CLOZAPINE-ELSaad (amp)
-
Chemical Name:
Clozapine -
Therapeutic Category:
Central nervous system drugs -
Pharmacologic Category:
Antipsychotic Agent, Atypical -
Pharmaceutical Form:
Ampoule -
Composition:
Clozapine 100mg
CLOZAPINE
Ampoules - Tablets
Clozapine
1-COMPOSITION:
CLOZAPINE - Ampoule. Each Ampoule 2 ml contains
Clozapine 50 mg. ( for I. M. use only)
CLOZAPINE -25 Tablet Each Tablet contains Clozapine 25 mg.
CLOZAPINE -100 Tablet Each Tablet contains Clozapine 100 mg.
2-PHARMACOLOGY:
Clozapine has been shown to be an antipsychotic agent that is different from classic neuroleptics.
In pharmacological experiments, the compound does not induce catalepsy or inhibit apomorphine- or amphetamine-induce stereotyped behaviour. 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-a- adrenergic, anticholinergic, antihistaminic. It has also been shown to possess antiserotoninergic properties.
Clinically Clozapine produces rapid and marked sedation, and exerts strong antipsychotic effects. It is of particular interest that the latter have been observed in schizophrenic patients resistant to other drug treatment. In such cases, Clozapine has proven effective in relieving both positive and negative schizophrenic symptoms. In addition, improvement in some aspects of cognitive dysfunction has been described. Also, epidemiological studies showed an approximately sevenfold decrease in suicide and suicide attempts in-patients treated with Clozapine, compared with schizophrenic not on Clozapine.
Clozapine is unique in that it produces virtually no major extra-pyramidal reactions such as acute dystonia. In contrast to classical neuroleptics, Clozapine produces little or no prolactin elevation, thus avoiding adverse effects such as gynaecomastia, amenorrhoea, galactorrhoea, and impotence.
3-PHARMACOKINETICS:
The absorption of orally administered CLOZAPINE is 90% to 95%; neither rate nor extent of absorption is influenced by food.
Clozapine, the active ingredient of CLOZAPINE, is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50% to 60%. 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. 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 increase to 14.2 hours when steady-state conditions were reached by administering daily doses of 75 mg for at least 7 days. Dosage increases from 37.5 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.
Clozapine is almost completely metabolized before excretion. Of the main metabolites only the demethyl metabolite was found to be active. Its pharmacological actions resemble those of Clozapine, but are considerably weaker and of short duration. Only trace amounts of unchanged drug are detected in the urine and faeces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the faeces.
4-INDICATIONS:
Treatment with CLOZAPINE 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 prescribed for adequate duration.
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 or tardive dyskinesia)
5-CONTRA–INDICATIONS:
- Previous hypersensitivity to Clozapine or any other components of the formulation.
- 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.
6-PRECAUTIONS:
- 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 who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may be started on CLOZAPINE after agreement of a haematologist. Blood tests are weekly required in order to monitor for the occurrence of agranulocytosis. Patients should report the appearance of lethargy, weakness, fever, sore throat, malaise mucous membrane ulceration or other possible signs of infection.
- In the event of thrombocytopenia, it is recommended to discontinue CLOZAPINE therapy if the platelet count falls below 50 000/mm³.
- The possibility of impaired glucose tolerance should be considered in-patients receiving CLOZAPINE who develop symptoms of hyperglycaemia.
- The possibility of pulmonary embolism should be considered in patients receiving Clozapine who present with acute dyspnea or other respiratory signs and symptoms.
- Clozapine has anticholinergic effects and care should be exercised in using this drug in the presence of prostatic enlargement or narrow angle glaucoma.
7-DRUG INTERACTIONS:
- Drugs known to have a substantial potential to depress bone marrow function should not be used concurrently with CLOZAPINE.
- CLOZAPINE may enhance the central effects of alcohol, MAO inhibitors and CNS depressants such as narcotics, antihistamines, and benzodiazepines.
- Particular caution is advised when CLOZAPINE therapy is initiated in-patients who are receiving (or have recently received) a benzodiazepine or any other psychotropic drug, as these patients may have an increase risk of circulatory collapse.
- Because of the possibility of additive effects, caution is essential in the concomitant administration of drugs possessing anticholinergic, hypotensive, or respiratory depressant effects.
- Owing to its anti-α-adrenergic properties, CLOZAPINE may reduce the blood pressure-increasing effect of norepinephrine or other predominantly α-adrenergic agents and reverse the pressor effect of epinephrine.
- Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where CLOZAPINE was co-administrated with valproic acid have been reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not been determined.
8-PREGNANCY AND LACTATION:
- Pregnancy:
Reproduction studies in animals have revealed no evidence of impaired fertility or harm to the foetus due to Clozapine.
However, the safe use of CLOZAPINE in pregnant women has not been established. Therefore, the drug should be used in pregnancy only if the expected benefit clearly outweighs any potential risk.
* Lactation:
Animal studies suggest that Clozapine is excreted in breast milk; therefore, mothers receiving CLOZAPINE should not breast-feed.
9-EFFECTS ON ABILITY TO DRIVE AND USE MACHINES:
Owing to the ability of CLOZAPINE to cause sedation, activities such as driving or operating machinery should be avoided, especially during the initial weeks of treatment.
10-SIDE EFFECTS:
- Haematological:
Development of granulocytopenia and agranulocytosis is a risk inherent to CLOZAPINE treatment, although generally reversible on withdrawal of the drug.
The majority of cases occur within the first 18 weeks of treatment.
Because immediate withdrawal of the drug is required to prevent the development of life-threatening agranulocytosis, monitoring of the WBC count is mandatory.
Unexplained leucocytosis and/or eosinophilia may occur, especially in the initial weeks of treatment. Very rarely, CLOZAPINE may cause thrombocytopenia.
- Central Nervous System:
Fatigue, drowsiness and sedation are among the most common side effects observed. Dizziness or headache may also occur.
In-patients with pre-existing epilepsy, the dose should be reduced and, if necessary, anticonvulsant treatment initiated.
Carbamazepine should be avoided because of its potential to depress bone marrow function, and with other anticonvulsant drugs the possibility of a pharmacokinetic interaction should be considered.
- Miscellaneous:
Dry mouth, disturbances in sweating, hypersalivation, tachycardia and postural hypotension, especially in the initial weeks of treatment.
Nausea, constipation, and both urinary in continence and urinary retention and, in a few cases. On rare occasions, hyperglycaemia,
With prolonged treatment considerable weight gain has been observed in some patients.
11-DOSAGE AND ADMINISTRATION:
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 CLOZAPINE, such as been benzodiazepines, or selective serotonin re-uptake inhibitors. The following dosages for oral administration are recommended:
- Starting Therapy:
12.5 mg (½ of a 25-mg tablet) 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. Therefore, 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 increments to 25 mg/day.
- Therapeutic Dose Range:
In most patients, antipsychotic efficacy can be expected with 300 to 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 at bedtime.
- Maximum Dose:
To obtain full therapeutic benefit, a few patients may require larger doses, 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 CLOZAPINE therapy, a gradual reduction in dose over a 1 to 2-week period is recommended.
- Re-starting Therapy:
In patients in whom the interval since the last dose of CLOZAPINE exceeds 2 days, treatment should be re-initiated with 12.5 mg (½ of a 25-mg tablet) 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.
- Intramuscular Use of CLOZAPINE:
It is recommended to start treatment with 12.5 mg (corresponding to 0.5 ml), given once or twice on the 1st day. The usual therapeutic dose is 150 mg/day, given in divided doses, and the maximum dose is 300 mg/day. The solution is suitable for i.m. injection only. As a rule, I.M. Injections can be replaced by oral administration after a few days.
- Switching from a previous neuroleptic therapy to CLOZAPINE:
When CLOZAPINE therapy is to be initiated in a patient 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, CLOZAPINE treatment can be started as described above. It is generally recommended that CLOZAPINE should not be used in combination with other neuroleptics.
12-PACKAGING:
- Ampoules:
- 5 Ampoules in one carton.
- 25 Ampoules in one carton.
-Tablets:
- 10 Tablets in one blister.
- 1 Blisters in one carton
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