Cromolyn Sodium

Mechanism of Action

Cromolyn sodium is a mast cell stabilizer that prevents the subsequent release of inflammatory mediators, including histamine and leukotrienes, which cause allergic symptoms and bronchoconstriction.[13][14] This treatment inhibits mast cell degranulation, normally implicated in anaphylaxis following exposure to reactive allergens. Cromolyn sodium differs from antihistamine medications, which reduce the action of histamines following the release from mast cells. Unlike corticosteroids that inhibit the late response of antigen-induced asthmatic reactions, cromolyn sodium inhibits immediate and late reactions.[15][12] Additionally, cromolyn sodium has been associated with improvement in flushing, headaches, diarrhea, vomiting, nausea, urticaria, abdominal pain, and itching in patients with mastocytosis.

Pharmacokinetics

Cromolyn sodium is absorbed poorly via oral solution and has a delayed onset of action of 2 to 6 weeks after initiation. Similarly, less than 0.07% of administered cromolyn sodium is absorbed from ophthalmic solution or drops. The effect of cromolyn sodium on mast cells lasts approximately 6 hours following administration. The bioavailability of cromolyn sodium is 0.5% to 2%, with a half-life of 80 to 90 minutes. Cromolyn sodium is primarily excreted (98%) in the feces unabsorbed, with the remainder excreted in the urine.

Administration

Cromolyn Sodium Dosage Forms and Strengths

The following dosage forms are recommended for cromolyn sodium:

• Oral solution: 100 mg/5 mL ampule
• Nasal spray: 5.2 mg/1 actuation
• Ophthalmic solution: 4% (10 mL)
• Inhalation solution: 10 mg/1 mL, 20 mg/2mL nebulization vial

Recommended Dosages for FDA-Approved Indications

 The following dosage formulations for each indication are recommended for cromolyn sodium:

• Asthma prophylaxis 
  • Metered-dose inhaler: 2 oral inhalations (800 µg/spray) 4 times daily at regular intervals; may need to titrate
  • Nebulizer: 20 mg (1 vial) via nebulization 4 times daily at regular intervals
    • Reactive bronchoconstriction: In patients who develop acute bronchoconstriction when exposed to environmental pollutants, toluene diisocyanate, and in response to exercise, cromolyn sodium should be administered shortly before exposure to the precipitating factor.

• Mastocytosis (systemic) 
  • Oral solution: Empty ampules into a glass of water and drink 30 minutes before meals and bedtime
    • Children older than 12 years and adults: Cromolyn sodium solution 200 mg by mouth 4 times daily, 30 minutes before meals and bedtime; may increase to 40 mg/kg/day if symptoms remain uncontrolled for 2 to 3 weeks
    • Children younger than 2 years: Safety and efficacy not established
    • Children aged 2 to 12 years: Cromolyn sodium solution 100 mg orally 4 times daily, 30 minutes before meals and at bedtime; not to exceed 40 mg/kg/day

• Allergic rhinitis
  • Nasal inhalation: One spray/nostril 3 to 6 times daily

• Keratitis, vernal conjunctivitis, and vernal keratoconjunctivitis
  • Ophthalmic solution: Children older than 4 years old, 1 to 2 drops in each eye 4 to 6 times daily, at regular intervals

Off-Label Dosages of Cromolyn Sodium

Cromolyn sodium oral solution may be used for food allergy and irritable bowel syndrome using the following dosages based on the patient's age:

• Children older than 12 years and adults: Cromolyn sodium solution 200 mg by mouth 4 times daily; may double dose if inadequate symptom control within 2 to 3 weeks with a maximum dosage of 400 mg orally 4 times daily
• Children younger than 2 years: Not recommended
• Children aged 2 to 12 years: Cromolyn sodium solution 100 mg orally 4 times daily initially, may increase as indicated to a maximum dosage of 40 mg/kg/day

Specific Patient Populations

For the following special populations, management considerations regarding cromolyn sodium include:

• Renal impairment: The manufacturer's labeling does not recommend specific dosage adjustments for patients with renal impairment. However, the recommended dosage for cromolyn oral solution should be decreased in patients with reduced renal function.
• Hepatic impairment: The manufacturer's labeling does not recommend a specific dosage adjustment for patients with hepatic impairment. However, the recommended dosage for cromolyn oral should be decreased in patients with reduced hepatic function.
• Pregnancy: Cromolyn sodium is pregnancy category B, though risk has not been entirely ruled out. As per manufacturer labels, subcutaneous doses up to 540 mg/kg in mice similar to the maximum recommended daily oral dosage in adults), 164 mg/kg in rats (oral dosage less than the maximum recommended daily dosage in adults), or intravenous doses up to 485 mg/kg in rabbits (4 times the maximum recommended oral dosage in adults) produced no evidence of fetal malformations. As per the Global Initiative for Asthma 2023 guidelines, other therapies with better efficacy are available and should be recommended as treatment for asthma while pregnant.[16]
• Breastfeeding: The amount of cromolyn sodium excreted in breast milk is unknown.[17]
• Pediatric: According to available clinical data, the dose should not exceed 20 mg/kg/day for infants up to 6 months of age.[18] A risk-benefit analysis should be performed before using this product in pediatric patients younger than 2 years of age.
• Older individuals: The safety and efficacy of cromolyn sodium have not been systematically studied in older adults. However, due to the greater probability of decreased hepatic, renal, or cardiac functions, concomitant disease, or other drug therapy in this patient population, cromolyn sodium treatment should usually be initiated at the lowest dosage range.

Adverse Effects

The frequency of adverse events in patients using cromolyn sodium remains unclear. Adverse events also vary depending on the administration route.[19] The ophthalmic solution is associated with transient eye burning upon administration, and eye dryness, puffiness, irritation, itchiness, rash, and styes may be seen. Adverse events reported with the cromolyn sodium nasal spray were nasal congestion, sneezing, nasal itching, nosebleeds, rhinoconjunctivitis, and headaches. Adverse events reported with the inhalation solution were throat irritation and hoarseness, esophagitis, laryngeal and pharyngeal edema, drowsiness, dizziness, bronchial irritation, pulmonary infiltrates, and cough.[20]

Most of the adverse events reported in patients with mastocytosis have been transient and can be symptoms of the disease. The most frequently reported adverse events in patients with mastocytosis who received oral cromolyn sodium solution in clinical studies were headache, diarrhea, pruritus, nausea, myalgia, abdominal pain, rash, and irritability. In addition, adverse events associated with oral solution include vomiting, constipation, erythema, photosensitivity, urticaria, and angioedema. Other reported adverse events, including reports of dyspepsia, constipation, glossitis, flatulence, stomatitis, vomiting, dysphagia, and esophagospasm, in clinical studies of patients with comorbid conditions as well as postmarketing patient experience were infrequent; attribution to cromolyn could not be determined.

Contraindications

Absolute Contraindications

Hypersensitivity to cromolyn products or components of the formulation is the absolute contraindication for cromolyn sodium. 

Cromolyn Sodium Precautions

Clinicians should consider the following cautions in the management of cromolyn sodium:

• Bronchospasm may occur with a cough after inhalation; if this happens, manage using a fast-acting bronchodilator.
• Cromolyn inhalation solution should not be used in status asthmaticus.
• Caution should be exercised when withdrawing cromolyn inhalation solution use or tapering the dosage as symptoms may reoccur.

Monitoring

Symptomatic improvement should be assessed via pulmonary function tests for individuals diagnosed with bronchial asthma. Symptoms may reoccur when tapering or withdrawing cromolyn sodium. Since it is preventive medicine, cromolyn sodium may take up to 4 weeks for the patient to experience maximum benefit. Patients with a history of cardiac arrhythmias or coronary artery disease using inhalation solution should undergo cardiac follow-up due to the contents of metered-dose inhaler propellants.

The clinician should closely monitor kidney and liver function in patients with hepatic or renal insufficiency and begin with a reduced dose when considering treatment with cromolyn sodium. The medication's effects may increase in patients with these medical conditions, thus increasing the chance of adverse effects. Regular eye examinations are necessary when using cromolyn sodium ophthalmic solution.

Toxicity

Cromolyn sodium is poorly absorbed and is low in toxicity. No severe toxicity reactions have been reported, and a specific toxic dose has not been established. Research verifying the efficacy or safety of cromolyn sodium is insufficient regarding use in pediatric patients younger than 2 years. However, acute life-threatening reactions have been reported. 

In the event of a hypersensitivity reaction, patients should receive treatment with antihistamines with or without beta-agonists, corticosteroids, and epinephrine. In the case of a severe hypersensitivity reaction, oxygen, antihistamines, epinephrine, corticosteroids, electroencephalogram monitoring, and intravenous fluids should be administered. No specific labs or testing are necessary unless indicated.[21][22] Management of mild to moderate toxicity is symptomatic and supportive. The clinician should correct any significant fluid and electrolyte abnormalities in patients with vomiting or diarrhea. Severe toxicity is not expected following an overdose, which should be managed with symptomatic and supportive treatment.

Enhancing Healthcare Team Outcomes

The management of cromolyn sodium therapy requires a coordinated, interprofessional approach involving physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals to ensure patient-centered care, improved outcomes, and patient safety. Cromolyn sodium is available in various forms and should be administered at regular intervals for optimal efficacy. Clinicians should follow the Global Initiative for Asthma 2023 guidelines, which suggest that while cromolyn is FDA-approved for asthma, it is less effective than other therapies and is not recommended for routine use.

Even though these are rare, effective communication between healthcare professionals is crucial in monitoring and managing potential adverse events or hypersensitivity reactions. Nurses and pharmacists must be vigilant in recognizing any adverse events and collaborate with the clinical team to manage them. In a severe reaction, the healthcare team must quickly withdraw cromolyn, administer emergency treatments like epinephrine, oxygen, antihistamines, and corticosteroids, and ensure continuous patient monitoring. A pharmacist should review the patient’s medication records to avoid future complications, while the intensivist may be consulted for hospital observation. After a hypersensitivity event, clinicians must discuss alternative therapies with the patient. This interprofessional coordination enhances patient safety and team performance in cromolyn sodium management for asthma, allergic rhinitis, and mastocytosis.