The active ingredient of INTAL Nebulizer Solution is cromolyn
sodium, USP. It is an inhaled anti-inflammatory agent for the preventive management
of asthma. Cromolyn sodium is disodium 5,5'-[(2-hydroxytrimethylene)dioxy]bis[4-oxo-4H-1-benzopyran-2-carboxylate]. The empirical
formula is C23H14Na2O11; the molecular
weight is 512.34. Cromolyn sodium is a water soluble, odorless, white, hydrated
crystalline powder. It is tasteless at first, but leaves a slightly bitter
aftertaste. INTAL Nebulizer Solution is clear, colorless, sterile, and has
a target pH of 5.5.
The molecular structure is:
2 mL ampule of INTAL Nebulizer Solution (cromolyn sodium inhalation solution,
USP) contains 20 mg cromolyn sodium, USP, in purified water.
In vitro and in vivo animal studies have shown that cromolyn
sodium inhibits sensitized mast cell degranulation which occurs after exposure
to specific antigens. Cromolyn sodium acts by inhibiting the release of mediators
from mast cells. Studies show that cromolyn sodium indirectly blocks calcium
ions from entering the mast cell, thereby preventing mediator release.
sodium inhibits both the immediate and non-immediate bronchoconstrictive reactions
to inhaled antigen. Cromolyn sodium also attenuates bronchospasm caused by
exercise, toluene diisocyanate, aspirin, cold air, sulfur dioxide, and environmental
Cromolyn sodium has no intrinsic bronchodilator
or antihistamine activity.
After administration by
inhalation, approximately 8% of the total cromolyn sodium dose administered
is absorbed and rapidly excreted unchanged, approximately equally divided
between urine and bile. The remainder of the dose is either exhaled or deposited
in the oropharynx, swallowed and excreted via the alimentary tract.
Indications and Usage
INTAL is a prophylactic agent indicated in the management
of patients with bronchial asthma.
In patients whose
symptoms are sufficiently frequent to require a continuous program of medication,
INTAL is given by inhalation on a regular daily basis (see DOSAGE AND ADMINISTRATION). The effect of INTAL is usually evident after several weeks of
treatment, although some patients show an almost immediate response.
patients who develop acute bronchoconstriction in response to exposure to
exercise, toluene diisocyanate, environmental pollutants, etc., INTAL should
be given shortly before exposure to the precipitating factor (see DOSAGE AND ADMINISTRATION).
INTAL is contraindicated in those patients who have shown
hypersensitivity to cromolyn sodium.
INTAL has no role in the treatment
of status asthmaticus.
with cromolyn sodium administration have been reported rarely.
Occasionally, patients may experience cough and/or bronchospasm
following INTAL inhalation. At times, patients who develop bronchospasm may
not be able to continue INTAL administration despite prior bronchodilator
administration. Rarely, very severe bronchospasm has been encountered.
of asthma may recur if INTAL is reduced below the recommended dosage or discontinued.
Information for Patients
INTAL is to be taken as directed by the physician. Because
it is preventive medication, it may take up to four weeks before the patient
experiences maximum benefit.
INTAL Nebulizer Solution
should be used in a power-driven nebulizer with an adequate airflow rate equipped
with a suitable face mask or mouthpiece.
and safety of INTAL Nebulizer Solution when mixed with other drugs in a nebulizer
have not been established.
For additional information,
see the accompanying leaflet entitled Living
a Full Life with Asthma.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term studies of cromolyn sodium in mice (12 months intraperitoneal
administration at doses up to 150 mg/kg three days per week), hamsters (intraperitoneal
administration at doses up to 53 mg/kg three days per week for 15 weeks followed
by 17.5 mg/kg three days per week for 37 weeks), and rats (18 months subcutaneous
treatment at doses up to 75 mg/kg six days per week) showed no neoplastic
effects. These doses correspond to approximately 1.0, 0.3, and 2 times, respectively,
the maximum recommended human daily inhalation dose on a mg/m2 basis.
sodium showed no mutagenic potential in Ames Salmonella/microsome plate assays,
mitotic gene conversion in Saccharomyces cerevisiae and in an in vitro cytogenetic
study in human peripheral lymphocytes.
of impaired fertility was shown in laboratory reproduction studies conducted
subcutaneously in rats at the highest doses tested, 175 mg/kg/day in males
and 100 mg/kg/day in females. These doses are approximately 18 and 10 times,
respectively, the maximum recommended adult human daily inhalation dose on
a mg/m2 basis.
Pregnancy Category B. Reproduction
studies with cromolyn sodium administered subcutaneously to pregnant mice
and rats at maximum daily doses of 540 mg/kg and 164 mg/kg, respectively,
and intravenously to rabbits at a maximum daily dose of 485 mg/kg produced
no evidence of fetal malformations. These doses represent approximately 27,
17, and 98 times, respectively, the maximum recommended adult human daily
inhalation dose on a mg/m2 basis. Adverse fetal effects (increased
resorptions and decreased fetal weight) were noted only at the very high parenteral
doses that produced maternal toxicity. There are, however, no adequate and
well-controlled studies in pregnant women.
reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.
Drug Interaction During Pregnancy:Cromolyn sodium and isoproterenol were studied following subcutaneous
injections in pregnant mice. Cromolyn sodium alone in doses up to 540 mg/kg
(approximately 27 times the maximum recommended adult human daily inhalation
dose on a mg/m2 basis) did not cause significant increases in resorptions
or major malformations. Isoproterenol alone at a dose of 2.7 mg/kg (approximately
7 times the maximum recommended adult human daily inhalation dose on a mg/m2 basis)
increased both resorptions and malformations. The addition of cromolyn sodium
(approximately 27 times the maximum recommended adult human daily inhalation
dose on a mg/m2 basis) to isoproterenol (approximately 7 times
the maximum recommended adult human daily inhalation dose on a mg/m2 basis)
appears to have increased the incidence of both resorptions and malformations.
It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised
when INTAL is administered to a nursing woman.
Safety and effectiveness in pediatric patients below the
age of 2 years have not been established.
Clinical studies of INTAL did not include sufficient numbers
of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients.
Clinical experience with the use of INTAL suggests that adverse
reactions are rare events. The following adverse reactions have been associated
with INTAL Nebulizer Solution: cough, nasal congestion, nausea, sneezing,
Other reactions have been reported in
clinical trials; however, a causal relationship could not be established:
drowsiness, nasal itching, nose bleed, nose burning, serum sickness, and stomachache.
addition, adverse reactions have been reported with INTAL Capsules (cromolyn
sodium for inhalation, USP). The most common side effects are associated with
inhalation of the powder and include transient cough (1 in 5 patients) and
mild wheezing (1 in 25 patients). These effects rarely require treatment or
discontinuation of the drug.
Information on the incidence
of adverse reactions to INTAL Capsules has been derived from U.S. postmarketing
surveillance experience. The following adverse reactions attributed to INTAL,
based upon recurrence following readministration, have been reported in less
than 1 in 10,000 patients: laryngeal edema, swollen parotid gland, angioedema,
bronchospasm, joint swelling and pain, dizziness, dysuria and urinary frequency,
nausea, cough, wheezing, headache, nasal congestion, rash, urticaria, and
Other adverse reactions have been reported
in less than 1 in 100,000 patients, and it is unclear whether these are attributable
to the drug: anaphylaxis, nephrosis, periarteritic vasculitis, pericarditis,
peripheral neuritis, pulmonary infiltrates with eosinophilia, polymyositis,
exfoliative dermatitis, hemoptysis, anemia, myalgia, hoarseness, photodermatitis,
There is no clinical syndrome associated with an overdosage
of cromolyn sodium. Acute toxicity testing in a wide variety of species has
demonstrated that toxicity with cromolyn sodium occurs only with very high
exposure levels, regardless of whether administration was parenteral, oral
or by inhalation. Parenteral administration in mice, rats, guinea pigs, hamsters,
and rabbits demonstrated a median lethal dose of approximately 4000 mg/kg.
Intravenous administration in monkeys also indicated a similar pattern of
toxicity. The highest dose administered by the oral route in rats and mice
was 8000 mg/kg, (approximately 261 and 130 times, respectively, the maximum
recommended human daily inhalation dose on a mg/m2 basis) and at
this dose level no deaths occurred. By inhalation, even in long term studies,
it proved impossible to achieve toxic dose levels of cromolyn sodium in a
range of mammalian species.
Dosage and Administration
For management of bronchial asthma in adults and pediatric
patients (two years of age and over), the usual starting dosage is the contents
of one ampule administered by nebulization four times a day at regular intervals.
stability and safety of INTAL Nebulizer Solution when mixed with other drugs
in a nebulizer have not been established.
chronic asthma should be advised that the effect of INTAL therapy is dependent
upon its administration at regular intervals, as directed. INTAL should be
introduced into the patient's therapeutic regimen when the acute episode has
been controlled, the airway has been cleared and the patient is able to inhale
For the prevention of acute bronchospasm
which follows exercise or exposure to cold dry air, environmental agents (e.g., animal danders, toluene diisocyanate,
pollutants), etc., the usual dose is the contents of one ampule administered
by nebulization shortly before exposure to the precipitating factor.
It should be emphasized to the patient that the drug is poorly
absorbed when swallowed and is not effective by this route of administration.
For additional information, see the accompanying
leaflet entitled “Living a Full Life with
Therapy in Relation to Other Treatments for Asthma: Non-steroidal agents: INTAL should be added to the patient's existing treatment regimen
(e.g., bronchodilators). When a clinical
response to INTAL is evident, usually within two to four weeks, and if the
asthma is under good control, an attempt may be made to decrease concomitant
medication usage gradually.
If concomitant medications
are eliminated or required on no more than a prn basis, the frequency of administration
of INTAL may be titrated downward to the lowest level consistent with the
desired effect. The usual decrease is from four to three ampules per day.
It is important that the dosage be reduced gradually to avoid exacerbation
of asthma. It is emphasized that in patients whose dosage has been titrated
to fewer than four ampules per day, an increase in the dose of INTAL and the
introduction of, or increase in, symptomatic medications may be needed if
the patient's clinical condition deteriorates.
Corticosteroids: In patients
chronically receiving corticosteroids for the management of bronchial asthma,
the dosage should be maintained following the introduction of INTAL. If the
patient improves, an attempt to decrease corticosteroids should be made. Even
if the corticosteroid-dependent patient fails to show symptomatic improvement
following INTAL administration, the potential to reduce corticosteroids may
nonetheless be present. Thus, gradual tapering of corticosteroid dosage may
be attempted. It is important that the dose be reduced slowly, maintaining
close supervision of the patient to avoid an exacerbation of asthma.
should be borne in mind that prolonged corticosteroid therapy frequently causes
an impairment in the activity of the hypothalamic-pituitary-adrenal axis and
a reduction in the size of the adrenal cortex. A potentially critical degree
of impairment or insufficiency may persist asymptomatically for some time
even after gradual discontinuation of adrenocortical steroids. Therefore,
if a patient is subjected to significant stress, such as a severe asthmatic
attack, surgery, trauma or severe illness while being treated or within one
year (occasionally up to two years) after corticosteroid treatment has been
terminated, consideration should be given to reinstituting corticosteroid
therapy. When respiratory function is impaired, as may occur in severe exacerbation
of asthma, a temporary increase in the amount of corticosteroids may be required
to regain control of the patient's asthma.
It is particularly
important that great care be exercised if, for any reason, INTAL is withdrawn
in cases where its use has permitted a reduction in the maintenance dose of
corticosteroids. In such cases, continued close supervision of the patient
is essential since there may be sudden reappearance of severe manifestations
of asthma which will require immediate therapy and possible reintroduction
INTAL Nebulizer Solution is a colorless solution supplied
in a low density polyethylene plastic unit dose ampule with 12 ampules per
foil pouch. Each 2 mL ampule contains 20 mg cromolyn sodium, USP, in purified
NDC 60793-010-60...................60 ampules
x 2 mL
NDC 60793-010-12..................120 ampules
x 2 mL
Store at Controlled
Room Temperature 20° to 25°C (68° to 77°F) [see USP].
Protect from light. Do not use if it contains a precipitate or becomes discolored.
Keep out of the reach of children.
Store ampules in foil pouch until ready for use.
a registered trademark King Pharmaceuticals, Inc.
Information as of September 2005
Distributed by: King
Pharmaceuticals, Inc. Bristol, TN 37620
by: Cardinal Health Woodstock, IL 60098 USA
cromolyn sodium inhalant
HUMAN PRESCRIPTION DRUG
Item Code (Source)
Route of Administration
Name (Active Moiety)
cromolyn sodium (cromolyn)
20 MILLIGRAM In 2 MILLILITER
contains a AMPULE
This package is contained within the POUCH (60793-010-60)
contains a AMPULE
This package is contained within the POUCH (60793-010-12)