Cromolyn sodium has been described as a mast-cell stabilizer.
Cromolyn sodium aerosol and solution for oral inhalation are used as adjuncts to the overall management of patients with bronchial asthma.205, 222 Cromolyn therapy is prophylactic in nature and has no value in the treatment of acute attacks of asthma, especially status asthmaticus.
Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma).222, 223 When control of symptoms deteriorates in patients with intermittent asthma and symptoms become persistent (e.g., daytime symptoms of asthma more than twice weekly but less than once daily, and nocturnal symptoms of asthma 3-4 times per month), current asthma management guidelines and most clinicians recommend initiation of an anti-inflammatory agent, preferably with a low-dose orally inhaled corticosteroid (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adolescents and adults, children 5-11 years of age, or children 4 years of age or younger, respectively) as first-line therapy for persistent asthma, supplemented by as-needed use of a short-acting, inhaled β2-agonist.207, 222, 223 Alternatives to low-dose inhaled corticosteroids for mild persistent asthma include mast-cell stabilizers (e.g., cromolyn, nedocromil [preparation for oral inhalation no longer commercially available in the US]), certain leukotriene modifiers (i.e., montelukast, zafirlukast), or extended-release theophylline (in adults and children older than 5 years of age), but these agents are less effective and generally not preferred as initial therapy.222, 223, 224 In children 4 years of age or younger with mild persistent asthma, cromolyn sodium is suggested based on extrapolation of data from studies in older children or montelukast is recommended by some experts as alternative, but not preferred, therapy.223 Other experts do not consider mast-cell stabilizers or extended-release theophyllines to be acceptable alternatives to inhaled corticosteroids for routine use as initial long-term therapy in such patients. For more information on the stepped-care approach to drug therapy in asthma, see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12 and see Asthma under Uses: Respiratory Diseases in the Corticosteroids General Statement 68:04.
A satisfactory response to cromolyn therapy is indicated by a reduction in the number of attacks, reduced cough, decreased sputum production, and/or by a decreased requirement for other drugs (e.g., corticosteroids) used in the treatment of asthma. Several studies have demonstrated improvements in the pulmonary function of many patients treated with cromolyn; however, improvement in pulmonary function tests does not necessarily accompany the successful use of cromolyn.
The requirement for long-term corticosteroids has been reduced or eliminated in many patients receiving cromolyn therapy, and there is some evidence that an increased response to bronchodilator drugs may occur in patients receiving cromolyn. Concomitant corticosteroid and bronchodilator therapy should be continued in patients receiving cromolyn; however, gradual reduction of corticosteroid dosage and/or institution of alternate day therapy should be attempted.
Response to cromolyn therapy generally occurs within the first 2-4 weeks of treatment. It is, as yet, unknown whether patients who fail to respond to cromolyn initially will respond after repeated trials. Only those patients showing an initial improvement, manifested by a decrease in clinical symptoms or requirements for concomitant drug therapy, should continue to receive cromolyn.
It is difficult to predict which asthmatic patients will respond to cromolyn therapy. Several reports have indicated that younger patients with extrinsic (skin-test positive) asthma will respond more favorably than will older patients with intrinsic (skin-test negative) asthma. Two, year-long, double-blind controlled trials, however, have failed to demonstrate that allergic patients respond substantially better to cromolyn than do nonallergic patients. One study demonstrated a correlation between the ability to prevent exercise-induced asthma by pretreatment with cromolyn and its later success in therapy. Another study demonstrated a correlation between a history of chronic cough and an above-average spirometric response to cromolyn. In a particular patient, however, a short trial of cromolyn therapy is the only definitive method of determining response.
Cromolyn sodium aerosol and solution for oral inhalation are used for the prevention of exercise-induced bronchospasm or that induced by exposure to other known precipitating factors (e.g., cold dry air, environmental pollutants, allergens). Numerous studies have shown cromolyn to be more effective than placebo in preventing exercise-induced bronchospasm in adults and children, but only in some patients. Comparative studies to date suggest that cromolyn is as effective as theophylline but less effective than orally inhaled β2-adrenergic agonists in preventing exercise-induced bronchospasm. Orally inhaled β2-adrenergic agonists are generally considered the drugs of choice for the prevention of exercise-induced bronchospasm. In some patients, cromolyn combined with an orally inhaled β2-adrenergic agonist and/or with theophylline may be more effective than the latter agents used alone or in combination.
Although cromolyn sodium is poorly absorbed following oral administration, the drug is used orally in the symptomatic treatment of systemic mastocytosis. Cromolyn sodium has been designated an orphan drug for the treatment of this condition. In one placebo-controlled study, oral cromolyn sodium (100 mg 4 times daily) produced marked amelioration of signs and symptoms of the disease including diarrhea, abdominal pain, pruritus, whealing, flushing, and cognitive dysfunction. Therapy with the drug also has improved headaches, nausea, vomiting, and urticaria associated with the disease. Urinary histamine excretion and peripheral-blood eosinophilia were unrelated to clinical manifestations of the disease in the placebo-controlled study and were unaffected by the drug.203 Beneficial effects of the drug were apparent within 2-6 weeks of therapy, and exacerbation of signs and symptoms of the disease occurred within 2-3 weeks after discontinuance of the drug.203 In another study comparing oral cromolyn sodium therapy (200 mg 4 times daily) and combined therapy with a histamine H1- (chlorpheniramine maleate 4 mg 4 times daily) and an H2- (cimetidine 300 mg 4 times daily) receptor antagonist, the therapies were similarly effective in reducing the signs and symptoms of mastocytosis.203 Neither therapy had a substantial effect on plasma histamine concentration or urinary histamine excretion.
Cromolyn sodium has been administered orally for the prophylactic management of food allergy† and for the treatment of chronic inflammatory bowel disease† (e.g., Crohn's disease, ulcerative colitis). Limited data suggest that orally administered cromolyn sodium may be beneficial in the management of gold-induced eosinophilic enterocolitis†.
Cromolyn sodium is administered orally and via oral inhalation.203, 205, 206 The oral concentrate of the drug in ampuls should not be used for oral inhalation therapy nor injected .203 Proper administration of cromolyn sodium is necessary to obtain optimum results, and it is important that the patient receive careful instruction on the particular dosage form employed.203, 205, 206
Cromolyn sodium may be administered by oral inhalation using an oral aerosol inhaler.205, 215 Cromolyn sodium oral inhalation solution is administered by nebulization using a power-operated nebulizer with an adequate flow rate and suitable face mask; hand-operated nebulizers are not suitable for administration of the solution. For young children who have difficulty using the oral aerosol inhaler, the manufacturer recommends that the drug be administered by nebulization.205 The safety and stability of cromolyn sodium oral inhalation solution when mixed with other drugs in the nebulizer have not been established.206
Patients should be carefully instructed in the use of the oral inhaler, including the need to prime the unit prior to first use and after a period of nonuse by pressing once on the top of the metal canister (actuation).215 The canister should be at room temperature prior to use.205, 215 When the oral aerosol inhaler of cromolyn sodium is used, the inhaler should be shaken gently.205 After exhaling as completely as possible, the mouthpiece of the inhaler should be placed well into the mouth and the lips closed around the mouthpiece.215 The patient should tilt the inhaler upward and his head backward, and then inhale deeply and slowly while actuating the inhaler.205, 215 After removing the inhaler from the mouth, the patient should hold his breath for a few seconds and then exhale slowly.215 If a second inhalation is necessary, these steps should be repeated.215 Caution should be exercised to avoid spraying cromolyn sodium into the eyes.205, 215 To clean the aerosol inhaler, the canister containing the drug should be removed from the inhaler and the plastic mouthpiece cleansed with warm water.215
Cromolyn sodium also is administered orally for the management of GI disorders† (e.g., prophylaxis of food allergy, inflammatory bowel disease) and, although poorly absorbed from the GI tract, for systemic mastocytosis and other conditions. For oral administration, cromolyn sodium oral concentrate is diluted in a glass of water just prior to administration and given as a diluted solution. 203 The solution containing the drug should be taken at least 30 minutes before meals.203
Patients should be instructed to empty the contents of the ampul(s) (containing 100 mg each) into a glass of water and to stir the resultant solution.203, 216 The patient should be instructed to drink all of the resultant solution.203, 216 The drug or resultant solution should not be mixed with fruit juice, milk, or food.
The oral aerosol inhaler delivers 800 mcg of cromolyn sodium per metered spray from the mouthpiece.205 The commercially available aerosol containing 8.1 or 14.2 g of drug delivers at least 112 or 200 metered sprays, respectively; the canister should be discarded after the labeled number of actuations have been used since the correct drug dose per inhalation cannot be assured if used for additional doses.205, 215
For the management of bronchial asthma, the usual dosage of cromolyn sodium for adults and children 2 years of age or older (oral inhalation solution) is 20 mg inhaled 4 times daily at regular intervals.206 Alternatively, if the oral aerosol inhaler is used, the usual initial dosage for adults and children 5 years of age or older is 1.6 mg (2 inhalations) 4 times daily at regular intervals; some patients, at least those who are young, may respond adequately to lower dosages.205, 215 Although some patients may not respond to the usual initial dosage of cromolyn sodium oral inhalation aerosol, this dosage should not be exceeded.205 Patients should be advised that cromolyn sodium must be taken at regular intervals to be effective.205, 206, 215 Patients should not discontinue or reduce the dosage of cromolyn sodium without contacting their clinician.215 The full effects of cromolyn sodium may not be evident for 2-4 weeks after treatment initiation, so the drug should not be used for status asthmaticus.205, 206 Cromolyn sodium oral inhalation should be initiated after acute asthma has been controlled, the airway is clear, and the patient is able to inhale adequately.205, 206
Cromolyn sodium generally is used in conjunction with an inhaled β2-adrenergic agonist or inhaled corticosteroid for the prevention and long-term symptomatic control of bronchial asthma.205, 206, 207, 222 When cromolyn sodium therapy is added to existing therapy, the dosage of concurrent agents should initially remain unchanged.206 When a response to cromolyn sodium is evident, an attempt may be made to gradually reduce the dosage of concurrent agents.205, 206 Following stabilization, if the need for concurrent agents is eliminated or such agents are needed on no more than an as-needed basis, the frequency of administration of cromolyn sodium may be reduced gradually to the lowest possible effective level; the usual reduction is from 4 to 3 times daily in patients receiving the cromolyn sodium oral inhalation solution 206 and from 4 to 3 and then 3 to 2 times (2 inhalations per dose) daily in patients receiving the oral inhalation aerosol.205 If asthma control deteriorates in patients receiving a reduced dosage of cromolyn sodium (fewer than 4 doses daily), with or without concurrent agents at a reduced dosage, the dosage of cromolyn sodium may need to be increased, and therapy with concurrent agents may need to be reinitiated or the dosage of such agents increased.205, 206
In corticosteroid-dependent asthmatic patients receiving cromolyn sodium for several weeks, an attempt should be made to gradually reduce the dosage of corticosteroids even if symptomatic improvement in asthma is not observed.205, 206 Patients should be monitored closely during such dosage reduction to avoid an exacerbation of asthma.205, 206 When it is decided to discontinue cromolyn therapy in patients in whom the dosage of corticosteroid therapy has been reduced, patients should be closely monitored to avoid exacerbation of asthma, which may require immediate therapy and an increase in corticosteroid dosage.205, 206
For the prevention of exercise-induced bronchospasm or that induced by exposure to other known precipitating factors, the usual dose of cromolyn sodium oral inhalation solution for nebulization in adults and children 2 years of age or older is 20 mg inhaled shortly (within 10-15 minutes but not longer than 1 hour) before anticipated exercise or exposure to another precipitating factor. Alternatively, if the oral aerosol inhaler is used, the usual dose for adults and children 5 years of age or older is 1.6 mg (2 inhalations) inhaled shortly (i.e., within 10-15 minutes, but not longer than 1 hour) before anticipated exercise or exposure to another precipitating factor.205, 215 The shorter the interval between inhalation of cromolyn and the onset of exercise or exposure to another precipitating factor, the better the protective effect of the drug. During prolonged exercise or exposure, the usual dose may be repeated as necessary for protection.
For the symptomatic treatment of systemic mastocytosis, the usual initial oral dosage of cromolyn sodium for children and adults older than 12 years of age is 200 mg 4 times daily, administered at least 30 minutes before meals and at bedtime.203, 216 Patients should be advised that efficacy of the drug depends on administration at regular intervals as directed.203, 216
For children 2-12 years of age, the usual initial oral cromolyn sodium dosage is 100 mg 4 times daily, given at least 30 minutes before meals and at bedtime.203, 216
In full-term neonates and for infants up to 2 years of age, an initial oral cromolyn sodium dosage of 20 mg/kg daily in 4 divided doses has been used. However, use of the drug in this age group should be attempted only for patients with severe, incapacitating disease in whom the benefits clearly outweigh the risks.203
If an adequate response is not achieved after 2-3 weeks at the usual initial dosage, dosage may be increased according to clinical response but should not exceed 20 mg/kg daily for infants younger than 6 months of age, 30 mg/kg daily for infants 6 months to 2 years of age, or 40 mg/kg in adults and children 2 years of age or older.
Once an adequate therapeutic response is achieved, attempts should be made to reduce the dosage to the minimum effective level; long-term maintenance is necessary to prevent relapses.203
For the prevention of food allergy†, an initial adult oral dosage of 200 mg of cromolyn sodium 4 times daily given 15-20 minutes before meals has been used. If satisfactory control of symptoms is not achieved within 2-3 weeks, the dose may be doubled. Children 2-14 years of age have been given an initial oral dosage of 100 mg 4 times daily 15-20 minutes before meals. If satisfactory control of symptoms is not achieved with this initial dosage in these children within 2-3 weeks, the dose may be doubled but should not exceed 40 mg/kg daily. Once therapeutic response has been achieved, dosage may be reduced to the minimum effective level. In patients in whom prophylactic therapy is only occasionally necessary (e.g., in situations where avoidance of allergenic foods cannot be assured), oral administration of a dose of the drug about 15 minutes prior to the meal may provide some protection. An initial adult dose of 200 mg and an initial dose of 100 mg for children 2-14 years of age have been suggested, but optimal dosage must be individualized.
For the management of chronic inflammatory bowel disease†, an initial adult oral dosage of cromolyn sodium of 200 mg 4 times daily given 15-20 minutes before meals has been used. Children 2-14 years of age have been given an initial oral dosage of 100 mg 4 times daily 15-20 minutes before meals. To prevent relapse, maintenance dosages of 200 mg 4 times daily in adults and 100 mg 4 times daily in children have been used. Dosage should be individualized to the minimum effective level.
Dosage in Renal and Hepatic Impairment
Although cromolyn sodium is only minimally absorbed (up to 1%) following oral administration, the absorbed portion undergoes renal and biliary elimination.203 Severe anaphylactic reactions may occur rarely in patients receiving cromolyn sodium, and the manufacturer states that oral dosage of the drug should be reduced in patients with impaired renal or hepatic function.203 Dosage reduction of cromolyn sodium given via oral inhalation also should be considered in patients with renal or hepatic impairment.205
The most frequent adverse effects occurring in patients using cromolyn sodium aerosol inhalation include irritation or dryness of the throat, bad taste, cough, wheezing, and nausea.205
Adverse effects reported with use of cromolyn sodium solution for oral inhalation include nasal congestion205, 206 (sometimes severe),206 cough,205, 206 sneezing,206 wheezing,205, 206 and nausea.206 Drowsiness,205, 206 nasal itching,205, 206 epistaxis,205, 206 nasal burning,205, 206 serum sickness,205, 206 and stomachache205, 206 also have been reported in clinical trials with cromolyn sodium therapy; however, a causal relationship to the drug has not been established.205, 206
Adverse effects reported with formulations of cromolyn sodium other than inhalation aerosol or solution (e.g., powder for oral inhalation, no longer commercially available in the US) include bronchospasm,205, 206 transient cough,205, 206 pharyngeal irritation,205, 206 and mild wheezing.205, 206 Bronchospasm sometimes has been associated with a precipitous decline in pulmonary function (e.g., FEV1)205 and occasionally has been serious enough to necessitate discontinuance of cromolyn therapy.205, 206 Rash,205, 206 erythema, and urticaria205, 206 have been reported infrequently with cromolyn sodium formulations other than the inhalation aerosol or solution (e.g., powder for oral inhalation, no longer commercially available in the US); such cutaneous reactions have cleared promptly upon withdrawal of the drug. Anaphylaxis and angioedema also have been reported with cromolyn sodium formulations other than the inhalation aerosol or solution.205, 206 Rarely, eosinophilic pneumonia or pulmonary infiltrates with eosinophilia have occurred with oral inhalation of the powder (no longer commercially available in the US);205, 206 the drug should be discontinued if these conditions develop.
Other adverse effects occurring infrequently with cromolyn sodium formulations other than the inhalation aerosol or solution (e.g., powder for oral inhalation, no longer commercially available in the US) include laryngeal edema,205, 206 dizziness,205, 206 lacrimation,205, 206 nausea,205, 206 headache,205, 206 parotid gland swelling,205, 206 joint pain and swelling,205, 206 dysuria and urinary frequency,205, 206 substernal burning,205, 206 and myopathy.205, 206 Rarely, anemia,205, 206 exfoliative dermatitis,205, 206 photodermatitis,205, 206 hoarseness,205, 206 hemoptysis,205, 206 myalgia,205, 206 nephrosis,205, 206 polymyositis,205, 206 peripheral neuritis,205, 206 vertigo,205, 206 periarteritic vasculitis,205, 206 liver disease,205 and pericarditis205, 206 have been reported; however, a causal relationship to the drug has not been established.205, 206
When cromolyn sodium was administered orally for the treatment of systemic mastocytosis, most adverse effects associated with therapy were transient and could have been manifestations of the disease rather than effects of the drug. The most frequent adverse effects reported in patients receiving cromolyn sodium for this condition were headache and diarrhea, each occurring in about 5% of patients. Pruritus, nausea, myalgia, abdominal pain, rash, irritability, and malaise were reported less frequently. Adverse effects associated with oral cromolyn sodium therapy for other conditions include flushing, urticaria/angioedema, arthralgia, dizziness, fatigue, paresthesia, dysgeusia, migraine, psychosis, anxiety, mental depression, insomnia, behavior change, esophagospasm, flatulence, dysphagia, abnormal liver function test results, edema, dyspnea, polycythemia, neutropenia, dysuria, hallucinations, skin erythema and burning, burning mouth and throat, stiffness and weakness of the legs, and postprandial light-headedness and lethargy. These effects occurred infrequently, usually in only a single report, and in many cases a causal relationship to the drug has not been established.
During toxicity testing of cromolyn in macaque monkeys, proliferative arterial lesions occurred, principally in the kidneys in both treated and untreated animals. The relevance of this effect to toxicity of cromolyn in man is unknown; pending further clinical experience with cromolyn, the possibility of adverse renal effects should be considered.
Precautions and Contraindications
Cromolyn is not a bronchodilator and the aerosol or solution for oral inhalation should not be used for relief of acute bronchospasm, especially status asthmaticus.205, 206 Patients receiving cromolyn sodium oral inhalation solution should be advised that the drug is poorly absorbed when taken orally and is not effective for bronchial asthma when taken by this route.206, 212 Patients receiving cromolyn via oral inhalation should be advised that cromolyn must be used at regular intervals to be therapeutically effective. In addition, patients should be advised that the drug will not provide immediate symptomatic relief, but 2-4 weeks of continuous therapy may be required for optimum effects to be achieved in the management of asthma.205
Caution should be used when decreasing the dosage of cromolyn or discontinuing the drug in patients with asthma because asthmatic symptoms may recur. Although corticosteroid requirements in patients with asthma may be reduced during therapy with cromolyn, only very careful, gradual reduction of the steroid dosage should be undertaken. Reduction or cessation of corticosteroid therapy may lead to exacerbation of the patient's asthma. Corticosteroid dosage that has been reduced as a result of cromolyn therapy may have to be fully reinstated if an exacerbation of asthma occurs, or during periods of patient stress such as surgery, trauma, or severe illness.205, 206
The manufacturer states that since cromolyn sodium is excreted via the bile and urine, dosage may have to be reduced or the drug discontinued in patients with renal or hepatic dysfunction.203, 205
If eosinophilic pneumonia or pulmonary infiltrates with eosinophilia occur during oral inhalation therapy with cromolyn, the drug should be discontinued.205
Because cromolyn sodium aerosol inhalation contains chlorofluorocarbon propellants, the aerosol should not be used in patients with coronary artery disease or a history of cardiac arrhythmia.205
Severe anaphylactic reactions can occur following administration of cromolyn sodium.205 Cromolyn sodium is contraindicated in individuals who have shown hypersensitivity to the drug or any ingredient in the commercially available formulations.205
Pending further accumulation of clinical data on the use of cromolyn in pediatric patients and the establishment of benefit-risk factors associated with long-term cromolyn therapy, the drug should be administered with caution in pediatric patients.203, 205 Safety and efficacy of cromolyn sodium given as the oral concentrate,203 or oral inhalation aerosol,205 or oral inhalation solution,206 have not been established in children younger than 2, 5, or 2 years of age, respectively.
Clinical studies of cromolyn sodium oral concentrate did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients. 203 While other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.203 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.203
Mutagenicity and Carcinogenicity
There was no evidence of carcinogenicity following long-term intraperitoneal or subcutaneous administration of cromolyn in mice, rats, or hamsters. There also was no evidence of chromosomal damage or cytotoxicity in mutagenicity studies with the drug.
Pregnancy, Fertility, and Lactation
In animal studies, cromolyn has produced adverse effects on the fetus (e.g., increased resorption, decreased fetal weight) only in very high parenteral doses.205 Healthy infants have been born to women who received cromolyn throughout pregnancy; nevertheless, there is insufficient evidence to establish the safety of cromolyn in pregnancy. Cromolyn sodium should be used during pregnancy only when clearly needed.205
There was no evidence of impaired fertility in reproduction studies in animals.
Since it is not known if cromolyn is distributed into milk in humans, the drug should be used with caution in nursing women.205, 206 Clinicians should weigh the potential benefits to the mother against the potential risks to the infant when considering cromolyn sodium therapy in nursing women.205
Cromolyn appears to act mainly through a local effect on the lung mucosa. Cromolyn prevents release of the mediators of type I allergic reactions, including histamine and cysteinyl leukotrienes (e.g., slow-reacting substance of anaphylaxis [SRS-A]),214 from sensitized mast cells after the antigen-antibody union has taken place.203, 3, 5, 6, 10, 12, 33 Cromolyn suppresses the IgE-mediated release of substances (e.g., histamine, cysteinyl leukotrienes)214 from mast cells.212 The drug also inhibits type III (late allergic, Arthus) reactions to a lesser extent. The action of cromolyn on the mast cell is not restricted to antigen-evoked secretion, since the drug has also been shown to inhibit secretion induced by other mast cell secretagogues (e.g., the polyamine 48/80). It has been suggested that the drug may block calcium channels in mast cell membranes.205 It has also been suggested that cromolyn may inhibit histamine release from mast cells by regulating phosphorylation of a specific mast cell protein involved in secretory mechanisms. Cromolyn sodium therapy in patients with asthma reduces the percentage of eosinophils in bronchial lavage fluid.212 However, the specific mechanism(s) of action of the drug on mast cells remains to be established.
There is some evidence to indicate that cromolyn may cause hyposensitization that persists after long-term use. Cromolyn has no direct antihistamine, anticholinergic, antiserotonin, anti-inflammatory, or corticosteroid-like properties. Although it has generally been stated that cromolyn has no direct bronchodilator activity, recent studies suggest that the drug may have a bronchodilating effect; the mechanism is not known.
Cromolyn is poorly absorbed from the GI tract, with no more than 1% of an oral dose absorbed following oral administration.203 The amount of cromolyn sodium powder (no longer commercially available in the US) that reaches the lungs after inhalation depends on the proficiency of the patient in using the inhaler, the degree of bronchoconstriction, and the presence or absence of mucous plugs. Approximately 8% of a dose of cromolyn sodium powder reaches the lungs after inhalation using the capsules (no longer commercially available in the US) and is readily absorbed into the systemic circulation.205 Following oral inhalation, systemic absorption of the drug is highest following administration of the powder via the Spinhaler® (no longer commercially available in the US) and lowest following administration of the solution via a power-operated nebulizer; absorption intermediate to that following these methods of administration is achieved following administration of the aerosol via a metered-dose inhaler.
The absorption half-life of cromolyn from the lungs is 1 hour. After inhalation of a 20-mg dose of radiolabeled cromolyn in one study, plasma concentrations averaging 9 ng/mL were achieved within 15 minutes.
Following administration of cromolyn sodium inhalation aerosol or solution, improvement in asthma usually occurs within the first 2-4 weeks; some patients show immediate response.205, 206
At physiologic pH, cromolyn is mostly ionized. Because both the ionized and free acid form of the drug are highly polar and lipid insoluble, they do not cross most biologic membranes well.
Following IV administration of large doses (up to 540 mg/kg) of cromolyn sodium in animals, the drug crossed the placenta minimally (less than 0.1%). Minimal concentrations (less than 0.001% of a dose) distributed into milk in monkeys following IV administration of cromolyn sodium. It is not known if the drug is distributed into human milk.
Following oral administration of cromolyn sodium, 98% or more of a dose is excreted in feces as unabsorbed drug; 0.5% or less of a dose is excreted in urine. The absorbed fraction of an inhaled dose of cromolyn is rapidly excreted unchanged in urine and bile with approximately equal proportions being excreted via each route; the remainder of the dose is deposited onto the oropharynx, swallowed, and excreted in feces.205 Very small amounts of an inhaled dose may be exhaled. The elimination half-life of cromolyn sodium is reported to be 81 minutes.
Cromolyn sodium has been described as a mast-cell stabilizer. Cromolyn sodium occurs as a hygroscopic, white, odorless, crystalline powder which is tasteless at first but has a slightly bitter aftertaste. The drug is soluble in water and insoluble in alcohol. Cromolyn is a dibasic acid with pKa1 and pKa2 of 2.0.
For oral use (e.g., in the treatment of systemic mastocytosis), cromolyn sodium is commercially available as an aqueous oral concentrate contained in ampuls; the oral concentrate occurs as a clear, colorless, sterile solution.
For oral inhalation, cromolyn sodium is commercially available as an aerosolized suspension and as a solution. Cromolyn sodium aerosol contains a suspension of micronized drug in a vehicle of fluorocarbon propellants (dichlorodifluoromethane and dichlorotetrafluoroethane) and sorbitan trioleate. Although cromolyn sodium is administered by an oral aerosol inhaler that produces metered sprays containing 1 mg of drug per spray (most particles have a diameter of 5 µm or less), each actuation of the aerosol inhaler delivers a dose of 800 mcg, since a portion of each spray is retained within the delivery device. Cromolyn sodium inhalation is a clear, colorless, sterile solution of the drug in purified water and has a pH of 5.5; the inhalation solution contains no additives.206
Aqueous solutions of cromolyn sodium are fluorescent at a pH greater than 2.
Cromolyn sodium oral concentrate (Gastrocrom®) should be stored at 15-30°C and protected from light.203, 216 The oral concentrate should not be used if it is discolored or contains a precipitate.203, 216
Cromolyn sodium aerosol for oral inhalation should be stored at 15-30°C.205 Because the contents of cromolyn sodium oral inhaler are under pressure, the aerosol container should not be punctured, used or stored near heat or an open flame, or placed into a fire or incinerator for disposal. Exposure of the canister to high temperatures may cause the canister to burst.205 The oral inhalation aerosol containing 8.1 or 14.2 g of the drug is stable for 36 or 48 months after the date of manufacture, respectively.
Cromolyn sodium oral inhalation solution should be protected from direct light and stored at 20-25°C.206
Cromolyn sodium is stable in solution at pHs ranging from 2-7. The drug is unstable in alkaline solutions, being susceptible to hydrolysis at a pH greater than 7. The drug tends to precipitate out of solution in the presence of calcium or magnesium salts. Cromolyn sodium oral inhalation solution should not be used if it is discolored or contains a precipitate.206
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | For solution, concentrate (contained in flexible ampuls) | 20 mg/mL (100 mg) | Gastrocrom® | Azur Pharma |
Oral Inhalation | Aerosol | 800 µg/metered spray | Intal® Inhaler (with chlorofluorohydrocarbon propellants) | King |
For solution, concentrate (contained in flexible ampuls) | 10 mg/mL (20 mg) | Intal® | King | |
Solution, for nebulization | 10 mg/mL (20 mg)* | Cromolyn Sodium Inhalation Solution | ||
Intal® Nebulizer Solution | King |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
3. Cox JS. Disodium cromoglycate: a specific inhibitor of reaginic antibody-antigen mechanisms. Nature . 1967; 216:1328-9. [PubMed 6080064]
5. Anon. Disodium cromoglycate. Lancet . 1972; 2:1299.
6. Anon. Disodium cromoglycate in allergic respiratory disease. Br Med J . 1972; 2:159-61. [PubMed 4622784]
10. Falliers CJ. Cromolyn sodium. J Allergy . 1971; 47:298-305. [PubMed 4104162]
12. Orr TS, Cox JS. Disodium cromoglycate, an inhibitor of mast cell degranulation and histamine release induced by phospholipase A. Nature . 1969; 223: 197. [PubMed 4183038]
33. Sheard P, Blair AM. Disodium cromoglycate activity in three in vitro models of immediate hypersensitivity reaction in the lung. Int Arch Allergy Appl Immunol . 1970; 217-24.
200. Brandstetter RD, Conetta R, Glazer B. Lactose intolerance associated with Intal capsules. N Engl J Med . 1986; 315:1613-4. [PubMed 3097545]
201. Michet CJ Jr, Rakela J, Luthra HS. Auranofin-associated colitis and eosinophilia. Mayo Clin Proc . 1987; 62:142-4. [PubMed 3807438]
202. Martin DM, Goldman JA, Gilliam J et al. Gold-induce eosinophilic enterocolitis: response to oral cromolyn sodium. Gastroenterology . 1981; 80:1567-70. [PubMed 6785145]
203. Celltech Pharmaceuticals. Gastrocrom® (cromolyn sodium) oral concentrate solution prescribing information. Rochester, NY; 2002 Apr.
204. Pharmacia. Nasalcrom®, Children's Nasalcrom®(cromolyn sodium) nasal spray patient information. In: Physicians'desk reference for nonprescription drugs. 21st ed. Montvale, NJ: Medical Economics Company Inc; 2000:710.
205. King Pharmaceuticals. Intal® inhaler (cromolyn sodium) inhalation aerosol prescribing information. Bristol, TN; 2004 Jul.
206. Aventis. Intal® (cromolyn sodium) nebulizer inhalation solution prescribing information. Bridgewater,NJ; 2001 Oct .
207. National Asthma Education and Prevention Program. Expert panel report II: guidelines for the diagnosis and management of asthma. 1997 Feb.
208. Kemp JP. Comprehensive asthma management: guidelines for clinicians. J Asthma . 1998; 35:601-20. [PubMed 9860081]
209. Kemp JP. Guidelines update: where do the new therapies fit in the management of asthma? Drugs . 2000; 59(Suppl 1):23-8.
210. Allergan. Opticrom® (cromolyn sodium) ophthalmic solution prescribing information. In: Physicians' desk reference. 55th ed. Montvale, NJ: Medical Economics Company Inc; 2001:518-9.
212. National Institutes of Health, National Heart, Lung, and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 2005 Oct. NIH/NHLBI Publication No. 02-3659. Available from NIH website. Accessed Nov 7, 2006. [Web]
214. Drazen JM, Israel E, O'Byrne PM. Treatment of athma with drugs modifying the leukotriene pathway. N Engl J Med . 1999; 340:197-206. [PubMed 9895400]
215. King Pharmaceuticals. Intal® inhaler (cromolyn sodium) inhalation aerosol information for the patient. Bristol, TN; 2004 Jul.
216. Celltech Pharmaceuticals. Gastrocrom® (cromolyn sodium) oral concentrate solution patient instructions. Rochester, NY; 2002 Apr.
221. GlaxoSmithKline. Advair® HFA (fluticasone propionate and salmeterol) medication guide. Research Triangle Park, NC; 2008 Mar.
222. National Institutes of Health, National Heart, Lung, and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention. Bethesda, MD: National Institutes of Health. 2009 Dec. Available from: [Web]. Accessed 2010 Sep 23. [Web]
223. National Asthma Education and Prevention Program. Expert panel report III: guidelines for the diagnosis and management of asthma. 2007 Jul. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute. Available from NIH website. Accessed Jul 27, 2008. [Web]
224. British Thoracic Society/Scottish Intercollegiate Guidelines Network. Guidelines on the management of asthma: a national clinical guideline. London, Eng; British Thoracic Society. 2008 May. Available from BTS website. Accessed Dec 5, 2008. [Web]
226. Eric Carter. Dear health care professional letter regarding decision to discontinue the manufacture of Intal® Inhaler (cromolyn sodium inhalation aerosol). Cary, NC: King Pharmaceuticals, Inc; 2009 Jul 31. Available from: [Web]/downloads/Drugs/DrugsSafety/DrugShortages/ucm175032.pdf. Accessed 2010 Oct 14.
227. Food and Drug Administration. Asthma and COPD inhalers that contain ozone-depleting CFCs to be phased out; alternative treatments available. 2010 Apr 13. Available from: [Web]/NewsEvents/Newsroom/PressAnnouncements/ucm208302.htm. Accessed 2010 Oct 14.