What to Do if Antihistamines Stop Working for a Chronic Hives Rash
Skin ConditionsHives

What to Do When Antihistamines Stop Working for Chronic Hives: 5 Options

Although over-the-counter antihistamines can often do the trick for hives, they may not fully relieve symptoms for everyone.
What to Do When Antihistamines Stop Working for Chronic Hives: 5 Options
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Updated on October 27, 2025
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Hives are raised red welts or splotches that tend to be itchy, tender, and swollen. They can come up suddenly and form anywhere on your body.

In many cases, over-the-counter antihistamines (also known as H1 antihistamines) tend to be enough to provide relief, says Nicole Weiler, MD, a dermatologist and clinical assistant professor of dermatology at NYU Langone Health in New York City. These medications block histamine, a chemical signal released in your body as a response to inflammation, which may be prompted by exposure to an allergen (like food or pollen) or to an infection (like a virus).

But even if antihistamines are working at first, they may stop working to treat chronic hives. That’s when you’ll likely need to try a different option.

“Although over-the-counter antihistamines can usually be enough to provide relief, the activity of hives can wax and wane, which means antihistamines may be more or less effective at different times,” says Dr. Weiler. “When it becomes less effective, there are other choices in stepping up treatment.”

Here are five options your doctor might recommend if your antihistamines stop working for you.

1. Blockers

When over-the-counter medications — such as cetirizine (Zyrtec Allergy), fexofenadine (Allegra Hives), levocetirizine (Xyzal Allergy 24HR), and loratadine (Claritin) — don’t work well for you, your doctor may prescribe a medication known as an H2 blocker, or H2 antihistamine.

Commonly prescribed for certain gastrointestinal issues, these drugs work by targeting histamine receptors in the stomach and blood vessels. That can bring down swelling and redness.

Options include:

  • cimetidine
  • famotidine
  • nizatidine
Your doctor may have you try one of these drugs together with an over-the-counter antihistamine. The combination can be very effective, says Brendan Camp, MD, a dermatologist at MDCS Dermatology in New York.

If that type of multi-medication approach also doesn’t work for you, then you’d likely be taken off antihistamines altogether to try a different strategy, he says.

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2. Corticosteroids

Oral corticosteroids (also called steroids or glucocorticoids) such as prednisone could be the next step if antihistamines aren’t working, Dr. Camp says.

These prescription medications work by reducing inflammation throughout your body. They’re similar to cortisol, a hormone that your body makes naturally. They can also relieve pain and temporarily suppress the immune system so it stops releasing histamines.

But steroids aren’t a long-term treatment. They’ll only be used to relieve a hives-related rash when it’s acute (short-term) rather than chronic (long-term). That’s because the chances of getting side effects — such as mood changes, muscle weakness, weight gain, and stomach irritation — increase the longer you take them.

3. Biologics

A next step in treatment is to consider biologic medications, particularly when hives become frequent or intense, and don’t respond to antihistamines or corticosteroids, says Amiirah Aujnarain, MD, an allergist, immunologist, and pediatrician at Kindercare Pediatrics in East York, Ontario, Canada.

“These medications target an antibody called immunoglobulin E (IgE), which [is] released by the immune system, usually when an allergen is detected,” she says. “This approach must be done under a specialist’s care.”

About 30 percent of chronic hives are linked with IgE. Biologics work by binding to this antibody and reducing its effects — a process that decreases the release of histamine as well.

One example of a biologic that targets IgE is called omalizumab (Xolair), which alters the immune response to reduce symptoms.

In April 2025, the U.S. Food and Drug Administration (FDA) approved dupilumab (Dupixent) for the treatment of chronic hives (also called chronic spontaneous urticaria) in people who still have symptoms despite treatment with H1 antihistamines. Dupixent targets inflammatory proteins in the body called interleukin (IL)-4 and IL-13, which also targets the eventual production of IgE.

4. BTK Inhibitors

In September 2025, the FDA approved remibrutinib (Rhapsido) for the treatment of chronic hives in adults whose symptoms are not relieved with H1 antihistamines.

Remibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, which targets and blocks the BTK protein. Experts believe this action helps prevent histamine and other inflammatory chemicals from being released into the body.

Remibrutinib is taken as an oral pill twice a day. Side effects may include:

  • Nasal congestion
  • Sore throat
  • Runny nose
  • Bleeding
  • Headache
  • Nausea
  • Abdominal pain
Remibrutinib is the first BTK inhibitor approved by the FDA to treat chronic hives.

5. Lifestyle Changes

Certain lifestyle changes can help address hives, and they may also play a role in preventing flare-ups of hives in the future.

Those include:

  • With the help of your doctor, identify and avoid any food triggers that may prompt symptoms.
  • Reduce exposure to airborne allergens, like pet dander or pollen, if you are allergic.
  • Use detergents and soaps without scents or dyes, which could irritate your skin.
  • Avoid extreme temperature changes, which can prompt hives or worsen symptoms for some people.
  • Do your best to manage stress, which doesn’t directly cause hives but can make them worse.
  • Wear loose-fitting, lightweight clothing to avoid skin irritation.

These lifestyle changes can be helpful for reducing the frequency, duration, and intensity of hives. But they’re often used as an addition to medications, not as a replacement.

The Takeaway

  • Over-the-counter (H1) antihistamines are nearly always the first line of treatment for a hives rash, since these meds can block histamine, a chemical in the body that prompts hives symptoms.
  • Prescription antihistamines, corticosteroids, biologic medications, and BTK inhibitors are the next steps when over-the-counter options aren’t working for you.
  • Some lifestyle changes may help ease hives. But they’re often used along with medication rather than in place of it.
  • If you’re getting more-frequent hives, and especially if they’re becoming worse and you’re not getting relief from over-the-counter antihistamines, talk with your doctor about other options that can help.

Resources We Trust

EDITORIAL SOURCES
Everyday Health follows strict sourcing guidelines to ensure the accuracy of its content, outlined in our editorial policy. We use only trustworthy sources, including peer-reviewed studies, board-certified medical experts, patients with lived experience, and information from top institutions.
Resources
  1. Hives. Cleveland Clinic. October 14, 2022.
  2. Farzam K et al. Antihistamines. StatPearls. July 10, 2023.
  3. Antihistamines. Cleveland Clinic. July 26, 2024.
  4. Monroe EW et al. Combined H1 and H2 Antihistamine Therapy in Chronic Urticaria. JAMA Dermatology. July 1981.
  5. Corticosteroids (Glucocorticoids). Cleveland Clinic. October 21, 2024.
  6. Immunoglobulin E (IgE) Defined. American Academy of Allergy, Asthma, and Immunology. July 8, 2024.
  7. Omalizumab (Subcutaneous Route). Mayo Clinic. May 1, 2025.
  8. Dupixent. U.S. Food and Drug Administration. April 2025.
  9. Novartis Receives FDA Approval for Rhapsido (Remibrutinib), the Only Oral, Targeted BTKi Treatment for Chronic Spontaneous Urticaria (CSU). Novartis. September 30, 2025.
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Asal Naderi, MD

Medical Reviewer

Asal Naderi, MD, is an assistant clinical professor of allergy and immunology at the Keck School of Medicine at the University of Southern California. Her areas of focus include allergic rhinitis, asthma, chronic sinusitis with nasal polyposis, chronic urticaria, angioedema, food allergy, drug allergy, and primary immunodeficiencies.

She received her bachelor's degree from the University of California Los Angeles and then received her medical degree from Saint Louis University. She completed her internal medicine residency at University of California Irvine, and her fellowship at the University of California Irvine. She has been a principal investigator in clinical trials for asthma as well as chronic sinusitis.

Outside of the office, she enjoys exercising, cooking and spending time with her family and friends.

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