Recent FDA Safety Warnings About Schizophrenia Drug Clozapine, Asthma/Allergy Drug Montelukast

The Food and Drug Administration (FDA) recently issued two important safety alerts for doctors and patients. The first alert described the risk of life-threatening bowel (intestinal) problems due to constipation caused by the schizophrenia medication clozapine (CLOZARIL, VERSACLOZ). The second advised against using montelukast (SINGULAIR) for allergic rhinitis (nasal allergies or hay fever) except for patients who are not treated effectively with or cannot tolerate other medicines and recommended that health care professionals weigh the benefits and mental-health risks of the drug before prescribing it to asthma patients.

Clozapine alert

On Jan. 28, the FDA issued a safety alert advising doctors and patients that constipation caused by clozapine rarely can progress to serious bowel complications.[1] The FDA warned that these complications can lead to hospitalization and even death if the constipation is not diagnosed and treated promptly.

Clozapine initially was approved by the FDA in 1989 for use in severely ill patients with treatment-resistant schizophrenia (schizophrenia that fails to respond adequately to standard antipsychotic treatment).[2] 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.[3]

Public Citizen’s Health Research Group has designated clozapine as a Limited Use drug. Because the drug has several serious unique risks — including severe neutropenia (low white blood cell count), which can lead to severe, sometimes fatal infections; seizures; syncope (sudden loss of consciousness); cardiac arrest; myocarditis (inflammation of the heart muscle); and cardiomyopathy (enlargement, thickening or scarring of the heart muscle) — it should be reserved for severely ill schizophrenia patients who have failed to respond adequately to other antipsychotic medications.

Constipation is a well-recognized common adverse effect of clozapine.[4] According to the FDA, in some patients, the constipation can progress to complete blockage of the bowel. The FDA alert noted that other schizophrenia medications can cause bowel problems, but the risk of this complication is greatest with clozapine. The risk increases with higher doses of clozapine and when it is taken concomitantly with other drugs that can slow movement in the intestines and cause constipation, like anticholinergic drugs, of which there are many (such as the antidepressants amitriptyline [available in generic only], doxepin [SILENOR] and nortriptyline [PAMELOR]; the antihistamines chlorpheniramine [ADVIL ALLERGY SINUS, ADVIL MULTISYMPTOM COLD & FLU, TUSSICAPS and others] and diphenhydramine [ADVIL PM, ALEVE PM, BENADRYL]; the diarrhea drug atropine [LOMOTIL]; and the overactive bladder medications oxybutynin [DITROPAN XL, GELNIQUE, OXYTROL, OXYTROL FOR WOMEN] and tolterodine [DETROL, DETROL LA]), and opioids. As a result, the agency has required the addition of a new warning about these risks to the labeling for all clozapine products.

The FDA’s safety alert was prompted in part by a review of adverse events reported to the agency or in the scientific medical literature. This review identified 10 reported cases of constipation from 2006 to 2016 in patients using clozapine that had progressed to serious bowel complications. These adverse events resulted in hospitalization, surgery and five deaths. Specific complications seen among the cases included necrotizing colitis (death of colon wall), intestinal ischemia (inadequate blood flow to the intestines), intestinal necrosis (death of part of the intestines) and volvulus (twisting of a loop of intestine that results in bowel obstruction).

The FDA advises that patients using clozapine should contact their health care professionals if they experience less frequent bowel movements than they normally have, especially if they have bowel movements less often than three times per week, have stools that are hard and dry, or have difficulty passing gas. Patients also should seek immediate medical attention if they develop nausea, vomiting, bloating or abdominal (belly) pain or swelling.

To prevent constipation, patients using clozapine should increase their intake of fruits, vegetables and high-fiber grains; drink plenty of water and other liquids; and exercise regularly. Some patients, in consultation with their health care professionals, may need to take a laxative.

Patients should not stop taking clozapine without first talking to their doctors because stopping treatment can cause schizophrenia symptoms to return or worsen.

Montelukast warning

On March 4, the FDA announced that it was requiring the product labeling for montelukast to include a black-box warning, the most stringent warning the agency can require, about the risk of serious behavior and mood-related adverse effects.[5]

Montelukast is a member of the selective leukotriene inhibitor family of asthma drugs and was initially approved by the FDA for treatment of asthma in 1998.[6] The FDA also approved the drug in 2002 for treatment of allergic rhinitis. Because montelukast has only limited benefits, none of which are unique, and poses some unique risks, including psychiatric adverse reactions, Public Citizen’s Health Research Group has designated it as Do Not Use since its initial approval.

For several years prior to the FDA’s March 4 safety alert, the product labeling for montelukast did include a less prominent non-black-box warning about adverse neuropsychiatric events having been reported in adult, adolescent and pediatric patients taking the drug.[7] This earlier warning had noted postapproval reports of patients taking montelukast who had experienced agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, bad or vivid dreams, stuttering, hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, sleepwalking and suicidal thoughts and behavior (including suicide).

The FDA’s decision to highlight the neuropsychiatric risks of montelukast in a new black-box warning was based on an updated assessment of the risks and benefits of the drug by agency scientists and recommendations from a panel of outside experts.[8] The FDA also had found that many health care professionals, patients and caregivers were not aware of the neuropsychiatric risks of the drug as presented in the previous warnings.

As part of its reassessment of montelukast, the FDA reviewed reports of suicides reported to the agency from 1998 to 2019. The FDA identified 82 reports of completed suicide associated with use of montelukast. In many of these cases, the patients had developed neuropsychiatric symptoms before the suicide. The agency noted, however, that most reports lacked key information needed to evaluate the relationship between the use of montelukast and the suicide and that for the other reports, many cited additional risk factors that may have contributed to the suicide. The FDA highlighted six cases that specifically reported concerns about not receiving education from a health care professional about the potential for adverse neuropsychiatric events.

The FDA also reviewed evidence from animal studies suggesting that montelukast could act directly on cells in the brain. Studies in rats also revealed that following oral administration, montelukast enters the brain tissues. These findings make it more plausible that the drug could cause neuropsychiatric adverse events.

As a result of its reassessment of montelukast, the FDA concluded that “because of the risk of mental health side effects, the benefits of montelukast may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with other medicines. For allergic rhinitis, also known as hay fever, we have determined that montelukast should be reserved for those who are not treated effectively with or cannot tolerate other allergy medicines.”[9]

The FDA’s findings and conclusions reinforce our designation of montelukast as Do Not Use for both allergic rhinitis and asthma.
 

References

[1] Food and Drug Administration. Drug safety communication: FDA strengthens warning that untreated constipation caused by schizophrenia medicine clozapine (Clozaril) can lead to serious bowel problems - Risk increased at higher doses or when taken with other constipating medicines. January 28, 2020. https://www.fda.gov/media/134733/download. Accessed May 26, 2020.

[2] HLS Therapeutics. Label: clozapine (CLOZARIL). February 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/019758s095lbl.pdf. Accessed May 26, 2020.

[3] 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 May 26, 2020.

[4] Food and Drug Administration. Drug safety communication: FDA strengthens warning that untreated constipation caused by schizophrenia medicine clozapine (Clozaril) can lead to serious bowel problems - Risk increased at higher doses or when taken with other constipating medicines. January 28, 2020. https://www.fda.gov/media/134733/download. Accessed May 26, 2020.

[5] Food and Drug Administration. Drug safety communication: FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis - Risks may include suicidal thoughts or actions. March 4, 2020. https://www.fda.gov/media/135840/download. Accessed May 26, 2020.

[6] Merck Sharp & Dohme. Label: montelukast (SINGULAIR). April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020829s073,020830s075,021409s051lbl.pdf. Accessed May 26, 2020.

[7] Merck Sharp & Dohme. Label: montelukast (SINGULAIR). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020829s069,020830s071,021409s047lbl.pdf. Accessed May 26, 2020.

[8] Food and Drug Administration. Drug safety communication: FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis - Risks may include suicidal thoughts or actions. March 4, 2020. https://www.fda.gov/media/135840/download. Accessed May 26, 2020.

[9] Food and Drug Administration. Drug safety communication: FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis - Risks may include suicidal thoughts or actions. March 4, 2020. https://www.fda.gov/media/135840/download. Accessed May 26, 2020.