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NAMI E-News
March 10, 1998

FDA REDUCES FREQUENCY OF REQUIRED WHITE BLOOD CELL MONITORING SCHEDULE FOR CLOZARIL (CLOZAPINE)

The U.S. Food and Drug Administration (FDA) gave official notice today that weekly testing for white blood cell (WBC) count for people taking clozapine, has been reduced. The FDA decision modifies the white blood cell count monitoring schedule from mandatory weekly testing during therapy to weekly white blood cell count monitoring for the first six months of continuous clozapine therapy. This will be followed by bi-weekly white blood cell count thereafter for patients with acceptable white blood cell counts.

Clozaril, the brand name for clozapine, is a product of Novartis Pharmaceuticals Corporation and was approved by the FDA for general use in 1990. This change in FDA policy holds the promise of increasing access to this effective medication and improving the lives of people with serious brain disorders as well as reducing the stress and inconvenience already involved in taking the medication and submitting to weekly blood tests.

Since 1990, NAMI has been concerned that frequent testing presented a barrier to practical care for treatment-resistant individuals who either ceased taking or did not initiate Clozaril therapy because of the frequent monitoring requirements. Although regular blood monitoring is an important requirement for the safety of Clozaril recipients, people with treatment-resistant schizophrenia have limited treatment options available to them.

Clozaril recipients undergo WBC monitoring for early detection of severe leukopenia, a decline in WBC counts. This condition often signals the development of agranulocytosis, a life-threatening blood disorder that prevents the body from defending against infections. In early clinical trials, approximately one to two percent of patients receiving Clozaril therapy developed agranulocytosis. The monitoring system required for patients receiving Clozaril permits early detection of emerging agranulocytosis. The average incidence of agranulocytosis in any Clozaril -treated patient is reduced to about 0.38 percent when monitored under the Clozaril treatment management system.

Below is a fact sheet on clozapine developed by NAMI

FACTS ABOUT CLOZAPINE

Clozapine is a relatively new medication for patients with treatment-resistant schizophrenia. Approved by the FDA for general use in the U.S. in 1990, the drug is used for patients with schizophrenia and other mental disorders who have not responded well to standard antipsychotic drugs or who have had intolerable side effects to them. Sandoz Pharmaceuticals manufactures and markets clozapine under the product name Clozaril.

What is new about clozapine?

Clozapine has unique benefits and unique risks. The benefits make it a source of hope for the substantial number of patients with schizophrenia who have not responded well to traditional antipsychotic medications. Although clozapine use has certain risks, a careful monitoring system has been designed to manage and minimize them.

What are the benefits of clozapine?

Unique Effectiveness: In responsive patients, clozapine adds another alternative to the traditional antipsychotics in treating the positive symptoms of schizophrenia such as hallucinations, delusions, bizarre behavior and hostility. It also effectively treats the negative symptoms - withdrawal, blunted emotions, lack of motivation, and inability to experience pleasure or enjoyment. It is the negative symptoms which seem to respond better to clozapine than to the traditional antipsychotics.

Lack of Usual Side Effects: Clozapine has virtually no incidence of the muscle spasms, cramps, and posturing movements common to neuroleptic (antipsychotic) drugs, and minimal incidence of the less serious neurological side effects such as restlessness, muscle rigidity, and tremor (extrapyramidal side effects - EPS).

Furthermore, clozapine does not seem to cause tardive dyskinesia (TD), a disfiguring side effect of standard antipsychotic drugs. TD is characterized by involuntary movements such as grimacing, sucking and smacking of lips, and spasmodic movements of the extremities. It usually begins after several months of treatment and may be irreversible. There have been no confirmed cases of TD directly caused by clozapine alone.

Does every patient respond to clozapine?

Clozapine is effective for about 60 percent of those who try it. A patient should try clozapine for at least four to six weeks. Some symptoms, such as hallucinations, anxiety, paranoia, and bizarre behavior, should improve within that time; other symptoms may take longer. Additional improvements may be noticed over six to twelve months.

Do the benefits of clozapine outweigh the risks?

Clozapine poses a unique risk. Consequently, the FDA would not have approved it unless its effectiveness was proven clearly superior to that of current antipsychotic drugs. This was done conclusively in a 16-center study involving over 300 severely ill patients. These patients had been ill for many years and had failed to respond to at least three potent drugs.

In other studies of clozapine patients, 55 percent of previously hospitalized patients were able to work at paying or volunteer jobs or return to school, and re-hospitalization was reduced by 83 percent after 12 months. This improvement in psycho-social functioning was largely due to clozapine response.

What is the "unique risk" associated with clozapine?

One to two percent of patients who take clozapine will develop a condition called agranulocytosis, in which the white blood cell count drops dramatically. The patient becomes extremely vulnerable to infections and unable to fight them off. This condition is dangerous and potentially fatal. Fortunately, if agranulocytosis does occur, most patients can be successfully treated by stopping clozapine. In addition to stopping clozapine, hospitalization and treatment with a drug that increases white blood cell production are available.

Isn't agranulocytosis associated with other drugs as well? Yes. Other medications, including other antipsychotics, also cause agranulocytosis, but the incidence with clozapine is over 10 times that of other antipsychotics.

How can the risk of agranulocytosis be minimized?

To maintain safety, the patient's white blood cell count must be checked each week. Patients must have a weekly blood test, and the results sent to the patient's pharmacy before the next week's supply can be picked up. If detected early enough, the condition can be reversed by simply withdrawing the patient from clozapine. Hospitalization and treatment with medication to stimulate production of white blood cells has been done with great success.

It is possible that, in some cases, agranulocytosis--and other adverse reactions--may be a result of the concurrent use of clozapine and certain other commonly used drugs--even Alka-Seltzer. The list of products associated with agranulocytosis includes many commonly prescribed drugs such as antibiotics (e.g., Amoxicillin and Doxylycline), anticonvulsants (e.g., Tegretol and Dilantin), certain antidepressants (e.g., Elavil and Desyrel), and even other-the-counter medications such as Alka Seltzer, Benadryl, Dimetane, Tylenol Cold Night Time, Tylenol PM, Tylenol Estra Strength, Triaminic, and Unisom Nighttime Sleep Aid.

If caught early, agranulocytosis is reversible. And of the 90,000 patients receiving Clozaril, only 317 cases had occurred as of December 7, 1994. Only 12 of those cases were fatal.

Are other risks associated with clozapine?

Seizures may occur in roughly one to five percent of patients. The higher the dose, the greater the risk of seizures. Cardiovascular and respiratory side effects are also possible but extremely rare. Lowered blood pressure and increased heart rate can usually be managed by gradually increasing a patient's clozapine dosage from an initially low level. Some patients may notice weight gain, drooling, and initial lethargy but can be managed by dose titration (adjustment) or other interventions.

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