervals.
Therapeutic dose range: In most patients, antipsychotic efficacy can be expected with 300to 450 mg/day given in divided doses. Some patients may be treated with lower doses, and some patients may require doses up to 600 mg/day. The total daily dose may be divided unevenly, with the larger portion being taken at bedtime.
Maximum dose: To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (not exceeding 100 mg) are permissible up to 900 mg/day. However, the possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day must be borne in mind.
Maintenance dose: After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses. 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.
Ending therapy: In the event of planned termination of Leponex therapy, a gradual reduction in dose over a 1- to 2-week period is recommended. If abrupt discontinuation 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.
Re-starting therapy: In patients in whom the interval since the last dose of Leponex exceeds 2 days, treatment should be re-initiated with 12.5 mg (half a 25 mg tablet) given once or twice on the first day. If this dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. However, in 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, re-titration should be done with extreme caution.
Reducing the risk of suicidal behaviour in schizophrenia and schizoaffective disorder: The dosage and administration recommendations described in the preceding section (4 Dosage and administration) regarding the use of Leponex in patients with treatment-resistant schizophrenia should also be followed when treating patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behaviour. A course of treatment with Leponex of at least two years is recommended in order to maintain the reduction of risk for suicidal behaviour. It is recommended that the patient’s risk of suicidal behaviour be reassessed after two years of treatment and that thereafter the decision to continue treatment with Leponex be re-visited at regular intervals, based on thorough assessments of patient’s risk for suicidal behaviour during treatment.
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.
Renal impairment: In patients with mild to moderate renal impairment the initial dose should be 12.5 mg given once on the first day, and dosage increase should be slow and in small increments.
Hepatic impairment: Patients with hepatic impairment should receive Leponex with caution along with regular monitoring of liver function tests.
Pediatrics: No pediatric studies have been performed. The safety and efficacy of Leponex in children and adolescents under the age of 16 have not been established.
Patients 60 years of age and older: It is recommended that treatment in patients 60 years and older is initiated at a particularly low dose (12.5 mg given once on the first day) with subsequent dose increments restricted to 25 mg/day.
For full details see prescribing information.
Treatment of resistant schizophrenic patients who are non-responsive to, or intolerant of classic neuroleptics. 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 risk for death.
Known hypersensitivity to clozapine or to any of the excipients of Leponex. Patients unable to undergo regular blood tests. History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy).
History of Leponex-induced agranulocytosis. 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. Leponex treatment must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis; concomitant use of depot antypsychotics is to be discouraged.
Special precautionary measure
Agranulocytosis: Leponex can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in those developing agranulocytosis have decreased markedly since the institution of WBC counts and ANC monitoring. Because of the association of Leponex 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 Leponex. In addition, the concomitant use of longacting depot antipsychotics should be avoided because of the impossibility of removing these medications, which may be potentially myelosuppressive, from the body rapidly in situations where this may be required, e.g. granulocytopenia. Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to starting Leponex. Patients who have low white blood cell (WBC) counts because of benign ethnic neutropenia should be given special consideration and may be started on Leponex after agreement of a haematologist. Leponex must be dispensed under strict medical supervision in accordance with official recommendations. Before initiating Leponex therapy patients should have a blood test and a history and physical examination. Patients with history of cardiac illness or abnormal cardiac findings on physical examination should be referred to a specialist for other examinations that might include an ECG, and the patient treated only if the expected benefits clearly outweigh the risks. The treating physician should consider performing a pre-treatment ECG.
Prior to treatment initiation physicians must ensure: to the best of their knowledge, that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitated its discontinuation. Prescriptions should not be issued for periods longer than the interval between two blood counts. Immediate discontinuation of Leponex is mandatory if either the WBC count is less than 3000/mm3 (3.0×10^9 /L) or the ANC is less than 1500/mm3 (1.5×10^9 /L) at any time during Leponex treatment. Patients in whom Leponex has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to Leponex. At each consultation, a patient receiving Leponex must 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. Patients and their caregivers must be informed that, in the event of any of these symptoms, they must have a blood cell count performed immediately. Prescribers are encouraged to keep a record of all patients’ blood results and to take any steps necessary to prevent these patients from accidentally being rechallenged in the future.
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 Leponex treatment to ensure that only patients with normal leukocyte (WBC ≥ 3500/mm3 (≥ 3.5 x 10^9/L))and absolute neutrophil counts (ANC ≥ 2000/mm3 (≥2.0 x 10^9/L)) will receive Leponex. After the start of Leponex treatment, regular WBC count and ANC must be performed and monitored weekly for the first 18 weeks, and thereafter at least every four weeks throughout treatment, and for 4 weeks after complete discontinuation of Leponex. Prescribing physicians should comply fully with the required safety measures. At each consultation, the patient must 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 Leponex therapy, the WBC count falls to between 3500/mm3(3.5 x 10^9/L) and 3000/mm3 (3.0 x 10^9/L) and/or the ANC falls to between 2000/mm3 (2.0 x 10^9/L) and 1500/mm3 (1.5 x 10^9/L), haematological evaluations must be performed at least twice weekly until the patient’s WBC count and ANC stabilise within the range 3000-3500/mm3 (3.0-3.5 x 10^9/L) and 1500-2000 mm3 (1.5-2.0 x 10^9/L), respectively, or higher. After 18 weeks of Leponex therapy, haematological evaluations should be performed at least twice weekly if the WBC count falls to be between 3000/mm3and 2500/mm3 and/or the ANC falls to between 1500/mm3 and 1000/mm3. In addition, if, during Leponex 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 Leponex is mandatory if the WBC count is less than 3000/mm3 or the ANC is less than 1500/mm3at any time during Leponex treatment. 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 Leponex, haematological evaluation is required until haematological recovery has occurred. If Leponex has been withdrawn and WBC count falls further to below 2000/mm3 (2.0 x 10^9/L) and/or the ANC falls below 1000/mm3 (1.0 x 10^9/L), the management of this condition must be guided by an experienced haematologist. If possible, the patient should be referred to a specialised haematological unit, where protective isolation and the administration of GM-CSF (granulocyte-macrophage colony stimulating factor) or G-CSF (granulocyte colony stimulating factor) may be indicated. It is recommended that the colony stimulating factor therapy be discontinued when the neutrophil count has returned to a level above 1000/mm³.
For full details see prescribing information.
The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects and fever. The most common side effects are drowsiness/sedation, dizziness, tachycardia, constipation and hypersalivation.
For full details see prescribing information.
Alcohol, CNS depressants, cimetidine, disulfiram, carbamazepine, levodopa. Antihypertensives, anticholinergics. Co-trimoxazole, chloramphenicol, sulphonamides, pyrazolone analgesics, phenylbutazone, penicillamine, cytotoxic agents, carbamazepine, depot antipsychotics. Lithium, warafarin, other plasma protein bound drugs. Adrenaline, alpha agonists, cimetidine, phenytoin, carbamazepine, fluvoxamine.
For full details see prescribing information.
Pregnancy and Lactation
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 Leponex in pregnant women has not been established. Therefore, Leponex 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 Leponex, 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 should not breast-feed.
In cases of acute intentional or accidental Leponex overdose, 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 Leponex, 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, dyspnoea, respiratory depression or failure.
Treatment: There are no specific antidotes for Leponex. Gastric lavage and/or the administration of activated charcoal within the first 6 hours after Leponex ingestion. (Peritoneal dialysis and haemodialysis 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.
Storage: Store below 30°C.