Cetirizine and Levocetirizine Withdrawal Pruritus: What Pharmacists Need to Know About the FDA’s New Safety Warning

Allergic diseases such as urticaria, allergic rhinitis, and anaphylaxis affect more than 100 million people in the US every year.^1,2 The incidence of these conditions is increasing worldwide, particularly in younger patients, including children and adolescents.³ Allergies can cause bothersome symptoms that range in severity, sometimes even prompting pharmacotherapy or emergency services for appropriate treatment.⁴

Patients who take allergy medication expect that their symptoms will be safely relieved. Recently, however, there have been reports of rare withdrawal reactions consisting of prolonged and sometimes severe pruritus following discontinuation of long-term use of cetirizine (Zyrtec; Kenvue) or levocetirizine (Xyzal; Opella). These reactions can be debilitating enough to warrant a change in therapy or additional management.

FDA Drug Safety Communication: What Pharmacists Need to Know

In May 2025, the FDA posted a drug safety communication about the OTC and prescription allergy medications cetirizine and levocetirizine. The communication explained that there could be a rare but serious reaction of severe itching upon discontinuation of these 2 agents. The FDA identified over 200 cases from the FDA Adverse Event Report System (FAERS), the majority of which were associated with cetirizine discontinuation (see Table 1⁵). The pruritus was not present in patients prior to medication use, had the potential to be serious (requiring medical intervention), and tended to appear in chronic (months to years), daily users.⁵

Based on the evidence gathered by the FDA, there seems to be a temporal relationship between the discontinuation of levocetirizine or cetirizine and pruritus. The mechanism behind this reaction is unknown. To increase patient safety, the FDA will add warnings about this possible reaction to the drugs’ prescribing information and request that drug manufacturers update their OTC drug facts labels accordingly.⁵

Cetirizine and Levocetirizine Usage Statistics: How Widely Are These Antihistamines Used?

Levocetirizine and cetirizine are perhaps the most widely used treatments for both allergic diseases and off-label indications. As of 2022, the FDA estimates that in the US, 62.7 million OTC packages have been sold and 26.8 million prescriptions have been dispensed.⁵ With the increasing availability of online medications, the true number of patients taking these 2 antihistamines is likely underreported.

Pharmacology of Cetirizine and Levocetirizine

Levocetirizine and cetirizine are second-generation antihistamines that competitively inhibit histamine at H₁ receptors, aiming to reduce uncomfortable symptoms such as rhinitis and pruritus. Among the second-generation class of antihistamines, these 2 piperazine derivatives are related to meclizine (Dramamine Less Drowsy; Prestige Consumer Healthcare Inc) and hydroxyzine (Vistaril; Pfizer) but are unrelated to loratadine (Claritin; Bayer) and fexofenadine (Allegra; Opella), which are piperidine derivatives.⁶ Structurally, levocetirizine is the R-enantiomer of the racemic mixture cetirizine.^7,8

Clinical Evidence for Withdrawal Pruritus After Cetirizine or Levocetirizine Discontinuation

The current prescribing information for levocetirizine and cetirizine does not mention the possibility of pruritus following discontinuation of either agent.^7,8 Pharmacovigilance data were not readily available through the manufacturers or a review of the literature. However, a PubMed search using the terms cetirizine, pruritis, and discontinuation resulted in a total of 5 relevant publications that supported the probability of a withdrawal reaction (see Table 2^5,9-12). Most of this available evidence points to the possibility of a causative relationship between discontinuation of these agents and withdrawal pruritus. The median onset of the reported reaction is approximately a few days after discontinuation and typically occurs in patients who are chronic, daily users of either agent (or both) for months to years.^9-12 A majority of cases were reported by consumers, predominantly females.^9,10,12 Of note, it has been reported that there is apparently insufficient evidence to support a classwide effect, and withdrawal reactions are likely limited to discontinuation of cetirizine and levocetirizine only.¹⁰

How Should Pharmacists Manage and Counsel Patients on Antihistamine Discontinuation Pruritus?

Pharmacists can use their unique role as drug information experts to help patients and health care providers in mitigating this rare but possibly serious adverse effect. Patients should be counseled on any antihistamine use and made aware of a possible withdrawal reaction with the use of levocetirizine and cetirizine products. Patients should also be urged to monitor their symptoms following discontinuation of antihistamines and to contact a health care provider if they experience severe itching or any other acute symptoms. If a pruritus withdrawal reaction is suspected, pharmacists should refer patients for appropriate treatment. Patients and clinicians should always be encouraged to report any reactions through MedWatch or another appropriate adverse reaction reporting agency, even if a causal relationship cannot be fully established.

Additionally, pharmacists can provide guidance to physicians on managing a second-generation antihistamine withdrawal reaction. Some treatment options that have been successful include gradual tapering of antihistamines, restarting the antihistamine, switching to an alternative antihistamine, or using concomitant steroid therapy.¹⁰ Interestingly, some clinicians have treated these pruritus reactions on an off-label basis with biologics such as dupilumab (Dupixent; Sanofi, Regeneron) or omalizumab (Xolair; Genentech, Novartis).¹¹

Clinical Takeaways for Pharmacists

Health care providers have a duty to make the public aware of the possible risk upon withdrawal of relatively long-term antihistamine use. The FDA’s safety concern described the reaction following discontinuation of levocetirizine and cetirizine as rare but possibly severe. The government agency is adding a warning to the drugs’ prescribing information about the risk of pruritus after stopping long-term use of the prescription agents and requesting that manufacturers add a warning about this reaction to the drug facts label of the OTC products, although at the time of this publication, the authors could not identify any changes in labeling or prescribing information.⁵ There is a possibility that there are more cases of this withdrawal effect than are reported on the FAERS site. Postmarketing pharmacovigilance data are limited, and no incidence or percent risk of the reaction can be reported at this time. The mechanism behind the reaction is primarily unknown, but there are several theories that may involve a histamine rebound effect.

REFERENCES

1. Ng AE, Boersma P. Diagnosed allergic conditions in adults: United States, 2021. NCHS Data Brief. 2023;(460):1-8.

2. Zablotsky B, Black LI, Akinbami LJ. Diagnosed allergic conditions in children aged 0-17 years: United States, 2021. NCHS Data Brief. 2023;(459):1-8.

3. Gutowska-Slesik J, Samolinski B, Krzych-Falta E. The increase in allergic conditions based on a review of literature. Postepy Dermatol Alergol. 2023;40(1):1-7. doi:10.5114/ada.2022.119009

4. Michelson KA, Dribin TE, Vyles D, Neuman MI. Trends in emergency care for anaphylaxis. J Allergy Clin Immunol Pract. 2020;8(2):767-768.e2. doi:10.1016/j.jaip.2019.07.018

5. FDA requires warning about rare but severe itching after stopping long-term use of oral allergy medicines cetirizine or levocetirizine (Zyrtec, Xyzal, and other trade names). FDA. May 16, 2025. Accessed February 18, 2026. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warning-about-rare-severe-itching-after-stopping-long-term-use-oral-allergy-medicines

6. Scolaro KL. Colds and allergy. In: Krinsky DL, Ferrari SP, Hemstreet BA, et al, eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. 20th ed. American Pharmacists Association; 2021:530-531.

7. Zyrtec. Prescribing information. Kenvue; 2002. Accessed February 18, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19835s15,%2020346s8lbl.pdf

8. Xyzal. Prescribing information. UCB, Inc; 2008. Accessed February 18, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022064s009lbl.pdf

9. Konkel K, Lee JY, Jones SC, et al. New onset pruritus following discontinuation of cetirizine or levocetirizine. J Allergy Clin Immunol Pract. Published online December 9, 2025. doi:10.1016/j.jaip.2025.11.040

10. Chung AH, La Grenade L, Harinstein LM. Pruritus after discontinuation of cetirizine. Ther Adv Drug Saf. 2019;10:2042098619859996. doi:10.1177/2042098619859996

11. In brief: pruritus following antihistamine discontinuation. Med Lett Drugs Ther. 2025;67(1735):135. doi:10.58347/tml.2025.1735e

12. Ekhart C, van der Horst P, van Hunsel F. Unbearable pruritus after withdrawal of (levo)cetirizine. Drug Saf Case Rep. 2016;3(1):16. doi:10.1007/s40800-016-0041-9