Cromolyn (Systemic/Oral-Local)


VA CLASSIFICATION
Primary: IM900

Commonly used brand name(s): Gastrocrom; Nalcrom.

Another commonly used name is
sodium cromoglycate .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Mast cell stabilizer—

antiallergic (systemic)—

Indications

Accepted

Mastocytosis (treatment)1—Cromolyn administered orally is indicated in the treatment of mastocytosis {22} {29}. It has been shown to improve the symptoms of mastocytosis, such as diarrhea, flushing, headache, vomiting, urticaria, abdominal pain, nausea, and itching. {04} {05} {07} {08} {09} {11} {24} {29}

Note: Although oral cromolyn is approved in Canada for gastrointestinal allergy, the USP DI Advisory Panels believe there is insufficient evidence to support the effectiveness of cromolyn in the prophylaxis of food allergy {03} {06} {07} {13} {15} {16} {17} {23} {25} {26} and the prophylaxis and treatment of chronic inflammatory bowel disease {03} {13} {14} {18} {23} {26}. Further studies are needed to determine the efficacy of oral cromolyn in these conditions. The preferred therapy for gastrointestinal allergy to food is avoidance of those foods to which the patient is allergic. In the prophylaxis and treatment of chronic inflammatory bowel disease, agents that have been proven effective in this condition should be used. {03} {06} {07} {13} {14} {15} {16} {17} {18} {23} {25} {26} {27}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    512.34

Mechanism of action/Effect:

Cromolyn inhibits mast cell release of histamine, leukotrienes, and other substances that cause hypersensitivity reactions, {11} {24} {29} probably by interfering with calcium transport across the mast cell membrane. {01} Cromolyn does not posess any intrinsic antihistamine, anti-inflammatory, glucocorticoid, or vasoconstrictive activity. {30}

In vitroand in vivo animal studies have shown that cromolyn inhibits degranulation of sensitized mast cells {11} that occurs after exposure to specific antigens. Some in vitro studies have shown that cromolyn inhibits both degranulation of nonsensitized rat mast cells stimulated by phospholipase A and the subsequent release of chemical mediators. {01} {28}

Absorption:

Poorly absorbed from the gastrointestinal tract; only about 1% of an oral dose is absorbed. {07} {11} {24} {29}

Half-life:

Approximately 80 minutes. {07}

Elimination:
    Renal/biliary; unchanged. {01} {03} {11} {24} {29}


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. {10} {11} {24} {29}

Mutagenicity

In various mutagenicity studies, there was no evidence of chromosomal damage or cytotoxicity. {10} {11} {24} {29}

Pregnancy/Reproduction
Fertility—
In animal reproduction studies with cromolyn, there was no evidence of impaired fertility. {10} {11} {24} {29}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. {10} {11} {24} {29}

Studies in mice, rats, and rabbits with cromolyn administered parenterally in doses up to 338 times the human clinical doses showed no evidence of fetal malformations. Adverse fetal effects (increased resorptions and decreased fetal weight) were noted only at very high parenteral doses that produced maternal toxicity. {10} {11} {24} {29}

Studies in pregnant mice have shown that cromolyn alone, administered subcutaneously in doses of 60 to 540 mg per kg of body weight (mg/kg) (38 to 338 times the human dose), does not cause significant increases in resorptions or major malformations; however, 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. {10} {24} {29}

FDA Pregnancy Category B. {10} {24} {29}

Breast-feeding

It is not known whether cromolyn is distributed into breast milk. {11} {24} {29} However, problems in humans have not been documented. {10} {24} Since cromolyn reaches very low concentrations in maternal serum, it would be expected to reach even lower and probably undetectable concentrations in breast milk.

Pediatrics

Appropriate studies on the relationship of age to the effects of oral cromolyn have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.

Studies in animals have suggested an increased risk of toxicity in premature animals when cromolyn was administered in doses much higher than those clinically recommended for human use. {11} {24} {29}

Use of oral cromolyn is not recommended in premature to term infants. {11} {24} {29}

Use of oral cromolyn in children younger than 2 years of age should be reserved for patients with severe, incapacitating disease. {11}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of cromolyn in the elderly. However, elderly patients are more likely to have age-related hepatic function impairment and renal function impairment, which may require reduction of dosage in patients receiving cromolyn.

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
Hepatic function impairment    (excretion via biliary route; dosage reduction may be necessary {10} {11} {24} {29})


Renal function impairment    (excretion via renal route; dosage reduction may be necessary {10} {11} {24} {29})


Sensitivity to cromolyn


Side/Adverse Effects

Note: Although not reported with oral use of cromolyn, some side/adverse effects that have occurred with cromolyn formulations for inhalation include angioedema, swelling of joints, and, reported rarely, serum sickness, periarteritic vasculitis, polymyositis, pericarditis, photodermatitis, exfoliative dermatitis, peripheral neuritis, and nephrosis. {01} {03}

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 less frequent
    
Skin rash {01}{03}{11}

Incidence rare
    
Anaphylactic reaction, severe {11}{24}{29}(coughing; difficulty in swallowing; hives; itching of skin; swelling of face, lips, or eyelids; wheezing or difficulty in breathing)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Diarrhea {01}{03}{11}{24}{29}
    
headache {01}{03}{11}{24}{29}

Incidence less frequent or rare {11}
    
Abdominal pain {01}{03}{11}{24}{29}
    
irritability {01}{03}{11}{24}{29}
    
myalgia {01}{03}{11}{24}{29}(muscle pain)
    
nausea {01}{03}{11}{24}{29}
    
trouble in sleeping {01}{03}{11}{24}{29}


Note: The above side/adverse effects occurring in patients with mastocytosis are usually transient and could represent symptoms of the disease.





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

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

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to cromolyn





Use in children—In premature to term infants, use of oral cromolyn is not recommended; in children younger than 2 years of age, use of oral cromolyn should be reserved for patients with severe, incapacitating disease


Proper use of this medication
Proper administration: Capsules—



• For optimal results, dissolving contents of capsule(s) in one-half glass (4 ounces) of hot water and stirring until the medication is completely dissolved (solution will become clear) and then adding and stirring in an equal amount (4 ounces) of cold water {30}


• Drinking all of liquid to receive full dose


• Not mixing medication with fruit juice, milk, or foods {29}Ampuls—



• Breaking open ampul(s) and squeezing all contents into a glass of water and then stirring the solution well {30}


• Drinking all of liquid to receive full dose


» Importance of not using more medication than the amount prescribed

» Importance of taking medication at regular intervals for optimum therapeutic effect

» Proper dosing
Missed dose: Taking as soon as possible; taking any remaining doses for that day at regularly spaced intervals

» Proper storage

Precautions while using this medication
» Checking with physician if symptoms do not improve or if condition becomes worse


Side/adverse effects
Signs of potential side effects, especially skin rash and severe anaphylactic reaction


General Dosing Information
For optimal results, the contents of the capsules should be dissolved in warm {22} water only and taken as a solution. The powder should not be mixed with fruit juice, milk, or food. {03} {11} {24} {29} Ampul(s) should be broken and the contents squeezed into a glass of water which is then stirred well. The entire glass of water, containing the medication, should be consumed for the patient to receive the full dose. {30}

If hepatic or renal impairment is present, the cromolyn dose should be reduced as neccessary. {30}

After the desired therapeutic response has been obtained, the dose may be reduced to the lowest level at which there is a reduction in the severity of the patient's symptoms. {30}


Oral Dosage Forms

CROMOLYN SODIUM CAPSULES

Usual adult and adolescent dose
Mastocytosis1
Oral, 200 mg four times a day, thirty minutes before meals and at bedtime. {05} {07} {08} {11} {30}


Usual pediatric dose
Mastocytosis1


Premature to term infants:
Use is not recommended. {30}



Term infants and children up to 2 years of age:
Oral, 20 mg per kg of body weight per day in four divided doses. If control of symptoms is not achieved within two to three weeks in children six months to two years of age, dosage may be increased, if necessary, up to 30 mg per kg of body weight per day. {11} {24} {29} {30}

Note: Use of oral cromolyn in children younger than 2 years of age should be reserved for patients with severe, incapacitating disease. {11} {24} {30}




Children 2 to 12 years of age:
Oral, 100 mg four times a day, thirty minutes before meals and at bedtime. If control of symptoms is not achieved within two to three weeks, dosage may be increased, if necessary, up to 40 mg per kg of body weight per day. {11} {30}



Children 12 years of age and older:
See Usual adult and adolescent dose {30}.



Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


100 mg (Rx) [Gastrocrom{30}]

Canada—


100 mg (Rx) [Nalcrom{31}]

Packaging and storage:
Store at temperatures between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer {30}. Store in a tight container. Keep out of the reach of children. {30}

Preparation of dosage form:
For optimal results, the contents of the capsule should be dissolved in one-half glass (4 ounces) of hot water, and stirred until completely dissolved. Then, one-half glass (4 ounces) of cold water is added {29} to the solution. {01} {03} {11} {29}

Auxiliary labeling:
   • Do not swallow capsule whole.
   • Mix with water only. Do not mix with fruit juice, milk, or food.


CROMOLYN SODIUM ORAL CONCENTRATE

Usual adult and adolescent dose
Mastocytosis
Oral, 200 mg four times a day, thirty minutes before meals and at bedtime. {30}


Usual pediatric dose
Mastocytosis


Premature to term infants:
Use is not recommended. {30}



Term infants and children up to 2 years of age:
Oral, 20 mg per kg of body weight per day in four divided doses. If control of symptoms is not achieved within two or three weeks in children six months to two years of age, the dosage may be increased, if neccessary, up to a maximum of 40 mg per kg per day. {30}

Note: Use of oral cromolyn in children younger than two years of age should be reserved for patients with severe, incapacitating disease. {30}




Children 2 to 12 years of age:
Oral, 100 mg four times a day, thirty minutes before meals and at bedtime. {30}



Children 12 years of age and older:
See Usual adult and adolescent dose. {30}



Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


100 mg per 5 mL (Rx) [Gastrocrom{30} (for oral use only)]

Note: The oral concentrate is available as unit dose ampuls.


Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Keep out of the reach of children. Store ampuls in foil pouch until ready for use. Protect ampuls from light. Do not use if solution becomes cloudy or discolored. {30}

Preparation of dosage form:
Ampul(s) should be broken and the contents squeezed into a glass of water which is then stirred well. {30}

Note: Not for inhalation or injection. {30}




Revised: 08/14/1998



References
  1. CPS 1988, Nalcrom monograph, pp 585-586.
  1. No reference
  1. CPS 1989, Nalcrom Capsules, p 649.
  1. Arch Intern Med, Vol 144, 11/84, pp 2249-53.
  1. Clinical Allergy 1984, Vol 14, pp 147-52.
  1. Allergy 1984, Vol 39, pp 535-41.
  1. AHFS 92:00, pp 2086-2090.
  1. Cecil Textbook of Medicine, 18th ed, p 1974.
  1. F & C, 8/88, National Information Center for Orphan Drugs & Rare Diseases (NICODARD) list, p 754e.
  1. USP DI 1990 Cromolyn (Inhalation-Local) monograph.
  1. Gastrocrom PI, Fisons, Rev 1989, Rec 2/1/90.
  1. Gastrocrom Basic Product Information, Fisons, Rev 1989, Rec 2/1/90.
  1. Panel comments, Rec 2/90, 6/90.
  1. Panel comments, Rec 6/90.
  1. Daughjerg PS, Bach-Mortensen N, Osterballe O. Oral sodium cromoglycate treatment of atopic dermatitis related to food allergy. Allergy 1984; 39: 535-41.
  1. Businco L, Cautani A, Benincori N, Perlini R, Infussi R De Angelis M, Businco E. Effectiveness of oral sodium cromoglycate in preventing allergy in children. Ann Allergy 1983; 51(1): 47-50.
  1. Molkhou P, Wagnet J-C. Food allergy and atopic dermatitis in children: treatment with oral sodium cromoglycate. Ann Allergy 1981; 47: 173-5.
  1. Peppercorn Mark A. Advances in drug therapy for inflammatory bowel disease. Ann Internal Med Jan 1990; 112(1): 50-60.
  1. Carini C, Brostoff J, Wraith D G. IgE complexes in food allergy. Ann Allergy Aug 1987; 59(2):110–7.
  1. Panel comments, Rec 6/90.
  1. Panel comments, Rec 6/90.
  1. Manufacturer's comments, Rec 6/15/90.
  1. Reviewers' comments Rec 7/90.
  1. PDR, Gastrocom (Fisons), p 946.
  1. Burks AW, Sampson HA. Double-blind placebo-controlled trial of oral cromolyn in children with atopic dermatitis and documented food hypersensitivity. J Aller Clin Immunol 1988; 81: 417-23.
  1. Panel comments, 3/3/90.
  1. Panel comments.
  1. Panel comments, Rec 5/7/91.
  1. PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company; 1994. p. 927.
  1. Gastrocrom (Medeva Pharmaceuticals). In: PDR Physicians' desk reference. 52nd ed. 1998. Montvale, NJ: Medical Economics Company; 1998. p. 1565-7.
  1. Nalcrom (Rhone-Poulenc Rorer). In: CPS Compendium of Pharmaceuticals and Specialties. 33rd ed. Ottawa, Ontario, Canada: Canadian Pharmacists Association; 1998. p. 1066.
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