CLOZAPINE Rami James Aoun
CLOZAPINEIs an atypical antipsychotic medication marketed                 under several brands
CLOZAPINE                                             Historic Facts•The first of the atypicalantipsychotics to be develope...
CLOZAPINE                               Mechanism of ActionStrong antagonism for D4receptor , weak antagonism             ...
CLOZAPINEMechanism of Action             •Blockage of dopaminergic neurons to the             limbic and prefrontal cortex...
CLOZAPINE                              Pharmacodynamics/kinetics•Clozapine is administered PO•The absorption of clozapine ...
CLOZAPINE  Indications       •Principally in treating treatment-resistant       schizophrenia also known as refractory    ...
CLOZAPINE                             Contraindications•Hypersensitivity to clozapineor any component of theformulation;• ...
CLOZAPINE Drug Interactions              •Any drug that increases QT interval,              may cause Ventricular arrhythm...
CLOZAPINE                                                      DosingSchizophrenia:•Initial: 12.5 mg once or twice daily;•...
CLOZAPINE   Pricing
CLOZAPINE         Pricing25 mg (100tabs): $242.17
CLOZAPINE                                        FDA Blackbox Warning1. Agranulocytosis, this is a potentially fatal side ...
CLOZAPINE  Agranulocytosis              •Therapy should not be initiated in patients with              WBC <3500 cells/mm3...
CLOZAPINE                                                Agranulocytosis•Patients taking clozapine are required to have ab...
CLOZAPINEDosage Relation to Side Effects                   • Agranulocytosis is not                   dose dependant.     ...
CLOZAPINE                                    Other Side Effects•The risks of extrapyramidalsymptoms are much more lesswhen...
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Clozapine

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  • Transcript of "Clozapine"

    1. 1. CLOZAPINE Rami James Aoun
    2. 2. CLOZAPINEIs an atypical antipsychotic medication marketed under several brands
    3. 3. CLOZAPINE Historic Facts•The first of the atypicalantipsychotics to be developed, NEW DRUG IS SAID TO HELP SEVERE SCHIZOPHRENICS•Clozapine was developed by Sandoz in AP Published: May 15, 19871961, Nearly one-third of the severe schizophrenics who were given a•It was first introduced in Europe in 1971, new drug improved significantly, but the drug requires weekly bloodbut was voluntarily withdrawn by tests because of a potentially fatal side effect, researchers said today.the manufacturer in 1975 after it The severly affected victims had irreversible, structural brain damage that ledwas shown to cause agranulocytosis, researchers to think no drug would ever be able to help them, said Dr. Herbert Meltzer, one of the directors of a new study conducted at 16that led to death in some patients. hospitals around the country. Its a major, major advance, Dr. Meltzer said at the annual•In 1989, after studies demonstrated that meeting of the American Psychiatric Association. The findings of theit was more effective than any study by Dr. Meltzer of Case Western Reserve University in Cleveland andother antipsychotic for treating Dr. John Kane of Long Island Jewish Medical Center were reported for theschizophrenia first time at the meeting. It is estimated that 300,000 Americans have the most severe form of schizophrenia. Many other neuroleptic or antipsychotic drugs are used to•the FDA approved clozapines use but treat schizophrenia, in which people become grossly out of touch with reality,only for treatment-resistant but they are of no value in the most severe cases, Dr. Meltzer said.schizophrenia
    4. 4. CLOZAPINE Mechanism of ActionStrong antagonism for D4receptor , weak antagonism It blocks alpha- of D1, D2, D3, and D5 adrenergic, histamine dopamine receptor subtypes, H1, and cholinergic but receptors Serotonin (5HT2) antagonist
    5. 5. CLOZAPINEMechanism of Action •Blockage of dopaminergic neurons to the limbic and prefrontal cortex will decrease psychotic symptoms •However blockage of the dopaminergic neurons to the Basal Ganglia (mainly striatum) will produce extra pyramidal symptoms •Atypical antipsychotics, of which clozapine is a member of, differ from traditional anti- psychotics in treating the negative symptoms of schizophrenia in addition to less side effects
    6. 6. CLOZAPINE Pharmacodynamics/kinetics•Clozapine is administered PO•The absorption of clozapine is almost complete, but theoral bioavailability is 50 to 60% due to first-passmetabolism•Peak concentration is at 2.5 hours, and fooddoes not appear to affect the bioavailability•The elimination half-life is 12 hours•The major metabolite, norclozapine (desmethyl-clozapine), has limited pharmacological activity•The cytochrome P450 isoenzyme 1A2 in theliver is primarily responsible for clozapine metabolism.Agents that induce (e.g., cigarette smoke) or inhibit (e.g.,theophylline, ciprofloxacin, fluvoxamine) CYP1A2 mayincrease or decrease, respectively, the metabolism ofclozapine•The induction of metabolism caused by smoking meansthat smokers require up to double the dose ofclozapine compared with non-smokers to achieve anequivalent plasma concentration•Excretion: Urine (50%) and feces (30%)
    7. 7. CLOZAPINE Indications •Principally in treating treatment-resistant schizophrenia also known as refractory schizophrenia. • It is not used routinely for treating schizophrenia because of its adverse effects (will be discussed later) •The label “refractory” is given to schizophrenia after failure of symptoms to respond satisfactorily to at least two different antipsychotics •Also Clozapine is used to reduce risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder • Unlabeled indications include; Schizoaffective disorder, bipolar disorder, childhood psychosis, severe obsessive-compulsive disorder; psychosis/agitation related to Alzheimer’s dementia
    8. 8. CLOZAPINE Contraindications•Hypersensitivity to clozapineor any component of theformulation;• History of agranulocytosisor severe granulocytopenia withclozapine;• Uncontrolled epilepsy, severecentral nervous system depression orcomatose state• Paralytic ileus• Myeloproliferative disordersor use with other agents which havea well-known risk of agranulocytosisor bone marrow suppression
    9. 9. CLOZAPINE Drug Interactions •Any drug that increases QT interval, may cause Ventricular arrhythmias •Metoclopromide, May enhance the adverse/toxic effect of Antipsychotics •Macrolide Antibiotics: May decrease the metabolism of CloZAPine •CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates.(ex; theophylline, ciprofloxacin, fluvoxamine) •Carbamazepine: May increase the metabolism of Clozapine •Benzodiazepines: May enhance the adverse/toxic effect of Clozapine. •Anti-Parkinsons Agents (Dopamine Agonist): Antipsychotics (Atypical) may diminish the therapeutic effect of Anti-Parkinsons Agents
    10. 10. CLOZAPINE DosingSchizophrenia:•Initial: 12.5 mg once or twice daily;•Increased, as tolerated, in increments of 25-50 mg/day to a target dose of 300-450 mg/day after 2 weeks;•May require doses as high as 600-900 mg/day (maximum dose: 900 mg/day).•In some efficacy studies, total daily dosage was administered in 3 divided doses.Suicidal behavior in schizophrenia or schizoaffective disorder:•Initial: 12.5 mg once or twice daily;•increased, as tolerated, in increments of 25-50 mg/day to a target dose of 300-450 mg/day after 2 weeks;•mean dose is ~300 mg/day (range: 12.5-900 mg); treatment duration 2 years then reassess need.•If no longer a suicide risk, may resume prior antipsychotic therapy after gradually tapering off clozapine over 1-2 weeks.Termination of therapy:•If dosing is interrupted for ≥48 hours, therapy must be reinitiated at 12.5-25 mg/day; may be increased more rapidly than with initial titration, unless cardiopulmonary arrest occurred during initial titration.•In the event of planned termination of clozapine, gradual reduction in dose over a 1- to 2-week period is recommended. If conditions warrant abrupt discontinuation (leukopenia), monitor patient for psychosis and cholinergic rebound (headache, nausea, vomiting, diarrhea).
    11. 11. CLOZAPINE Pricing
    12. 12. CLOZAPINE Pricing25 mg (100tabs): $242.17
    13. 13. CLOZAPINE FDA Blackbox Warning1. Agranulocytosis, this is a potentially fatal side effect. Clozapine is available only through a distribution system that ensures monitoring of WBC count and ANC prior to delivery of the next supply of medication.2. Seizures have been associated with the use of Clozapine, with a greater likelihood at higher doses. Caution should be used in patients with a history of seizures or predisposing factors.3. Myocarditis Analyses of post-marketing safety databases suggested an increased risk of fatal myocarditis, especially during the first month of therapy.4. Cardiovascular and Respiratory Effects; Orthostatic hypotension, with or without syncope, more likely to occur during initial titration in association with rapid dose escalation. Respiratory arrest and cardiac arrest during initial treament has occurred in patients who were being administered benzodiazipines or other psychotropic drugs,5. Increased Mortality in Elderly Patients With Dementia Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular or infectious
    14. 14. CLOZAPINE Agranulocytosis •Therapy should not be initiated in patients with WBC <3500 cells/mm3 or ANC <2000 cells/mm3 or history of myeloproliferative disorder. •Without monitoring, agranulocytosis occurs in about 1% of patients who take clozapine during the first few months of treatment •Initial episodes of moderate leukopenia or granulopoietic suppression confer up to a 12- fold increased risk for subsequent episodes of agranulocytosis. •Use with caution in patients receiving other marrow suppressive agents. •Eosinophilia has been reported to occur in 1% of patients on clozapine. Interrupt therapy for eosinophil count >4000/mm3. May resume therapy when eosinophil count <3000/mm3. •Patient must fail at least two trials of other primary medications for the treatment of schizophrenia before initiating therapy with clozapine.
    15. 15. CLOZAPINE Agranulocytosis•Patients taking clozapine are required to have ablood cell count every week, for the first 6months of therapy• Then every other week for the second6 months after initiation of therapy.•After twelve months, blood cell countsneed be performed every 4 weeks.•The manufacturers of both the brand andgeneric clozapine are required by the FDAto track white blood cells counts forpatients receiving clozapine, and pharmaciesare required to obtain a copy of the CBCprior to dispensing the medication to the patient.•WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3•If the number of white blood-cells drops notablythen referral to a hematologist isundertaken.
    16. 16. CLOZAPINEDosage Relation to Side Effects • Agranulocytosis is not dose dependant. •Seizures on the other hand is dose dependant
    17. 17. CLOZAPINE Other Side Effects•The risks of extrapyramidalsymptoms are much more lesswhen compared to the typicalantipsychotics;• Weight gain and DM.• Anticholinergic effects:extreme constipation, dry mouth(Xerostomia), blurred vision, urinaryretention• Night-time drooling, or wet pillowsyndrome(Sialorrhea• Muscle stiffness• Sedation, Drowziness• Tachycardia, Tremors• Hyperglycemia• Many male patients have experiencedcessation of ejaculation duringorgasm as a side effect of clozapine

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