Clozapine for Treatment-Resistant Schizophrenia: Use With Great Caution

Clozapine (CLOZARIL, FAZACLO ODT, VERSACLOZ) was approved by the Food and Drug Administration (FDA) in 1989 for use in severely ill patients with treatmentresistant schizophrenia (schizophrenia that fails to respond adequately to standard antipsychotic treatment).[1] Symptoms of schizophrenia include agitation, delusions, hallucinations and paranoia. The FDA also approved the drug in 2002 for reducing suicidal behavior in patients with schizophrenia and schizoaffective disorder who are judged to be at chronic risk of re-experiencing suicidal behavior.[2]

Clozapine was the first member of the drug class known as atypical or second-generation antipsychotics,[3] which now includes olanzapine (ZYPREXA), risperidone (RISPERDAL) and many other newer antipsychotics.[4] One advantage of atypical antipsychotics is that they carry a somewhat lower risk of movement disorders, including tardive dyskinesia (uncontrollable jerky movement of the face, arms and legs), than do the older typical (first-generation) antipsychotics, such as haloperidol (HALDOL).[5] However, atypical antipsychotics carry a greater risk of weight gain and type 2 diabetes.[6]

Public Citizen’s Health Research Group has designated clozapine as a Limited Use drug. Because the drug has several serious unique risks, it should be reserved for severely ill schizophrenia patients who have failed to respond adequately to other antipsychotic medications.

Serious blood disorder

The most serious risk associated with clozapine is severe neutropenia (low white blood cell count), which can lead to severe, sometimes fatal infections. Neutropenia — which is the first of several dangers highlighted in a black-box warning, the strongest warning required by the FDA, in the product labeling for the drug[7] — occurs in approximately 3 percent of patients treated with the drug for one year.[8]

The risk of neutropenia appears to be highest during the first 18 weeks of treatment with clozapine but can occur after any duration of use. How the drug causes neutropenia is unknown, and it can occur at any dose. Because of this risk, the FDA mandated extraordinarily tight restrictions on the prescribing, dispensing and receiving of clozapine.

Under the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program, physicians who prescribe, and pharmacies that dispense, clozapine first must complete specific certification and enrollment procedures.[9] As part of this process, physicians and pharmacists must undergo education and demonstrate appropriate knowledge regarding clozapine’s risk of severe neutropenia and the requirement for monitoring patients for this adverse reaction.

The most important feature of the Clozapine REMS Program is the requirement that patients who are prescribed clozapine be enrolled in a monitoring program that includes frequent blood tests to measure their white blood cell counts. This testing must be done before filling the initial prescription for the drug and at the following minimum intervals while taking the drug:

• Weekly for the first six months
• Every two weeks for the next six months
• Monthly after 12 months

Patients must complete the required blood testing in order to receive their clozapine from the pharmacy for the next treatment interval.[10]

If a patient develops neutropenia while using clozapine, the frequency of white blood cell count tests must be increased to at least three times per week until the count returns to normal. The drug may be continued if the neutropenia is only mild, but it should be discontinued if the neutropenia is moderate or severe, at least until the neutropenia becomes only mild.

Cardiovascular risks

The black-box warning in clozapine’s product labeling also indicates that the drug can cause the following adverse cardiovascular events:

• Orthostatic hypotension (sudden drop in blood pressure upon sitting up or standing)
• Bradycardia (slow heart rate)
• Syncope (sudden loss of consciousness)
• Cardiac arrest[11]

The risk of these potentially fatal adverse events is highest at the start of treatment when the dosage is being titrated upward, particularly if the dosage is escalated rapidly. These events can occur with the first dose, even at the recommended starting dose of 12.5 milligrams (mg) once or twice daily (the maximum recommended total daily dose is 900 mg). Patients who have a history of cardiovascular disease, such as a heart attack, heart failure or stroke; are taking medications for hypertension; or are dehydrated are more susceptible to these adverse events.

Clozapine also is associated with myocarditis (inflammation of the heart muscle) and cardiomyopathy (enlargement, thickening or scarring of the heart muscle).[12] Estimates of the frequency of myocarditis in clozapine-treated patients range from less than one in 1,000 to as many as 3 percent of patients.[13] Ten to 30 percent of patients who experience this adverse event die.[14]

Symptoms of myocarditis and cardiomyopathy include chest pain, shortness of breath, rapid heart rate, palpitations, fever and flu-like symptoms. Myocarditis occurs most frequently within the first two months of clozapine treatment but may occur at any time during treatment. For patients who develop myocarditis or cardiomyopathy while taking clozapine, the drug should be discontinued and generally not restarted.

Seizures

The risk of seizure is another danger highlighted in the black-box warning in clozapine’s product labeling.[15] Although all atypical antipsychotic drugs can increase the risk of seizures, this risk appears to be greatest with clozapine.[16] The manufacturer of clozapine reports that seizures are estimated to occur in approximately 5 percent of patients treated with the drug for one year.[17] Seizures are more likely to occur as the dose of the drug is increased. The most common type of seizures seen with clozapine is tonic-clonic (generalized) seizures, which cause impaired consciousness and widespread jerking movements.[18]

Patients with a history of seizures or other predisposing risk factors for seizures — such as head trauma, use of certain medications or alcohol abuse — are more susceptible to having seizures while taking clozapine. Because of the high seizure risk, the drug label warns patients about engaging in activities where loss of consciousness could cause serious harm to themselves or others, such as driving an automobile, operating complex machinery, swimming or climbing.

Never use in dementia patients

As with all antipsychotic drugs,[19] the product labeling for clozapine includes a black-box warning that states that use of the drug increases the risk of death in elderly patients with psychotic symptoms related to dementia.[20] The warning emphasizes that clozapine is not approved for use in patients with dementia-related psychosis.

What You Can Do

You should use clozapine only if you have severe schizophrenia that has not responded adequately to other antipsychotic medications. If used, adhering to the aforementioned blood-testing schedule is essential to minimize your risk of a dangerously low white blood cell count.

You should contact your doctor immediately if you develop any symptoms of infection, cardiovascular disease or seizures while taking clozapine (see box, above).

References

[1] HLS Therapeutics. Label: clozapine (CLOZARIL). February 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf. Accessed December 5, 2017.

[2] Food and Drug Administration. Approval package for sNDA 19-758/S047, Clozaril. December 18, 2002. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/019758Orig1s047.pdf. Accessed December 5, 2017.

[3] Curto, M, Girardi N, Lionetto L, et al. Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep. 2016;18(7):68. doi:10.1007/s11920-016-0704-3.

[4] Drugs for psychotic disorders. Med Lett Drugs Ther. 2016;58(1510):160-165.

[5] Ibid.

[6] Ibid.

[7] HLS Therapeutics. Label: clozapine (CLOZARIL). February 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf. Accessed December 5, 2017.

[8] Clozapine. Prescrire Int. 1992;1(3):99-101.

[9] Food and Drug Administration. Risk evaluation and mitigation strategy single shared system for clozapine. September 2015. https://www.accessdata.fda.gov/drugsatfda_docs/rems/clozapine_2015-09-15_REMS_document.pdf. Accessed December 5, 2017.

[10] Clozapine REMS. A guide for patients and caregivers: What you need to know about clozapine and neutropenia. September 2015. https://www.clozapinerems.com/CpmgClozapineUI/rems/pdf/resources/Clozapine_REMS_Guide_Patients_Caregivers.pdf. Accessed December 5, 2017.

[11] HLS Therapeutics. Label: clozapine (CLOZARIL). February 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf. Accessed December 5, 2017.

[12] Ibid.

[13] Curto M, Girardi N, Lionetto L, et al. Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep. 2016;18(7):68. doi:10.1007/s11920-016-0704-3.

[14] Ibid.

[15] HLS Therapeutics. Label: clozapine (CLOZARIL). February 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf. Accessed December 5, 2017.

[16] Williams AM, Park SH. Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs. 2015;29(2):101-111.

[17] HLS Therapeutics. Label: clozapine (CLOZARIL). February 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf. Accessed December 5, 2017.

[18] Williams AM, Park SH. Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs. 2015;29(2):101-111.

[19] Food and Drug Administration. FDA news release: FDA requests boxed warnings on older class of antipsychotic drugs. June 16, 2008. https://wayback.archive-it.org/7993/20161022204622/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116912.htm. Accessed December 5, 2017.

[20] HLS Therapeutics. Label: clozapine (CLOZARIL). February 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf. Accessed December 5, 2017.