Recommended Treatment for Urticaria
Start with a standard-dose second-generation H1 antihistamine (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, or mizolastine), and if symptoms remain inadequately controlled after 2-4 weeks, increase the dose up to 4 times the standard dose before considering additional therapies. 1, 2
First-Line Treatment: Second-Generation Antihistamines
Second-generation non-sedating H1 antihistamines are the definitive first-line treatment for all forms of urticaria, with cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, and mizolastine as preferred options. 2, 3
Offer patients at least two different non-sedating antihistamines to trial, as individual responses and tolerance vary significantly between agents. 2, 3 This is critical because what works for one patient may not work for another, even within the same drug class.
Cetirizine reaches maximum concentration fastest, making it advantageous when rapid symptom relief is needed. 2
Avoid first-generation antihistamines (diphenhydramine, hydroxyzine, chlorpheniramine) as first-line therapy due to marked sedation and anticholinergic effects that impair quality of life. 4, 5 These may be added at night only if second-generation agents fail to control symptoms. 3
Dose Escalation Strategy for Inadequate Response
If symptoms persist after 2-4 weeks on standard dosing, increase the antihistamine dose up to 4 times the standard dose before adding other therapies. 1, 2 This step is often skipped in practice but is essential—many patients respond to higher doses who failed standard dosing.
Do not add second-line therapy until you have tried updosing the antihistamine to 4 times the standard dose. 1 This is a common pitfall where clinicians prematurely escalate to more expensive or risky therapies.
For patients with complete disease control on higher doses, consider step-down only after at least 3 consecutive months of complete control, reducing by no more than 1 tablet per month. 1 If control is lost during step-down, return to the last dose that provided complete control. 1
Second-Line Treatment: Omalizumab
For chronic spontaneous urticaria unresponsive to high-dose antihistamines (up to 4x standard dose), add omalizumab 300 mg subcutaneously every 4 weeks. 1, 2, 6 This is FDA-approved for patients 12 years and older who remain symptomatic despite H1 antihistamine treatment. 6
Allow up to 6 months for patients to respond to omalizumab before declaring treatment failure. 1, 2 Many clinicians give up too early—response can be delayed.
If insufficient response at standard dosing, increase omalizumab to 600 mg every 2 weeks as the maximum recommended dose. 1, 2 This updosing is particularly beneficial in patients with high body mass index. 1
Approximately 30% of patients have insufficient response to omalizumab, particularly those with IgG-mediated autoimmune urticaria. 2 This is important for setting realistic expectations.
Omalizumab dosing for chronic spontaneous urticaria is NOT dependent on serum IgE level or body weight—use the fixed 300 mg every 4 weeks dosing. 6 This differs from asthma dosing and is a common source of confusion.
Third-Line Treatment: Cyclosporine
For patients who fail to respond to high-dose antihistamines and omalizumab within 6 months, add cyclosporine at 4-5 mg/kg daily for up to 2 months. 1, 2, 3 Some guidelines suggest treatment duration of 16 weeks is superior to 8 weeks for reducing therapeutic failures. 7
Cyclosporine is effective in approximately 54-73% of patients, particularly those with autoimmune chronic spontaneous urticaria. 2, 3
Monitor blood pressure and renal function (blood urea nitrogen and creatinine) every 6 weeks due to potential nephrotoxicity, hypertension, and other serious adverse effects including epilepsy in predisposed patients, hirsutism, and gum hypertrophy. 1, 2
The risk-benefit profile of high-dose omalizumab is superior to that of cyclosporine, which is why cyclosporine is reserved for omalizumab failures. 1
Role of Corticosteroids: Use Sparingly
Restrict oral corticosteroids to short courses (3-10 days) for severe acute urticaria or angioedema only—never use chronically. 2, 7, 3 This is a critical pitfall: corticosteroids have slow onset of action, work by inhibiting gene expression, and are ineffective for acute symptom relief. 2
Chronic corticosteroid use leads to cumulative toxicity that outweighs any benefit. 2 Long-term use should not occur except in very selected cases under regular specialist supervision. 7
Critical Management Pitfalls to Avoid
Never use antihistamines or corticosteroids in place of epinephrine for anaphylaxis. 2 Antihistamines take 30-120 minutes to reach peak plasma concentrations and lack the vasoconstrictive, bronchodilatory, and mast cell stabilization properties of epinephrine. 2
Avoid first-generation antihistamines in acute infusion reactions, as they can exacerbate hypotension, tachycardia, and shock. 2
Do not confuse urticaria with anaphylaxis or angioedema affecting the airway—these require immediate intramuscular epinephrine 0.5 mL of 1:1000 (500 µg). 3
Trigger Identification and Avoidance
Identify and minimize aggravating factors including overheating, stress, alcohol, aspirin, NSAIDs, and codeine. 2, 7, 3
Avoid NSAIDs in aspirin-sensitive patients with urticaria. 2, 3
Avoid ACE inhibitors in patients with angioedema without wheals. 2, 3
Special Population Adjustments
Renal Impairment
- Avoid acrivastine in moderate renal impairment. 2, 3
- Halve the dose of cetirizine, levocetirizine, and hydroxyzine in moderate renal impairment. 2, 3
Hepatic Impairment
- Avoid mizolastine in significant hepatic impairment. 2, 3
- Avoid hydroxyzine in severe liver disease. 2, 3
Pregnancy
- Avoid antihistamines if possible, especially during the first trimester. 2, 3
- If necessary, choose chlorphenamine due to its long safety record. 2, 3
Prognosis and Patient Counseling
Approximately 50% of patients with chronic urticaria presenting with wheals alone will be clear by 6 months. 2, 3
Patients with both wheals and angioedema have a poorer outlook, with over 50% still having active disease after 5 years. 2, 3 This information is important for setting realistic expectations and ensuring appropriate follow-up.