Clozapine chemical structure
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Clozaril

Clozapine (sold as Clozaril®, Leponex®, Fazaclo®) was the first of the atypical antipsychotics to be developed. It was approved by the United States FDA in 1989 and is the only FDA-approved medication indicated for treatment-resistant schizophrenia and for reducing the risk of suicidal behaviour in patients with schizophrenia. more...

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History and main uses

Clozapine was developed by Sandoz in 1961, and introduced in Europe ten years later. In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, Clozapine was voluntarily withdrawn by the manufacturer. Clozapine fell out of favor for more than a decade. However, when studies demonstrated that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics, the FDA and health authorities in most other countries approved its use only for treatment-resistant schizophrenia, and required regular haematological monitoring to detect granulocytopenia, before agranulocytosis develops. In December of 2002, Clozapine was also approved for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior.

Commonly approved indications

  • Treatment-resistant schizophrenia, if the required hematologic monitoring is adhered to
  • Reducing the risk of suicide in schizophrenic or schizoaffective patients judged to belong to a high risk group with chronic risk for suicidal behavior. Clozapine was shown to prolong the time to suicidal attempt significantly greater than Olanzapine (Zyprexa®).

Clozapine works equally well against positive (e.g. delusions, hallucinations) and negative (e.g. emotional and social withdrawal) symptoms of schizophrenia. It has no dyscognitive effect often seen with other psychoactive drugs and is even able to increase the capabilities of the patient to react to this environment and thereby fosters social rehabilitation.

Off-label and investigational drug use

  • Treatment of psychosis in L-Dopa treated patients (25 to 50 mg at bedtime is often sufficient); this indication is currently approved in Switzerland
  • Treatment of otherwise resistant acute episodes of mania
  • Treatment of psychotic symptoms occurring in patients with dementia of the Levy-body-type
  • Treatment of severe cases of obsessive compulsive disorder
  • Treatment of intractable chronic insomnia, if all other measurements have failed

Though much research has been done evaluating the benefit of clozapine in treating the aforementioned conditions, it is too early to come to a conclusive result. If you contemplate clozapine as drug for these conditions, weigh carefully benefits and risks and inform the patients fully, if possible, about the advantages and risks of clozapine treatment, before a joint decision is made. If the patient is not able to make own decisions, parents or guardians or the competent court must give their consent.

Chemistry

Clozapine is yellow crystalline solid with melting point 183-184 °C. It is insoluble in water, soluble in acetone, very well soluble in chloroform. Chemical name is <8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzodiazepine>.

Read more at Wikipedia.org


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New & Approved: Inspra Clozaril - Clinical Rounds
From OB/GYN News, 2/15/03 by Elizabeth Mechcatie

Inspra

(eplerenone, Pharmacia)

An aldosterone blocker for treating hypertension, used alone or in combination with other antihypertensives. The first drug in this class to be approved.

Recommended Dosage: Starting dose of 50 mg once a day, increasing to 50 mg twice a day if necessary.

Special Considerations: The most common side effects reported in trials included dizziness (3%), and fatigue, flulike symptoms, diarrhea, and cough (all occurring at a rate of 2%). Contraindicated in patients with serum potassium above 5.5 mEq/L; type 2 diabetes with microalbuminuria; serum creatinine above 2 mg/dL in men or 1.8 mg/dL in women; or a creatinine clearance below 50 mL/min. Also contraindicated in people on potassium supplements, potassium-sparing diuretics (amiloride, spironolactone, or triamterene), and drugs that are strong inhibitors of CYP450 3A4, such as ketoconazole or itraconazole.

Comment: Inspra blocks the binding of aldosterone, part of the renin-angiotensin-aldosterone system. In studies of more than 3,000 patients, Inspra lowered systolic and diastolic blood pressure, as monotherapy and when used with other antihypertensives. In a 16-week trial of about 500 black and white patients with mild to moderate hypertension, use of Inspra (50-200 mg) was associated with greater reductions in blood pressure in black patients than use of the angiotensin receptor blocker Cozaar (losartan). In white patients, blood pressure reductions were comparable with both.

Inspra is expected to become available sometime in 2003, a company spokesman said. The company plans to file an application this year with the Food and Drug Administration for approval of the drug for treating post-MI heart failure, based on the results of an international study of more than 6,000 patients.

Clozaril

(clozapine, Novartis)

An atypical antipsychotic for reducing the risk of recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder. This is the first time the FDA has approved a suicidality claim for any medication. Approved in 1990 for severely ill schizophrenic patients who fail to respond adequately to standard drug therapy.

Recommended Dosage: Target dose of 300-450 mg/day.

Special Considerations: Treatment recommended for at least 2 years to reduce the risk of recurrent suicidal behavior, the FDA said in a statement. Weekly white blood cell counts and weekly drug dispensing mandatory because of the risk of agranulocytosis, which can be reversed if detected at an early stage. Postmarketing data suggest that Clozaril is "associated with an increased risk of fatal myocarditis," especially during the first month of therapy. The seizure risk ranges from 1% to 2% of patients on low doses (under 300 mg/day) to 5% of those on high doses (300-600 mg/day).

Comment: Approval was based on results of the International Suicide Prevention Trial (InterSePT), data from a national clozapine registry, and other data. In InterSePT, a prospective open-label trial of 980 patients with schizophrenia or schizoaffective disorder at high risk for suicide, the risk of suicide attempts or hospitalizations to prevent suicide over 2 years was reduced by 26% among those on Clozaril, vs. those treated with another atypical antipsychotic, Zyprexa (olanzapine). The reduction in risk did not appear to be attributable to a greater effect on psychotic or depressive symptoms, or to greater use of concomitant psychotropic medications, according to Novartis. No difference was seen in the number of completed suicides, which was similar in both groups. Data from clozapine treatment registries in the United Kingdom and Texas also showed a reduced suicide rate associated with Clozaril.

The FDA advised health care professionals that most of the patients on Clozaril and Zyprexa were receiving other treatments aimed at reducing their risk of suicide, including antidepressants, psychotherapy, and hospitalization. "The contributions of these additional measures are unknown," the FDA said in a statement. The approval does not apply to generic clozapine because Novartis has been granted exclusive rights to market Clozaril for this indication for 36 months.

An estimated 3,600 suicides associated with schizophrenia occur each year in the United States.

COPYRIGHT 2003 International Medical News Group
COPYRIGHT 2003 Gale Group

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