The U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication requiring new warnings about the rare but severe pruritus that can occur when patients discontinue oral allergy medications cetirizine (Zyrtec) or levocetirizine (Xyzal) after long-term use.
The FDA identified 209 cases worldwide of post-discontinuation pruritus reported between April 2017 and July 2023, including 197 cases in the U.S. The cases involved cetirizine (n = 180), levocetirizine (n = 27), or both medications (n = 2) and were submitted to the FDA Adverse Event Reporting System (FAERS) database.
Market Context
In 2022, an estimated 26.8 million cetirizine and levocetirizine prescriptions were dispensed from U.S. outpatient pharmacies, with 65% (17.5 million) being over-the-counter versions and 35% (9.3 million) being prescription products. Additionally, an estimated 62.7 million packages of over-the-counter cetirizine and levocetirizine products were purchased through point-of-sale transactions from U.S. retail outlets, representing more than 60 million packages total in 2022.
Both medications are second-generation antihistamines approved for treating seasonal allergic rhinitis, perennial allergic rhinitis, and chronic idiopathic urticaria. Cetirizine was approved for prescription use in December 1995 and over-the-counter use in November 2007, while levocetirizine received prescription approval in May 2007 and over-the-counter approval in January 2017.
Clinical Characteristics and Timeline
The median time to onset of pruritus after medication discontinuation was 2 days, with a range of 1 to 5 days. In 92% of cases where usage duration was reported (n = 97 of 106), patients had used the medications for more than 3 months before experiencing withdrawal symptoms. The median duration of medication use before pruritus occurrence was 33 months, ranging from 1 week to 23 years.
"The itching, also called pruritus, has been reported in patients who used these medicines daily, typically for at least a few months and often for years. Patients did not experience itching before starting the medicines," the FDA stated in its communication.
Severity and Impact on Quality of Life
The reported cases described widespread pruritus that significantly affected patients' quality of life and functional capacity. Serious outcomes included disability (n = 48), with one case describing "debilitating itching to the point of being bedridden," hospitalization (n = 3), and thoughts of suicide or self-harm (n = 2).
Of the 93 cases where patients reported attempting to restart and stop the medication(s), pruritus recurrence occurred in 92. However, restarting the medication(s) resolved symptoms in 71 of 79 individuals (90%), and tapering after restarting resolved symptoms in 9 of 24 patients (38%) who attempted this approach.
Mechanism and Risk Factors
The FDA noted that "the underlying mechanism for this risk is unknown, but our evaluation supports a causal relationship between stopping cetirizine or levocetirizine and pruritus." Data suggest that longer medication use may increase the risk of a discontinuation reaction, as "the number of pruritus cases increased with duration of use."
Other than prolonged use, no clear risk factors for post-discontinuation pruritus have been identified.
Regulatory Actions and Clinical Recommendations
The FDA is adding warnings about pruritus risk to cetirizine and levocetirizine prescribing information and will request manufacturers add similar warnings to over-the-counter Drug Facts Labels. The updated prescribing information states that "pruritus symptoms may improve with restarting the medicines."
For health care professionals, the FDA recommends discussing discontinuation risks with patients, especially those planning to take these medications long-term, and encouraging patients to report severe itching after stopping the agents. "Effective treatments for pruritus have not been evaluated. However, symptoms resolved in most patients who restarted the medicine and in some who tapered off the medicine after restarting it," according to the communication.
The FDA noted that while pruritus after medication discontinuation appears rare compared to usage frequency, patients planning long-term use should discuss benefits and risks with health care professionals who can provide individualized guidance.
Source: FDA
