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Sodium cromoglycate

Generic Name: Cromolyn


INN:

Cromoglicic acid {01}

BAN:
Cromoglycic acid {01}


JAN:
Sodium cromoglicate {01}

VA CLASSIFICATION
Primary: RE110
Secondary: RE160

Commonly used brand name(s): Intal; Intal Inhaler; Intal Syncroner; Novo-cromolyn; PMS-Sodium Cromoglycate.

Other commonly used names are
cromoglicic acid, cromoglycic acid, sodium cromoglicate , and sodium cromoglycate .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anti-inflammatory, nonsteroidal (inhalation)—

mast cell stabilizer—

asthma prophylactic—

antiallergic (inhalation)—

Indications

Accepted

Asthma (prophylaxis)—Cromolyn inhalation is indicated as first-line anti-inflammatory medication, either alone or as an adjunct to bronchodilator therapy, for the prevention of airway inflammation and bronchoconstriction in patients with mild to moderate asthma who require daily therapy {02} {12} {13} {15} {22}.

Bronchospasm (prophylaxis)—Cromolyn inhalation is indicated to prevent acute bronchospasm induced by exercise, or by exposure to allergens, cold, dry air, environmental pollutants, aspirin ingestion, or other known precipitating factors, whether exposure is episodic or continuous {02} {06} {13} {22} {23}.

Unaccepted
Cromolyn inhalation is not indicated for the reversal or relief of acute asthma attacks, especially in status asthmaticus; cromolyn has no immediate bronchodilating activity {02} {03}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    512.34 {01}

Mechanism of action/Effect:

The exact mechanism by which cromolyn prevents immediate-onset and delayed-onset asthmatic reactions to inhaled allergens or nonimmunological stimuli is not completely known {05} {15}. Cromolyn inhibits the release of mediators, such as histamine and leukotrienes, from mast cells. Prevention of mediator release is thought to result from indirect blockade of the entry of calcium ions into the cells. Cromolyn has also been shown to inhibit the movement of other inflammatory cells such as neutrophils, eosinophils, and monocytes. {14} {15} Additionally, cromolyn has been shown in animal studies to inhibit neuronal reflexes within the lung, prevent down-regulation of beta 2-adrenergic receptors on lymphocytes, and to inhibit bronchospasm caused by tachykinins {15}.

Cromolyn has no intrinsic bronchodilator, glucocorticoid, or antihistaminic action {02} {04} {24}.

Absorption:

Following administration by inhalation, approximately 8% {02} of the dose of cromolyn penetrates the lungs, from which it is readily absorbed into systemic circulation. The remainder is either exhaled or swallowed and excreted via the alimentary tract, with very little medication absorbed. {02} {23}

Onset of action:

Cromolyn inhibits a decrease in forced expiratory volume in 1 second (FEV 1) when inhaled 1 minute before antigen challenge {17}. When cromolyn is used as maintenance therapy, clinical improvement in symptoms and lung function usually occurs within 4 weeks of beginning treatment. However, in some patients improvement may occur almost immediately. {02}

Duration of action:

Protection against antigen or exercise challenge—Up to 2 hours {06} {17}.

Elimination:
    Unchanged, approximately equally divided between urine and bile {02} {23}.


Precautions to Consider

Carcinogenicity

Long-term studies in mice (12 months intraperitoneal treatment followed by 6 months observation), hamsters (12 months intraperitoneal treatment followed by 12 months observation), and rats (18 months subcutaneous treatment) showed that cromolyn has no neoplastic effect {02} {23}.

Mutagenicity

In various mutagenicity studies, there was no evidence of chromosomal damage or cytotoxicity {02} {23}.

Pregnancy/Reproduction
Fertility—
In animal reproduction studies with cromolyn, there was no evidence of impaired fertility {02} {23}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Studies in animals have not shown that cromolyn causes adverse effects in the fetus.

Although extensive studies in humans have not been done, some limited data suggest that cromolyn is not associated with an increased incidence of fetal anomalies {07} {23}. Poorly controlled asthma and loss of pulmonary function present a greater risk to the mother and may result in placental hypoxemia and increased perinatal mortality, increased prematurity, and low birth weight {09}.

Reproduction studies in mice, rats, and rabbits with cromolyn administered parenterally in doses of up to 338 times the human clinical dose showed no evidence of fetal malformations. Adverse fetal effects (increased resorptions and decreased fetal weight) were noted only with very high parenteral doses that produced maternal toxicity. {02} {23}

Studies in pregnant mice have shown that the addition of cromolyn (338 times the human dose) to isoproterenol (90 times the human dose) appears to increase the incidence of both resorptions and malformations {02}.

FDA Pregnancy Category B {02} {23}.

Breast-feeding

It is not known whether cromolyn is distributed into human breast milk; however, problems have not been documented {02} {07} {23}. Since cromolyn reaches very low concentrations in maternal serum, it would be expected to reach even lower, and probably undetectable, concentrations in breast milk.

In monkeys given intravenous cromolyn, concentrations in breast milk measured less than 0.001% of the administered dose {17}.

Pediatrics

Appropriate studies on the relationship of age to the effects of cromolyn administered by metered dose inhaler in children younger than 5 years of age or as a nebulizer solution in children younger than 2 years of age have not been performed. Safety and efficacy have not been established {23}.

Because of the possibility that adverse effects of this drug could become apparent only after many years of use, a benefit/risk consideration of the long-term use of cromolyn inhalation aerosol is particularly important in pediatric patients. {23}


Geriatrics


Although appropriate studies on the relationship of age to the effects of cromolyn inhalation have not been performed in the geriatric population, no geriatrics-specific problems have been documented to date.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Bronchial airway hyperreactivity assessment    (cromolyn alters bronchial airway hyperreactivity over time by its proposed anti-inflammatory effect; this may lead to a lessened response to methacholine challenge in some patients {08})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Sensitivity to cromolyn{22}{23}
» Coronary artery disease or history of cardiac arrhythmias{23}    (propellants in the metered-dose inhaler may worsen these conditions)




Side/Adverse Effects

Note: Adverse reactions to cromolyn sodium are uncommon. Angioedema, bronchospasm, cough, dizziness, dysuria and urinary frequency, headache, joint swelling and pain, lacrimation, laryngeal edema, nasal congestion, nausea, rash, swollen parotid glands, and urticaria attributed to cromolyn have been reported {02} {04} to occur in fewer than 1 in 10,000 patients {17}. Anemia, exfoliative dermatitis, hemoptysis, hoarseness, myalgia, nephrosis, periarteritic vasculitis, pericarditis, peripheral neuritis, photodermatitis, polymyositis, pulmonary infiltrates with eosinophilia, and vertigo have been reported {02} {04} in fewer than 1 in 100,000 patients {17}. In all cases the causal relationship is unclear {17} {22}. However, cromolyn should be discontinued if the patient develops eosinophilic pneumonia (pulmonary infiltrates with eosinophilia) {23} {24}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Bronchospasm, sometimes severe {22}{23}{24}(increased wheezing; tightness in chest; or difficulty in breathing)—associated with a precipitous fall in pulmonary function (FEV 1){22}{23}{24}

Incidence rare
    
Anaphylactic reaction {02}{04}{15}(difficulty in swallowing; hives; itching of skin; swelling of face, lips, or eyelids; increased wheezing or difficulty in breathing; low blood pressure)—reported in fewer than 1 in 100,000 patients{17}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Bad taste in mouth —for metered dose inhaler{02}{04}{22}
    
coughing or wheezing{04}{22}
    
nausea{04}{22}
    
throat irritation or dryness {02}{03}{04}{19}{22}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cromolyn (Inhalation) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to cromolyn
Other medical problems, especially coronary artery disease or a history of cardiac arrhythmias

Proper use of this medication
» Helps prevent, but does not relieve, acute attacks of asthma or bronchospasm

» Importance of taking medication at regular intervals

» Importance of not using more medication than the amount prescribed

Reading patient instructions carefully before using

Checking periodically with health care professional for proper use of inhaler to prevent incorrect dosage

» Proper dosing
Missed dose: If used regularly, using as soon as possible; using any remaining doses for that day at regularly spaced intervals

» Proper storage

For inhalation aerosol dosage form
Keeping record of number of sprays used, if possible; not floating canister in water to test fullness

Testing or priming inhaler before using first time or if not used for a while

Discarding canister after labeled number of metered dose sprays has been used, even if canister does not appear completely empty {22}

Proper administration technique

Proper administration technique with spacer device

Proper cleaning procedure for inhaler

For inhalation capsule dosage form
» Not swallowing capsules; medication not effective if swallowed

Using with Spinhaler or Halermatic inhaler

Proper loading technique for inhaler

Proper administration technique

Proper cleaning procedure for inhaler

For inhalation solution dosage form
Not using if solution cloudy or contains particles

Proper breaking of ampul

Using in a power-operated nebulizer with an adequate flow rate and equipped with face mask or mouthpiece; not using hand-squeezed bulb nebulizers

For patients on scheduled dosing regimen
» Compliance with therapy; may require up to 4 weeks for full benefit

Precautions while using this medication
» Checking with physician if symptoms do not improve within first 4 weeks; checking with physician immediately if condition becomes worse

» Importance of not discontinuing concurrent systemic corticosteroid or bronchodilator therapy without physician's advice

Possible throat irritation or dryness; gargling and rinsing mouth or taking drink of water after each dose to help prevent these effects


Side/adverse effects
Signs of potential side effects, especially bronchospasm or anaphylactic reaction

Cromolyn inhalation aerosol may cause an unpleasant taste


General Dosing Information
When cromolyn is introduced into the patient's therapeutic regimen after an acute episode, the episode must be under control, the airway clear, and the patient able to inhale adequately {02} {23}.

A decrease in the severity of clinical symptoms or the need for concomitant therapy is a sign of improvement that will be evident in the first 4 weeks of therapy if the patient responds to cromolyn therapy {02} {22} {23}.

In asthmatic patients receiving systemic corticosteroids and/or bronchodilators prior to institution of cromolyn, the dosage of corticosteroid and/or bronchodilator should be maintained following initiation of cromolyn therapy. When a clinical response to cromolyn is evident, usually within 2 to 4 weeks, and if the asthma is under good control, an attempt should be made to decrease (taper) the dosage of the systemic corticosteroid and other concomitant medications such as bronchodilators. This decrease should be implemented gradually to avoid an exacerbation of asthma. {02} {22}

If cromolyn is withdrawn in cases in which its use has permitted a decrease in the maintenance dose of corticosteroids, continued close patient monitoring is essential since acute asthma exacerbation may occur, requiring immediate therapy and possible reintroduction of corticosteroids {22}.

Patients with impaired hepatic or renal function may require a decrease in the recommended dosage of cromolyn. Consideration should be given to discontinuing the administration of cromolyn in these patients due to the extensive biliary and renal routes of excretion of this medication {23} {24}.

For inhalation solution dosage form only—Cromolyn solution should be administered from a power-operated nebulizer having an adequate flow rate (6 to 8 liters per minute) and equipped with a suitable face mask or mouthpiece {04} {24}. Hand-squeezed bulb nebulizers are not suitable for administration of cromolyn solution.


Inhalation Dosage Forms

CROMOLYN SODIUM INHALATION AEROSOL

Usual adult and adolescent dose
Asthma (prophylaxis)
Oral inhalation, 2 inhalations (1.6 or 2 mg) four times a day at regular intervals {22} of four to six hours {02}.

Note: When the patient is stabilized on a maintenance regimen of 2 inhalations of cromolyn four times a day, the dosing frequency may be gradually reduced to three times a day, then to two times a day in some patients {02} {15} {17}. However, if the patient's clinical condition deteriorates, an increase in cromolyn and/or the addition of concomitant medications may become necessary {22}.


Bronchospasm (prophylaxis)
Oral inhalation, 2 inhalations (1.6 or 2 mg) as a single dose administered at least ten to fifteen (but not more than sixty) minutes before exercise or exposure to any precipitating factor, such as allergens, cold, dry air, aspirin ingestion, or environmental pollutants {02} {22} {23} {24}.


Usual adult prescribing limits
16 puffs (12.8 or 16 mg) daily {04}.

Usual pediatric dose
Children up to 5 years of age: Safety and efficacy have not been established {23}.
Children 5 years of age and older: See Usual adult and adolescent dose{02}{22}{23} .

Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


800 mcg (0.8 mg) per metered dose actuation (spray) (Rx) [Intal]{22}

Canada—


1 mg per metered dose actuation (spray) (Rx) [Intal Inhaler; Intal Syncroner]{24}

Note: Intal Syncroner differs from Intal Inhaler in the design of the mouthpiece only. The Syncroner is an elongated mouthpiece approximately 8 cm in length, with a portion of its upper surface cut away {24}.
In Canada, metered dose inhalers are labeled according to the amount of cromolyn delivered at the valve; in the U.S., metered dose inhalers are labeled according to the amount of cromolyn delivered at the mouthpiece or actuator. Therefore, 1 mg of cromolyn delivered at the valve is equivalent to 800 mcg delivered at the mouthpiece. {02} {04} {24}


Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • For oral inhalation only.
   • Shake well before using.
   • Contents under pressure.
   • Avoid spraying in eyes.
   • Store away from heat and direct sunlight.

Note: Include patient instructions when dispensing.
Demonstrate inhalation technique to patient when dispensing.


Additional information:
U.S.—Each 8.1-gram aerosol canister delivers at least 112 metered dose actuations (sprays); each 14.2-gram canister delivers at least 200 metered dose actuations (sprays). {22}

Canada—Each canister delivers either 112 or 200 metered dose actuations (sprays). {04} {24}

Note: The correct amount of medication per inhalation cannot be assured after the dispensation of the maximum recommended number of metered dose actuations (sprays). Therefore, a record should be kept of the number of sprays dispensed, and the canister should be discarded when the labeled maximum number of sprays has been used, even though the canister may not appear completely empty. {22}



CROMOLYN SODIUM FOR INHALATION (CAPSULES) USP

Usual adult and adolescent dose
Asthma (prophylaxis)
Oral inhalation, 20 mg (1 capsule) four times a day at regular intervals of four to six hours.

Note: When the patient is stabilized on a maintenance regimen of four times a day, the dosing frequency may be gradually reduced to three times a day, then to two times a day in some patients. {04} {15} {17} {24}


Bronchospasm (prophylaxis)
Oral inhalation, 20 mg (1 capsule) as a single dose administered at least ten to fifteen (but not more than sixty) minutes before exercise or exposure to the precipitating factor {04} {24}.


Usual adult prescribing limits
160 mg (8 capsules) daily {04}.

Usual pediatric dose
Children up to 2 years of age: Safety and efficacy have not been established {24}.
Children 2 years of age and older: See Usual adult and adolescent dose{04}{24} .

Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


20 mg per inhalation capsule (Rx) [Intal]{24}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tightly closed container to exclude light and humidity {18} {24}.

Auxiliary labeling:
   • For inhalation only—Do not swallow capsules.

Note: Include patient instructions when dispensing.
Demonstrate administration technique to patient when dispensing.
Demonstration kits may be available.



CROMOLYN SODIUM INHALATION SOLUTION USP

Usual adult and adolescent dose
Asthma (prophylaxis)
Oral inhalation, 20 mg four times a day at regular intervals of four to six hours {03} {24}.

Note: When the patient is stabilized on a maintenance regimen of four times a day, the dosing frequency may be gradually reduced to three times a day, then to two times a day in some patients {02} {15} {17} {24}.


Bronchospasm (prophylaxis)
Oral inhalation, 20 mg as a single dose administered at least ten to fifteen (but not more than sixty) minutes before exercise or exposure to the precipitating factor {03} {23} {24}.


Usual adult prescribing limits
160 mg daily {04}.

Usual pediatric dose
Children up to 2 years of age: Safety and efficacy have not been established {23}.
Children 2 years of age and older: See Usual adult and adolescent dose{03}{23} .

Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


20 mg per 2-mL ampul (Rx) [Intal][Generic]{23}

Canada—


20 mg per 2-mL ampul (Rx) [Intal] [Novo-cromolyn] [PMS-Sodium Cromoglycate]{24}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. Protect from light and humidity. {03} {24}

Stability:
Solution should not be used if it is cloudy or contains a precipitate. {03}

Any solution remaining in the nebulizer should be discarded.

Cromolyn sodium inhalation solution has been shown to be physically and chemically compatible with acetylcysteine {16}, albuterol {10}, epinephrine, isoetharine, isoproterenol, metaproterenol, and terbutaline solutions for up to 60 minutes {16}.

When combining cromolyn and ipratropium inhalation solutions, it is recommended that only a preservative-free ipratropium solution be used. Mixing cromolyn inhalation solution with an ipratropium inhalation solution containing the preservative benzalkonium chloride is not recommended because mixing results in cloudiness of the solution, which is due to complexation between cromolyn sodium and benzalkonium chloride, although no precipitation or significant decrease in the concentration of cromolyn or ipratropium occurs. {10} {11}

Cromolyn should not be mixed with bitolterol inhalation solution {20}, since mixing results in cloudiness of the solution {21}.

Auxiliary labeling:
   • For inhalation only.

Note: Include patient information when dispensing.
Demonstrate opening and emptying of ampul when dispensing.




Revised: 5/28/1999



References
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 198.
  1. Cromolyn inhalation aerosol product labeling (Intal, Fisons—US), Rev 7/94, Rec 10/95.
  1. Cromolyn nebulizer solution product labeling (Intal, Fisons—US), Rev 4/94, Rec 10/95.
  1. Cromolyn product labeling (Intal, Fisons). In: Krough CME, editor. CPS Compendium of pharmaceuticals and specialties. 30th ed. Ontario: Canadian Pharmaceutical Association; 1995. p. 626-8.
  1. Gould MK, Raffin TA. Pharmacological management of acute and chronic bronchial asthma. Adv Pharmacol 1995; 32: 169-204.
  1. McFadden ER, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994; 330: 1362-7.
  1. Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation. Baltimore: Williams & Wilkins; 1994. p. 229.
  1. Fish JE. Bronchial challenge testing. In: Middleton E, Reed ER, Ellis EF, et al., editors. Allergy principles and practice. St Louis: CV Mosby Co; 1988. p. 451.
  1. National Institutes of Health. Working group on asthma and pregnancy. Management of asthma during pregnancy. J Allergy Clin Immunol 1994; 93: 139-62.
  1. Iacono M, Johnson GJ, Bury RW. An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions. Aust J Hosp Pharm 1987; 17: 158-61.
  1. Turner M. Compatibility of nebulizer solutions. Aust J Hosp Pharm 1987; 17: 241-2.
  1. Bergner A, Bergner RK. The international consensus report on diagnosis and treatment of asthma: a call to action for US practitioners. Clin Ther 1994; 16: 694-705.
  1. National Asthma Education Program. Expert Panel Report. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute; 1991.
  1. Gilman AG, Rall TW, Nies AS, et al., editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990. p. 630-1.
  1. Murphy S. Cromolyn sodium: basic mechanisms and clinical usage. Pediatr Asthma Allergy Immunol 1988; 2: 237-54.
  1. Lesko LJ, Miller AK. Physical-chemical compatibility of cromolyn sodium nebulizer solution–bronchodilator inhalant solution admixtures. Ann Allergy 1984; 53: 236-8.
  1. Murphy S, Kelly HW. Cromolyn sodium: a review of mechanisms and clinical use in asthma. DICP 1987; 21: 22-35.
  1. The United States pharmacopeia. The national formulary. USP 23rd revision (January 1, 1995). NF 18th ed. (January 1, 1995). Rockville, MD: The United States Pharmacopeial Convention Inc; 1995.
  1. Cromolyn nebulizer solution product monograph (Novo-cromolyn, Novopharm—Canada), Rev 4/15/94.
  1. Bitolterol inhalation solution (Tornalate, Dura—US), Rev 1994.
  1. Panel comment, Rec 2/22/96.
  1. Intal Inhaler package insert (RPR—US), Rev 9/97, Rec 2/99.
  1. PDR Physicians' Desk Reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 2589-91.
  1. Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 788-90.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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