What mast cell inhibitors (e.g., cromolyn sodium, nedocromil, ketotifen) are used for allergic rhinitis, asthma, chronic urticaria, and systemic mastocytosis, and what are their recommended doses and second‑line options?

Mast Cell Inhibitors: Clinical Applications and Dosing

Cromolyn sodium is the primary mast cell stabilizer for allergic conditions and mast cell disorders, dosed at 200 mg four times daily for systemic conditions, with topical formulations available for allergic conjunctivitis and asthma, while ketotifen and nedocromil serve as alternative agents with more limited availability. 1, 2

Primary Mast Cell Stabilizer: Cromolyn Sodium

Systemic Mastocytosis and Mast Cell Activation Syndrome

• Start at 20-40 mg four times daily and gradually titrate up to 200 mg four times daily over several weeks to minimize side effects including headache, sleepiness, irritability, and gastrointestinal symptoms 1, 3
• The standard therapeutic target is 200 mg taken four times daily before meals and at bedtime for gastrointestinal symptoms including diarrhea, abdominal pain, nausea, and vomiting 2, 3
• Requires at least 1 month trial to assess efficacy—this is not an acute rescue medication but preventive therapy 1, 2
• Progressive dose escalation (e.g., starting at 100 mg four times daily and increasing over 1-2 weeks) significantly reduces side effects 2
• Despite low systemic absorption, cromolyn can help with cutaneous symptoms including pruritus and may benefit cognitive symptoms in some patients 3, 2

Allergic Conjunctivitis

• Topical ophthalmic cromolyn sodium is prescription-only and effective for frequently recurrent or persistent allergic conjunctivitis 3, 4
• Can be refrigerated for additional cooling comfort upon instillation 3
• Particularly useful when combined with second-generation topical H1-receptor antagonists for comprehensive symptom control 3

Asthma and Allergic Rhinitis

• Cromolyn sodium inhalation solution requires prescription for exercise-induced bronchoconstriction and asthma prophylaxis 4
• Nasal spray formulations help alleviate allergic rhinitis symptoms, though the over-the-counter nasal spray is not appropriate for systemic mast cell disorders 3, 4
• Shows good therapeutic efficacy in intermittent or mildly persistent asthma, especially in children and young adults 5

Alternative Mast Cell Stabilizers

Nedocromil Sodium

• Currently not available in the United States as a metered-dose inhaler or dry powder inhaler 4
• When available, nedocromil (10 nM) demonstrates 40-60% inhibition of mediator release from mast cells through Annexin-A1 stimulation 6
• Historically used for allergic asthma, rhinitis, and conjunctivitis with rare and generally benign side effects 5

Ketotifen

• Distinguished from cromones by conjoint antihistamine effect in addition to mast cell stabilization 5
• Shows low potency as an inhibitor of mediator release from lung and tonsil mast cells, with variable effects on skin mast cells 7
• At concentrations below 1.0 μM, ketotifen does not inhibit mediator release from skin mast cells and may actually induce release above that concentration 7
• Indicated for prophylactic treatment of allergic asthma, rhinitis, allergic conjunctivitis, and food allergy manifestations 5

Essential Combination Therapy Approach

Cromolyn should NOT be used as monotherapy—comprehensive mast cell disorder management requires multi-mediator blockade 2:

• H1 antihistamines (second-generation preferred): Fexofenadine or cetirizine at 2-4 times FDA-approved doses for dermatologic and gastrointestinal symptoms 1
• H2 antihistamines: Ranitidine or famotidine for gastric hypersecretion, peptic ulcer disease, and additional gastrointestinal protection 3, 2
• Leukotriene modifiers: Montelukast is most effective when combined with H1 antihistamines, particularly if urinary LTE4 levels are elevated 1, 2

Combined H1 and H2 antihistamine treatment has proven effective for controlling severe pruritus and wheal formation in mastocytosis 3

Second-Line and Refractory Options

Topical Corticosteroids

• Brief 1-2 week course with low side-effect profile for inadequately controlled allergic conjunctivitis symptoms 3
• Chronic use requires baseline and periodic IOP measurement and pupillary dilation to monitor for glaucoma and cataract 3

Systemic Corticosteroids

• Prednisone 0.5 mg/kg/day with slow taper over 1-3 months for refractory mast cell activation syndrome 1
• Reserved for cases unresponsive to antihistamines and cromolyn due to potential adverse effects 1

Topical Immunomodulators

• Cyclosporine or tacrolimus can be considered for severe allergic conjunctivitis cases 3

PUVA Therapy

• Oral methoxypsoralen with long-wave psoralen plus ultraviolet A radiation has been effective in bullous diffuse cutaneous mastocytosis in children, even with life-threatening mediator release episodes 3

Critical Safety Considerations

Cromolyn Sodium Safety Profile

• Excellent safety profile with minimal systemic absorption and extremely low toxicity at customary dosages 2
• No significant drug interactions, no corticosteroid-related side effects, and no tolerance development with long-term use 2
• Safe for use in pregnancy and very young children 2
• Excreted renally—dose reduction required in renal impairment 2

Common Pitfalls to Avoid

• Do not use topical vasoconstrictor agents chronically—they cause rebound vasodilation after 10 days, unlike cromolyn which can be used long-term safely 4
• Avoid indiscriminate topical corticosteroid use—they can prolong adenoviral infections and worsen HSV infections in conjunctivitis 3
• Do not expect immediate results—cromolyn may require 1 month or more for maximum effect in severe cases 2
• Oral antihistamines may worsen dry eye syndrome and impair the tear film's protective barrier—consider concomitant preservative-free artificial tears 3

Monitoring and Follow-Up

• Assess improvement within 4-6 weeks of initiating cromolyn therapy 2
• If no response after 1 month of maximum dosing (200 mg four times daily), consider alternative or additional therapies 2
• Long-term maintenance therapy is typically required for chronic mast cell conditions 2
• For patients on chronic corticosteroids, monitor IOP and perform dilated eye examinations periodically 3