Jose De Leon, MD

The US Clozapine Package Insert Needs Major Changes
By Jose De Leon

Clozapine’s Package Insert

Clozapine is an antipsychotic approved for two conditions: treatment-resistant schizophrenia (TRS) and reducing suicidal behavior in schizophrenia. No other antipsychotics are approved treatments for these conditions. In the United States, the Food and Drug Administration (FDA) approves drugs. In 1989, the FDA approved clozapine for TRS using a study headed by Dr. John Kane. In 2003, the FDA added the other condition, suicidal behavior. To gain approval, the marketing pharmaceutical company must develop a complex bureaucratic document called a package insert, or drug label. In the FDA’s view, package inserts educate prescribers in a drug’s pharmacology. In reality, package inserts are seriously hampered by extreme length and complexity. However, all US prescribers know that lawyers can use package inserts against them in court. Package inserts use boxed warnings (previously called black boxes) for potentially lethal adverse drug reactions (ADRs).

Clozapine’s History

In 1975, after clozapine was marketed in Europe, the Finnish drug agency reported eight deaths associated with agranulocytosis in clozapine-treated patients, leading to the cessation of US studies. Agranulocytosis refers to a significant decrease in some white blood cells (WBCs) called neutrophils, needed to fight infections. FDA approval required a complex hematological monitoring system, the use of a centralized database for WBC counts, and a boxed warning for agranulocytosis.

Clozapine Was Not Studied as Current Drugs are Studied

The introduction of new drugs in the US now requires more sophisticated studies than those completed for clozapine. They include studies on: 1) basic pharmacology, and 2) ADRs. Furthermore, after marketing, the FDA is required to monitor potentially lethal ADRs in a process called pharmacovigilance and modify the boxed warnings accordingly. Pharmacovigilance varies in other national drug agencies, based on economic resources. ADR reports from all drug agencies are sent to the international database, called VigiBase, which is managed by the World Health Organization (WHO).

My History and Clozapine

In 1987, after being trained in medicine and psychiatry in Spain, I trained in Philadelphia as a clinical scientist in psychiatry.  My Spanish wife and I had no choice but to stay in the US, as the Spanish university did not hire me to teach. Our first two children were born in Philadelphia during our first nine years (1987-1995) in the US.  I conducted research in state hospitals, including supervising a clozapine study for five years for my boss, Dr. George Simpson, who published the first clozapine study in the US. In 1996, we moved to Lexington, Kentucky, where our youngest daughter was born. First, I managed a 30-bed unit for treatment-refractory patients at Eastern State Hospital. I converted it to a research unit by measuring blood levels and adding a laboratory to research genes that control the medication metabolism process. Second, over the last 20 years, I worked as a consultant for the state of Kentucky: 1) helping with the most difficult cases at the state mental health facilities, 2) reviewing patient deaths, 3) and developing pharmacological guidelines.

Prior Major Clozapine Articles

In 2019, I wrote an editorial on clozapine package inserts proposing that: 1) patients of Asian ancestry only need half the US-recommended dosage, 2) slower personalized titrations prevent clozapine-induced myocarditis (an inflammation of the heart), and 3) pneumonia is the most frequent cause of death in clozapine-treated patients. During severe infections, including pneumonia, the body’s ability to metabolize clozapine is impaired, so if clozapine dosing is not stopped or decreased, the patient develops a very dangerous combination of pneumonia and clozapine intoxication.  After 9 rejections of my editorial, the 10th version1 was published in Schizophrenia Research (a journal founded by Drs. Nasrallah and DeLisi) and included Dr. Kane as an author. The gracious support of Dr. Kane had little impact on the FDA and clozapine experts worldwide.

In VigiBase, until 2019, among worldwide clozapine-treated patients, there were 1) 34,491 reports of agranulocytosis with 550 deaths, and 2) 6,983 reports of pneumonia with 2,077 deaths. In February 2020, the editor of the journal that published our article sent it to a psychiatric colleague working at the FDA. The FDA psychiatrist informed me that the article was forwarded to the clozapine team, but I should not expect to hear back from them.  I was relieved; the COVID-19 pandemic was starting and it could cause COVID-19 pneumonia in clozapine-treated patients. I thought the FDA might choose to save thousands of lives worldwide by modifying the clozapine package insert. I was wrong; nothing happened.

In 2022, I published an international guideline with 104 authors from 50 countries/regions about personalizing clozapine dosing and titrations.2 In the spring of 2023, the FDA asked the company in charge for some changes in the package insert. The FDA sent this international guideline to the company. In another e-mail the FDA sent 6 articles on pneumonia, 3 written by me. The company asked for my help with the FDA changes. I spent many hours improving and updating the package insert, but the company told me the FDA rejected all my changes. The FDA rejected my suggestions regarding pneumonia which were based on my 3 published articles which had been sent to the company by the FDA.  Instead, the FDA proposed a paragraph on pneumonia that was not based on the literature and was confusing for clinicians.3

A Major Step in May 2025

In May 2025, in response to the inaction of the FDA, we published a two-part article proposing that the clozapine package insert needed major changes in the sections on pharmacology4 and potentially lethal ADRs.3 The article includes an encyclopedic review of the literature, has 40 authors including most of the US clozapine experts and is supported by 123 letters of recommendation from international experts from 44 countries/regions.

The US Package Insert’s Weakness Regarding Basic Pharmacology 

In 1989, the manner in which enzymes process drugs, including clozapine, was unknown, so clozapine was introduced with limited studies. Our proposed package insert modifications include:4  1) an explanation that clozapine is mainly metabolized by one liver enzyme, called CYP1A2; 2) an updated list of drug-drug interactions; 3) a warning that infections may decrease CYP1A2 activity and increase the risk of clozapine intoxication; 4) a warning that obesity may decrease CYP1A2 activity; 5) an acknowledgment that patients of Asian or Native American ancestry have lower CYP1A2 activity and need lower doses; and 6) a recommendation that personalized titrations with monitoring of a blood protein (c-reactive protein) for inflammation should be considered until prospective studies are available.

The US Package Insert’s 5 Boxed Warnings

The first boxed warning concerned agranulocytosis. Over time, the FDA added 3 more boxed warnings for seizures, hypotension, and myocarditis. No other antipsychotics had boxed warnings, but in 2005, the FDA added another boxed warning for all second-generation antipsychotics, including clozapine, regarding the risk of death in elderly patients with dementia.

The FDA has approved the elimination of the hematological monitoring database, but as of today (June 10, 2025), this has not been implemented in the package insert. In our article,3 we propose that the package insert should focus on saving lives when pneumonia or other severe infections are present, as they kill many more clozapine-treated patients in the US than agranulocytosis.

Apology

I am convinced that, since 2019, thousands of fatal cases of infection in clozapine-treated patients could have been prevented worldwide if the FDA had modified the package insert. Other drug agencies would have followed the example of the FDA. I do not know how to apologize to patients and families of clozapine-treated patients around the world who have suffered or died due to my inability to convince the FDA. At least I would like to apologize to you, the readers of this newsletter. The Trump administration appointed a new FDA Commissioner on April 1 who says that he wants to reform the FDA, but the outcome is currently unknown. I do not know whether or not our two-part clozapine article will have any impact on the FDA. I can only promise you that I will keep trying to modify the US clozapine package insert. Clozapine experts from other countries are hoping for that modification, so they can convince their drug agencies, too.

References

  1. de Leon, J., Ruan, C. J., Schoretsanitis, G., & Kane, J. M. (2020). “Dose and safety concerns of clozapine: Worldwide package inserts need revisions.” Schizophrenia Research, 216, 2–4. https://doi.org/10.1016/j.schres.2019.12.009
  2. de Leon, J., Schoretsanitis, G., Smith, R. L., … Müller, D. J. (2022). An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry, 55(2), 73–86. https://doi.org/10.1055/a-1625-6388.
  3. de Leon, J., Baldessarini, R. J., Balon, R., … De Las Cuevas, C. (2025). Letter to the FDA proposing major changes in the US clozapine package insert supported by clozapine experts worldwide. Part II: a review of fatal outcomes in US pharmacovigilance data and proposed changes. Journal of Clinical Psychopharmacology, 45(3), 197–218. https://doi.org/10.1097/JCP.0000000000001990. Freely available.
  1. de Leon, J., Baldessarini, R. J., Balon, R., … De Las Cuevas, C. (2025). Letter to the FDA proposing major changes in the US clozapine package insert supported by clozapine experts worldwide. Part I: a review of fatal outcomes in US pharmacovigilance data and proposed changes. Journal of Clinical Psychopharmacology, 45(3), 179-196. https://doi.org/10.1097/JCP.0000000000001987. Freely available due to the generosity of the CURESZ Foundation.