Pharmacology: Pharmacodynamics: Clozapine is classified as 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 more typical antipsychotic drug products. In particular, although Clozapine does interfere with the binding of dopamine at D-1, D-2 , D-3, D-4 and D-5 receptors and have a high affinity for D-4 receptor, it does not induce catalepsy or inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that Clozapine is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of Clozapine from extrapyramidal side effects. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors.
Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion: In man, following a dosage of 100 mg b.i.d., the average steady state peak plasma concentration was 319 ng/mL (range: 102-771 ng/mL), occurring at the average of 2.5 hours (range: 1-6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41-343 ng/mL), after 100 mg b.i.d. dosing. Food does not appear to affect the systemic bioavailability of Clozapine. Thus, Clozapine may be administered with or without food.
Clozapine is approximately 97% bound to serum proteins. The interaction between Clozapine and other highly protein-bound drugs has not been fully evaluated but may be important. Clozapine is almost completely metabolized prior to excretion and 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. The demethylated, hydroxylated and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. The mean elimination half-life of Clozapine after a single 75 mg dose was 8 hours (range: 4-12 hours), compared to a mean elimination half-life, after achieving steady state with 100 mg b.i.d. dosing, of 12 hours (range: 4-66 hours). A comparison of single-dose and multiple-dose administration of Clozapine showed that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration dependent pharmacokinetics. However, at steady state, linearly dose-proportional changes with respect to AUC (area under the curve), peak and minimum Clozapine plasma concentrations were observed after administration of 37.5 mg, 75 mg, and 150 mg b.i.d.
Human pharmacology: In contrast to more typical antipsychotic drugs, Clozapine therapy produces little or no prolactin elevation.
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. Patients on rare occasions may report an intensification of dream activity during Clozapine therapy. 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.
Treatment with CLORIL is indicated in treatment-resistant schizophrenic patients only, i.e. schizophrenic patients who are non-responsive to or intolerant of classic neuroleptics. Non-responsiveness is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two marketed neuroleptics prescribed for adequate durations. Intolerance is defined as the impossibility of achieving adequate clinical benefit with classic neuroleptic drugs because of severe and untreatable neurological adverse reactions (extrapyramidal side effects of tardive dyskinesia.)
The dosage must be adjusted individually. For each patient the lowest effective dose should be used. Dose adjustment is indicated in patients receiving drugs interacting with CLORIL, such as benzodiazepines, or selective serotonin re-uptake inhibitors.
The following dosages for oral administration are recommended: Starting therapy 12.5 mg once or twice on the 1st day, followed by one or two 25 mg tablets on the 2nd 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.
Use in the elderly: It is recommended to initiate treatment at a particularly low dose (12.5 mg given once on the 1st day) and to restrict subsequent dose increment to 25 mg/day.
Therapeutic dose range: In most patients, antipsychotic efficacy can be expected with 300 to 450 mg/day given in divided dose. 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 at bedtime. Maximum dose to obtain full therapeutic benefit, a few patients may require larger dose, in which case judicious increments (i.e. not exceeding 100 mg) are permissible up to 900 mg/day. 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 CLORIL 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 such as headache, nausea, vomiting and diarrhoea.
Re-starting therapy: In patients in whom the interval since the last dose of CLORIL exceeds 2 days, treatment should be re-initiated with 12.5 mg given once or twice on the 1st 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. Switching from a previous neuroleptic therapy to CLORIL. When CLORIL therapy is to be initiated in a patients undergoing oral neuroleptic therapy, it is recommended that the other neuroleptic should first be discontinued by tapering the dosage downwards over a period of approximately 1 week. Once the neuroleptic has been completely discontinued for at least 24 hours, CLORIL treatment can be started as described above. It is generally recommended that CLORIL should not be used in combination with other neuroleptics.
Signs and symptoms: Drowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extrapyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmia; aspiration pneumonia, dyspnoea, respiratory depression or failure.
Treatment: Gastric lavage and/or administration of activated charcoal within the first 6 hours after the ingestion of the drug. 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.
Patients with history of hypersensitivity to Clozapine or any other components of the formulation.
Patients with history of toxic or idiosyncratic granulocytopenia or agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy).
Patients with myeloproliferative disorders.
Patients with history uncontrolled epilepsy.
Patients with alcohol psychosis or other toxic psychosis, drug intoxication, comatose conditions.
Patients with blood circulation collapse.
Patients with CNS depression of any cause.
Patients with hepatic failure, renal failure or cardiac failure.
Do not use in combination with other agents having a bone marrow suppression activity or long acting antipsychotics which may be potentially myelosuppressive from the body rapidly in situations where this may be required, e.g granulocytopenia.
Clozapine can cause agranulocytosis, it should be reserved for use in schizophrenic patients; Who are non-responsive or intolerance to classical neuroleptics.
Who have WBC count ≥3500/mm3 and normal differential blood count.
Who can have WBC counts performed weekly during the first 18 weeks, at least monthly thereafter throughout treatment, and for 1 month after complete discontinuation of Clozapine.
Who are informed about the significant risk of developing agranulocytosis.
Patient should be advised to report the physician immediately the appearance of lethargy, weakness, sore throat, fever or possible signs of infection, which may be indication of neutropenia.
The following patients required at least twice weekly haematological evaluations: During the first 18 weeks of Clozapine therapy, the WBC count falls to between 3000-3500/mm3 and/ or the ANC falls to between 1500-2000/mm3.
After 18 weeks of Clozapine therapy, the WBC count falls to between 2500-3000/mm3 and / or the ANC falls to between 1000-1500/mm3 .
During the therapy, if the WBC count has dropped by a substantial amount from baseline (as single drop of 3000/mm3 or more or a cumulative drop of 3000/mm3 or more within 3 weeks), a repeat WBC count and a differential blood count should be done.
Discontinuation of Clozapine is mandatory if; WBC count of patients <3000/mm3 or ANC <1500/mm3 during the first 18weeks of therapy and WBC, count of patients <2500/mm3 or ANC <1000/mm3 after the first 18 weeks of therapy. Then, WBC counts and differential blood counts should be performed daily and patients should be carefully monitored for flu - like symptom s or other symptoms suggestive of infection.
After discontinuing the Clozapine therapy and a further drop in the WBC count <2000/mm3 and/ or neutrophil granulocytes fall below <1000/mm3, it is recommended that in - patients are placed in protective isolation with observation by haematologist 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.
Interruption of Clozapine therapy due to non-haematological reasons: If patients have been on Clozapine for more than 18 weeks and the treatment was interrupted for more than 3 days but less than 4 weeks, it is recommended to perform WBC count weekly for 6 weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed.
If the treatment was interrupted for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given this confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
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.
Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and 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 antipsychotics was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
Other Precautions: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. In the event of eosinophilia, discontinuation of CLORIL is recommended if the eosinophil count rises above 3000/mm3 (3.0x109/L); therapy should be restarted only after the eosinophil count has fallen below 1000 /mm3 (1.0x109/L). In the event of thrombocytopenia, discontinuation of CLORIL therapy is recommended if the platelet count falls below 50,000/mm3 (50x109/L). Orthostatic hypotension, with or without syncope, can occur during CLORIL treatment. Rarely, collapse can be profound and may be accompanied by cardiac and/or respiratory arrest. The use of CLORIL is associated with an increased risk of myocarditis especially during, but not limited to, the first two months of treatment. Some cases of myocarditis have been fatal. Pericarditis/pericardial effusion and cardiomyopathy have also been reported in associated with CLORIL use; these reports also include fatalities. Patients with a history of epilepsy should be closely observed during CLORIL therapy since dose-related convulsions have been reported. In such cases, the dose should be reduced and, if necessary, an anti-convulsant treatment should be initiated. Patients with stable preexisting liver disorders may receive CLORIL, but need regular liver function tests. Liver function tests should be performed in patients in whom symptoms of possible liver dysfunction, such as nausea, vomiting and/or anorexia, develop during CLORIL therapy. CLORIL exerts anticholinergic activity, which may produce undesirable effects throughout the body. Careful supervision is indicated in the presence of prosatic enlargement and narrow-angle glaucoma. Probably on account of its anticholinergic properties, CLORIL has been associated with varying degrees of impairment of intestinal peristalsis, ranging form constipation to intestinal obstruction, faecal impaction and paralytic ileus. During CLORIL 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. Since CLORIL may be associated with thromboembolism, immobilisation of patients should be avoided. Acute withdrawal reactions have been reported following abrupt cessation of clozapine therefore gradual withdrawal 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 such as profuse sweating, headache, nausea, vomiting and diarrhoea.
Use in Pregnancy: Pregnancy for CLORIL, there are only limited clinical data on exposed pregnancies. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Caution should be exercised when prescribing to pregnant women.
Use in Lactation: Animal studies suggest that clozapine is excreted in breast milk and has an effect in the nursing infant; therefore, mothers receiving CLORIL should not breast-feed.
Women of child-bearing potential: A return to normal menstruation may occur as a result of switching from other antipsychotics to CLORIL. Adequate contraceptive measures must therefore be ensured in women of childbearing potential.
Haematological: Granulocytopenia, agranulocytosis. Although generally reversible on withdrawal of the drug, agranulocytosis may be fatal. The majority of cases (approx. 85%) occur within the first 18 weeks of treatment. Immediate withdrawal of Clozapine is required if the patients develop agranulocytosis.
Leucocytosis and/or eosinophilia (especially in the initial weeks of treatment).
Thrombocytopenia.
Central nervous system: Fatigue, drowsiness and headache.
Confusion, restlessness, agitation, delirium.
EEG changes, seizure threshold decrement.
Extrapyramidal symptoms may occur. Rigidity, tremor and akathisia have been reported but acute dystonia is not an established side effect.
Cases of neuroleptic malignant syndrome (NMS) have been reported in patients receiving Clozapine either alone or in combination with lithium or other CNS-active agents.
Cardiovascular system: Tachycardia, postural hypotension with or without syncope, ECG changes.
Circulatory collapse, cardiac arrhythmias, pericarditis, myocarditis (with or without eosinophilia).
Autonomic nervous system: Dry mouth, blurred vision and disturbances in sweating and temperature regulation have been reported. Hypersalivation is a relatively common side effect.
Respiratory system: In isolated cases, without circulatory collapse, respiratory depression or arrest has occurred. Rarely, aspiration of ingested food may occur in patients presenting with dysphagia.
Gastro-intestinal system: Nausea, vomiting, constipation and, very rarely, ileus may occur.
Hepatitis and cholestatic jaundice may occur. If jaundice develops, Clozapine should be discontinued.
Clozapine treatment may be associated with dysphagia, a possible cause of aspiration.
There have also been reports of parotid gland enlargement.
Acute pancreatitis.
Genito-urinary system: Both urinary incontinence and urinary retention and, in a few cases, priapism have been reported.
Acute interstitial nephritis.
Miscellaneous: Skin reactions.
Benign hyperthermia may occur, especially in the initial weeks of treatment.
May be caused severe hyperglycemia.
Increases in CPK values have occurred.
With prolonged treatment considerable weight gain has been observed in some patients.
Clozapine should not be used with other agents having a known potential to suppress bone marrow function.
Clozapine should not be used concurrently with any CNS suppressants such as alcohol, MAOIs, opiates, antihistamines and benzodiazepines as it may enhance the CNS suppressants effect.
The possibility of additive effect may occur if the concomitant administration of drugs possessing anticholinergic, hypotensive or respiratory depressant effects.
Concomitant use of lithium or other CNS-active agents may increase the risk of development of neuroleptic malignant syndrome (NMS).
Seizures may occur, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Clozapine was co-administered with valproic acid have been reported.
Caution should be used in concomitant administering of drugs which are either inhibitor or inducer of enzyme CYP4501A2, CYP3A4 and CYP4502D6. Because these enzymes are involved in the metabolism of Clozapine.
Elevated Clozapine plasma concentration have been reported in patients receiving the drug in combination with SSRIs (selective serotonin re-uptake inhibitors) such as paroxetine or fluvoxamine, cimetidine, erythromycin.
Concomitant administration of phenytoin or carbamazepine or rifampicin may cause interactions with Clozapine and may decreased level of the Clozapine treatment.
Clozapine has anti-α-adrenergic properties which may reduce the blood pressure-increasing effect of norepinephrine or other α-adrenergic agents and reverse the pressor effect of epinephrine.
The plasma concentration of Clozapine is increased by caffeine intake and decreased when the caffeine is discontinued.
Potent inhibitors of CYP3A, such as a azole antimycotics and protease inhibitors, could potentially also increase Clozapine plasma.
Cases have been reported of an interaction between citalopram and clozapine, which may increase the risk of adverse events associated with clozapine. CLORIL can potentiate the hypotensive effects of antihypertensives drugs due to its sympathomimetic antagonistic effects. CLORIL may cause an increase in plasma concentration of highly protein bound drugs (e.g. warfarin and digoxin, due to displacement from plasma proteins.
N05AH02 - clozapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics.
Cloril tab 100 mg
10 × 10's
Cloril tab 25 mg
10 × 10's
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