Presentations:

Each tablet contains 25 or 100mg of clozapine.

Indications:

Treatment-Resistant Schizophrenia patients and schizophrenic patients who have severe untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics. Psychotic disorders occuring during the course of Parkinson’s disease, in cases where standard treatment has failed.

Posology & Administration:

Oral administration. Adjust dose individually. The lowest effective dose should be used; Initiation of clozapine treatment is restricted to patients with a white blood count (WBC) ≤3.5 x 109/L  and absolute neutrophil count (ANC) ≤2.0 x 109/L  within standardised normal limits. Patients starting clozapine treatment require close medical supervision.

Treatment-resistant schizophrenic patients: 12.5mg once or twice on first day, then one or two 25mg tablets on second day. If well tolerated, dose may be increased slowly in increments of 25 to 50mg up to 300mg/day within 2-3 weeks. If required, daily  dose may  be further  increased  in increments of 50 to 100mg at half-,veekly or weekly intervals, usual therapeutic dose 200-450mg/day in divided doses. Larger dose at night, up to 200mg/day may be taken as a single  dose  at bedtime. Maximum dose 900mg/day. Once control is achieved, a lower maintenance  dose  may be effective. Maintain treatment for at least 6 months.

Psychotic disorders occurring during the course of Parkinson’s disease in patients: 12.5mg/day in the evening then increase dose in 12.5mg increments, maximum two increments per week up to maximum of 50mg. Mean effective dose range 25 to 37.5mg/day. If satisfactory therapeutic response is not achieved with at least a one week dose of 50mg, the dose may be cautiously increased by increments of 12.5mg/week. Do not exceed 100mg/day. Limit or defer dose increases if orthostatic hypotension, excessive sedation or confusion occurs. Monitor blood  pressure during first weeks of treatment. A gradual reduction is recommended in the event of termination. The patient should be observed for withdrawal reactions.  Children  and adolescents under 16 years: Not recommended. Patients aged 60 years and  older:  12.5mg  once on first day, with subsequent maximum increments of 25mg/day.

Contraindications:

Hypersensitivity to active substance or any excipients. Patients unable to undergo  regular blood tests. History of granulocytopenia/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. Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure. Paralytic ileus. Concurrent treabnent with drugs known to have substantial potential for causing agranulocytosis. Concomitant use of depot antipsychotics discouraged.

Warnings & Precautions:

Clozapine can cause fatal agranulocytosis, so is restricted to patients who have initially normal leukocyte findings and in whom regular WBC counts and ANC can be performed. Prescribing physicians must comply fully with the required safety measures. Physicians must ensure that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitates its discontinuation. Prescriptions should not be issued for periods longer than the interval between two blood counts. WBC and differential blood counts must be performed within 10 days of starting treatment. WBC count and ANC must be monitored weekly for the first 18 weeks and at 4 week intervals thereafter. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation or until haematological recovery has occurred.

Immediate discontinuation of clozapine is mandatory if either the WBC count is <3.5 x 109/L or the ANC is <1.5 x 109/L at any time during treatment. These patients must not be re-exposed to clozapine. If clozapine has been withdrawn and either WBC count is <2.0 x 109/L or ANC falls to <1.o x 109/L, management of condition should be by an experienced haematologist. Patients must be reminded to contact their treating physician immediately if any kind of infection begins to develop. Attention should be paid to flu-like complaints (fever/sore throat) and to other evidence of infection which may be indicative of neutropenia. In the event of any of these symptoms, a blood cell count must be performed immediately. 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 treatment. Patients with low WBC counts due to benign ethnic neutropenia may only start clozapine treatment with the agreement of a haematologist Educate patient to contact treating physician immediately if any sign of infection develops, particularly flu-like symptoms.

If during treatment, WBC count falls to between 3.5 x 109/L and 3.0 x 109/L or the ANC falls to between 2.0 x 109/L and 1.5 x 109/L, haematological evaluations must be performed at least twice weekly until the patient’s W13C count and ANC stabilise within the range 3.0-3.5 x 109/L and 1.5-2.0 x 109/L, respectively or higher. 

Other precautions:

This product contains lactose: Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine. Discontinue clozapine if eosinophil count rises above 3.0x 109/L; restart therapy only after the eosinophil count has fallen below l.0 x 109/L. Discontinue clozapine if the platelet count falls below 50 x 109/L.

Patients with a history of cardiac illness or abnormal cardiac findings should be referred to a specialist for other examinations, and the patient treated only if the expected benefits outweigh the risks. The treating physician should consider performing a pre-treatment ECG. Orthostatic hypotension, with or without syncope, can occur during clozapine treatment Rarely, collapse can be profound and may be accompanied by cardiac and/or respiratory arrest which is more likely to occur with concurrent use of benzodiazepine or psychotropic agents and during initial titration with rapid dose escalation. Clozapine is associated with an increased risk of myocarditis, pericarditis/pericardial effusion and cardiomyopathy. Suspect myocarditis or cardiomyopathy in patients who experience persistent tachycardia at rest, especially in the first two months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure or symptoms mimicking myocardial infarction. Flu–like symptoms may also be present. If myocarditis or cardiomyopathy is suspected, stop clozapine treatment and refer patient immediately to a cardiologist. Do not re-expose patients with clozapine­ induced myocarditis or cardiomyopathy to clozapine. There have been post-marketing reports of myocardial infarction which may be fatal. Caution is advised in patients with known cardiovascular diseases or family history of

QT prolongation. As with other anti-psychotics, caution should be exercised when concomitant drugs are used known to increase QTc interval or cause an electrolyte imbalance. Clozapine should be used with caution in patients with risk factors for stroke. All possible risk factors for venous thromboembolism (VTE) should be identified before and during treatment with clozapine and preventative measures undertaken. Immobilisation of patients should be avoided. Observe patients with a history of epilepsy closely during clozapine therapy. Clozapine can cause unwanted effects through anticholinergic activity. These include impairment of intestinal peristalsis, faecal impaction and paralytic ileus. Use with care in patients with a history of colonic disease, a history of lower abdominal surgery, glaucoma and in patients receiving concomitant medications !mown to cause constipation, prostatic enlargement and narrow-angle glaucoma. High temperatures (fever) should be evaluated carefully to rule out underlying infection, agranulocytosis or neuroleptic malignant syndrome. Atypical antipsychotic drugs including clozapine have been associated with metabolic changes (hyperglycaemia, dyslipidaemia, body weight gain) that may increase cardiovascular/cerebrovascular risk. Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely. Patients with established diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Clinical monitoring is also recommended for lipids and weight. Acute withdrawal reactions have been reported following abrupt cessation of clozapine therefore gradual withdrawal is recommended. Monitor for recurrence of psychotic symptoms and symptoms of cholinergic rebound in case of abrupt discontinuation. Patients with stable, pre-existing liver disorders, or patients in whom symptoms of possible liver dysfunction develop during therapy, need regular liver function tests (LFTs). If the elevation of the LFTs is clinically relevant or jaundice occurs, discontinue treatment with clozapine. Resume only if LFTs return to normal and monitor closely. Patients aged 60 years and older may be particularly susceptible to the anticholinergic effects of  clozapine, orthostatic hypotension, tachycardia, urinary retention and constipation. Elderly patients with dementia who are treated with antipsychotics are at a small risk of death. Zaponex is not approved for treatment of dementia-related behavioural disturbances.

Interactions:

Bone marrow suppressants, pyrazolone analgesics, penicillamine, cytotoxic agents, long-acting depot injections of antipsychotics, other  psychotropic  drugs,  benzodiazepines, anticholinergics, antihypertensives, a,-adrenergic agents, alcohol, smoking cessation, MAOis, CNS depressants, antihistamines, inhibitors and inducers of cytochrome P450 isoenzymes, highly protein bound d1ugs, phenytoin, valproic acid and lithium.

Pregnancy & Lactation:

Caution when prescribing to pregnant women. Mothers receiving clozapine should not breast feed. Adequate contraceptive measures must be used by women of childbearing potential. Neonates exposed to antipsychotics during the third trimester should be monitored carefully.

Effects on Ability to Drive and Use Machines:

Activities such  as driving or operating machinery should be avoided, especially during the initial weeks of treatment.

Adverse Reactions:

Very common: Drowsiness/sedation, dizziness, tachycardia, constipation and hypersalivation.

Common: Leukopenia/decreased WBC/neutropenia, eosinophilia, leukocytosis, weight gain, blurred vision, headache, tremor, rigidity, akathisia, extrapyramidal symptoms, seizures/convulsions/myoclonic jerks, ECG changes, hypertension, postural hypotension, syncope, nausea, vomiting, anorexia, dry mouth, elevated liver enzymes, urinary incontinence, urinary retention, fatigue, fever, benign hyperthermia, disturbances in sweating/temperature regulation, dysarthria.

Serious: Fatal agranulocytosis, neuroleptic malignant syndrome, VTE (including cases of pulmonary embolism and cases of deep vein thrombosis), myocarditis, hepatitis, cholestatic jaundice, pancreatitis thrombocytopenia, hyperosmolar coma, cardiomyopathy, cardiac arrest, respiratory depression/arrest, sudden unexplained death, confusion, delirium, circulatory collapse, pericarditis/pericardial effusion, aspiration of ingested food, increased CPK, ketoacidosis, severe hyperglycaemia, hypertriglyceridaemia, cardiac arrest, intestinal obstruction/paralytic ileus/faecal impaction, fulminant hepatic necrosis, intestinal nephritis, colitis, systemic lupus erythematosus. Consult the SPC in relation to other side effects. Reporting suspected adverse reactions is important. Healthcare professionals are asked to report any suspected adverse  reactions. 

Overdose:

Signs and symptoms include drowsiness, lethargy, areflexia, co1na, confusion, hallucinations, agitation, delirium, extrapyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, respiratory depression or failure. No specific antidote available. Treatment with gastric lavage and/or administration of activated charcoal within the first 6 hours after the ingestion of the drug. 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 due to the possibility of a ‘reverse epinephrine’ effect. Close medical supervision is necessary for at least 5 days because of the possibility of delayed reactions.

Basic NHS Price:

Packs of 84: Zaponex 25mg tablets £8.28. Zaponex 100mg tablets £33.88. Pots of 500: Zaponex 25mg tablets £48.39. Zaponex 100mg tablets £196.43.

Legal Category:

POM.

Marketing Authorisation Numbers:

Zaponex 25mg tablets PL 32553/0001; Zaponex l001ng tablets PL 32553/0002.

Marketing Authorisation Holder:

Leyden Delta BV, Neerbosscheweg 620, 6544 LL Nijmegen, The Netherlands (info@leydendelta.nl).

Date of Preparation:

June 2018

Job Code:

UK/MED/18/001/004