Nasalcrom Cromolyn Sodium

DESCRIPTION

Chemically, cromolyn sodium is the disodium salt of 1,3-bis (2-carboxychromon-5-yloxy)-2-hydroxypropane. The empirical formula is C23H14Na2O11; the molecular weight is 512.34.

Gelatin Capsules

Each gelatin capsule of Gastrocrom (cromolyn sodium, USP) contains 100 mg cromolyn sodium. Cromolyn sodium is a hygroscopic, white powder having little odor. It may leave a slightly bitter aftertaste. It is soluble in water (1 proof in 20) and the resulting solution is neutral. It is intended for oral use.

Pharmacologic Category: Mast cell stabilizer

Therapeutic Category: Antiallergic

Capsules for Inhalation, Inhalation Aerosol, and Inhalation Solution

The active ingredient is cromolyn sodium, USP. It is an inhaled anti-inflammatory agent for the preventive management of asthma. Cromolyn sodium is a water-soluble, odorless, white, hydrated crystalline powder. It is tasteless at first, but leaves a slightly bitter aftertaste.

Capsules for Inhalation: Each cromolyn sodium for inhalation capsule contains 20 mg cromolyn sodium and 20 mg lactose. The contents of the capsule are intended for inhalation use only, with the Spinhaler turbo-inhaler.

Inhalation Aerosol: Cromolyn sodium Inhaler is a metered dose aerosol unit for oral inhalation containing micronized cromolyn sodium, sorbitan trioleate with dichlorotetrafluoroethane and dichlorodifluoromethane as propellants. Each metered inhalation delivers approximately 800 mcg cromolyn sodium through the mouthpiece to the patient. Each 8.1 g canister delivers at least 112 metered inhalations (56 doses); each 14.2 g canister delivers at least 200 metered inhalations (100 doses).

Inhalation Solution: Cromolyn sodium inhalation solution is clear, colorless, sterile, and has a target pH of 5.5.

Each 2 ml ampule of Intal Nebulizer Solution contains 20 mg cromolyn sodium, USP, in purified water.

Nasal Solution

Each milliliter of Nasalcrom Nasal Solution contains 40 mg cromolyn sodium in purified water with 0.01% benzalkonium chloride to preserve and 0.01% EDTA (edetate disodium) to stabilize the solution. Cromolyn sodium nasal solution possesses a natural pH of 4.5-6.5 and negligible titratable acidity.

Pharmacologic Category: Mast cell stabilizer/antiallergic.

Therapeutic Category: Antiallergic.

After priming the delivery system for Nasalcrom, each actuation of the unit delivers a metered spray containing 5.2 mg of cromolyn sodium. The contents of one bottle delivers at least 100 sprays (13 ml bottle) or 200 sprays (26 ml bottle).

INDICATIONS

Gelatin Capsules

Gelatin capsules are indicated in the management of patients with mastocytosis. Use of this product has been associated with improvement in diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching in some patients.

Capsules for Inhalation, Inhalation Aerosol, and Inhalation Solution

Cromolyn sodium 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, cromolyn sodium is given by inhalation on a regular daily basis (see

DOSAGE AND ADMINISTRATION

.) The effect of cromolyn sodium is usually evident after several weeks of treatment, although some patients show an almost immediate response.

Capsules for Inhalation and Inhalation Solution

In patients who develop acute bronchoconstriction in response to exposure to exercise, toluene diisocyanate, environmental pollutants, etc., cromolyn sodium should be given shortly before exposure to the precipitating factor (see

DOSAGE AND ADMINISTRATION

.)

Inhalation Aerosol

If improvement occurs, it will ordinarily occur within the first 4 weeks of administration as manifested by a decrease in the severity of clinical symptoms of asthma, or in the need for concomitant therapy, or both.

In patients who develop acute bronchoconstriction in response to exposure to exercise, toluene diisocyanate, environmental pollutants, known antigens, etc., cromolyn sodium inhaler should be used shortly before exposure to the precipitating factor, i.e., within 10-15 minutes but not more than 60 minutes (see

DOSAGE AND ADMINISTRATION

.) cromolyn sodium inhaler may be effective in relieving bronchospasm in some, but not all, patients with exercise induced bronchospasm.

Nasal Solution

Cromolyn sodium nasal solution is indicated for the prevention and treatment of the symptoms of allergic rhinitis.

DOSAGE AND ADMINISTRATION

Gelatin Capsules

NOT FOR INHALATION. SEE DIRECTIONS FOR USE.

The usual starting dose is as follows:

Adults: Two capsules four times daily one-half hour before meals and at bedtime.

Premature to Term Infants: Not recommended.

Term to 2 years: 20 mg/kg/day in four divided doses. Use of this product in children less than 2 years is not recommended and should be attempted only in those patients with severe incapacitating diseases where the benefits clearly outweigh the risks.

Children 2-12 years: One capsule four times daily one-half hour before meals and bedtime.

If satisfactory control of symptoms is not achieved within two to three weeks the dosage may be increased but should not exceed 40 mg/kg/day (30 mg/kg/day for children six months to two years).

Patients should be advised that the effect of oral cromolyn sodium capsule therapy is dependent upon its administration at regular intervals, as directed.

Maintenance Dose: Once a therapeutic response has been achieved the dose may be reduced to the minimum required to maintain the patient with a lower degree of symptomatology. To prevent relapses, the dosage should be maintained.

Administration: Oral cromolyn sodium capsules should be administered as a solution in water at least 1/2 hour before meals after preparation according to the following directions:

    Open capsule(s) and pour powder contents of capsule(s) into 1/2 glass of hot water.

    Stir until completely dissolved (clear solution).

    Add equal quantity of cold water while stirring.

    DO NOT MIX WITH FRUIT JUICE, MILK OR FOODS.

    Drink all of the liquid.

Capsules for Inhalation

For management of bronchial asthma in adults and children (two years of age and over) who are able to use the Spinhaler turbo-inhaler, the usual starting dosage is the contents of one cromolyn sodium Capsule inhaled four times daily at regular intervals.

Inhalation Aerosol

For management of bronchial asthma in adults and young children (5 years of age and over) who are able to use the inhaler, the usual starting dosage is two metered inhalations four times daily at regular intervals. This dose should not be exceeded. Not all patients will respond to the recommended dose and there is evidence to suggest, at least in younger patients, that a lower dose may provide efficacy.

Inhalation Solution

For management of bronchial asthma in adults and children (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.

Capsules for Inhalation, Inhalation Aerosol, and Inhalation Solution

Patients with chronic asthma should be advised that the effect of cromolyn sodium therapy is dependent upon its administration at regular intervals, as directed. Cromolyn sodium 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 adequately.

Capsules for Inhalation

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 cromolyn sodium Capsule inhaled 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.

Inhalation Aerosol

For the prevention of acute bronchospasm which follows exercise, exposure to cold dry air or environmental agents, the usual dose is two metered inhalations shortly, i.e., 10-15 minutes but not more than 60 minutes, before exposure to the precipitating factor.

Inhalation Solution

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.

Capsules for Inhalation, Inhalation Aerosol, and Inhalation Solution

Cromolyn Sodium Therapy in Relation to Other Treatments for Asthma: Non-steroidal agents: Cromolyn sodium should be added to the patient's existing treatment regimen (e.g., bronchodilators). When a clinical response to cromolyn sodium 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.

Capsules for Inhalation

If concomitant medications are eliminated or required on no more than a p.r.n. basis, the frequency of administration of cromolyn sodium may be titrated downward to the lowest level consistent with the desired effect. The usual decrease is from four capsules to three to two capsules 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 capsules per day, an increase in the dosage of cromolyn sodium and the introduction of, or increase in, symptomatic medications may be needed if the patient's clinical condition deteriorates.

Inhalation Aerosol

If concomitant medications are eliminated or required on no more than a prn basis, the frequency of administration of cromolyn sodium inhaler may be titrated downward to the lowest level consistent with the desired effect. The usual decrease is from two metered inhalations four times daily to three times daily to twice daily. 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 inhalations per day, an increase in the dosage of cromolyn sodium inhaler and the introduction of, or increase in, symptomatic medications may be needed if the patient's clinical condition deteriorates.

Inhalation Solution

If concomitant medications are eliminated or required on no more than a prn basis, the frequency of administration of cromolyn sodium 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 cromolyn sodium and the introduction of, or increase in, symptomatic medications may be needed if the patient's clinical condition deteriorates.

Capsules for Inhalation, Inhalation Aerosol, and Inhalation Solution

Corticosteroids: In patients chronically receiving corticosteroids for the management of bronchial asthma, the dosage should be maintained following the introduction of cromolyn sodium. If the patient improves, an attempt to decrease corticosteroids should be made. Even if the corticosteroid-dependent patient fails to show symptomatic improvement following cromolyn sodium 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.

It 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, cromolyn sodium 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 of corticosteroids.

Nasal Solution

The dose for adults and children 6 years and older is one spray in each nostril 3-4 times daily at regular intervals. If needed, this dose may be increased to one spray to each nostril 6 times daily. The patient should be instructed to clear the nasal passages before administering the spray and should inhale through the nose during administration.

In the management of seasonal (pollenotic) rhinitis, and for prevention of rhinitis caused by exposure to other types of specific inhalant allergens, treatment with cromolyn sodium nasal solution will be more effective if started prior to expected contact with the offending allergen. Treatment should be continued throughout the period of exposure i.e., until the pollen season is over or until exposure to the offending allergen is terminated.

In the management of perennial allergic rhinitis, the effects of treatment with cromolyn sodium nasal solution may become apparent only after two to four weeks of treatment. The concomitant use of antihistamines and/or nasal decongestants may be necessary during the initial phase of treatment, but the need for this type of medication should diminish and may be eliminated when the full benefit of cromolyn sodium nasal solution is achieved.

HOW SUPPLIED

Gelatin Capsules

Each capsules contains 100 mg of cromolyn sodium and is supplied in aluminum cans containing 100 capsules.

Each capsule contains a precisely measured dose. The capsules are intentionally oversized to prevent the powder from spilling when the capsule is opened.

Keep tightly closed and out of the reach of children.

Store between 15°-30°C (59°-86°F).

Capsules for Inhalation

Capsules for inhalation, each containing 20 mg of cromolyn sodium, are available in foil strip packs of 120 capsules. Each yellow and clear capsule is imprinted with the product identification code: Fisons 670

Store capsules between 15°-30°C (59°- 86°F). Keep out of the reach of children. Spinhaler turbo- inhalers are supplied separately in individual containers. The Spinhaler should be replaced after 6 months of use.

Inhalation Aerosol

Intal Inhaler, 8.1 g or 14.2 g canister, box of one. Supplied with mouthpiece and patient instructions.

Store between 15°-30°C (59°-86°F). Contents under pressure. Do not puncture, incinerate, or place near sources of heat. Keep out of the reach of children.

Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's).

Warning: Contains CFC-12 and CFC-114, substances which harm public health and environment by destroying ozone in the upper atmosphere.

A notice similar to the above WARNING has been placed in the "Patient Instructions for Use" portion of this package circular pursuant to EPA regulations.

Inhalation Solution

Intal inhalation 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 water.

Intal inhalation solution should be stored between 15°- 30°C (59°-86°F) and protected 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.

Nasal Solution

Nasalcrom is available in bottles of 13 ml and 26 ml. Each fully assembled unit consists of a pump unit and actuator with cover in position on the bottle of nasal solution. The amount of cromolyn sodium in each bottle is: 13 ml - 520 mg (40 mg/ml); 26 ml - 1040 mg (40 mg/ml).

Nasalcrom should be stored between 15°-30°C (59°-86°F). Protect from light.

 

PATIENT INFORMATION

PATIENT PACKAGE INSERT

Gelatin Capsules

How to Use Cromolyn Sodium Capsules: As with all prescription drugs, follow the directions for dosage that your physician recommends.

The effect of oral cromolyn sodium capsule therapy is dependent upon its administration at REGULAR intervals, for as long as recommended by your physician.

Usual Starting Dose

Adults: Two capsules four times daily one-half hour before meals and at bedtime.

Children 2-12 years: One capsule four times daily one-half hour before meals and at bedtime.

Note: Your physician may decide to increase OR decrease your dosage to achieve optimum results with oral cromolyn sodium capsules. However, do not change your dose or stop taking oral cromolyn sodium capsules without first consulting your physician.

Directions for Use

    Open capsule(s) and pour powder contents into 1/2 glass of hot water.

    Stir until completely dissolved (clear solution).

    Add 1/2 glass of cold water while stirring.

    Drink all of the liquid.

Note: Mix the powder only with water. Do not mix with fruit juice, milk or foods.

Gelatin capsules are most effective when taken in a liquid form. It is not recommended that the capsules be swallowed whole.

Each capsule contains a precisely measured dose. The capsules are intentionally oversized to prevent the powder from spilling when the capsule is opened.

NOT FOR INHALATION

Inhalation Aerosol

Patient Instructions for Use of Intal Inhaler (cromolyn sodium inhalation aerosol) Metered Dose Inhaler

    Make sure the canister is properly inserted into the Inhaler unit. Take the cover off the mouthpiece. Shake the Inhaler gently.

    Hold Inhaler and breathe out slowly. Do not breathe into the Inhaler - it could clog the Inhaler valve.

    Place the mouthpiece into your mouth, close your lips around it, and tilt your head back. Keep your tongue below the opening of the Inhaler.

    Press the top of the metal canister down firmly and breathe in through your mouth at the same time.

    Remove the Inhaler from your mouth. Hold your breath for several seconds, then breathe out slowly. This step is very important. It allows the cromolyn sodium to spread throughout your lungs.

Repeat steps 2-5, then replace the mouthpiece cover.

Hints

    Keep the cap on the Inhaler while not in use so that dirt can't get into it. You can clean the Inhaler by removing the metal canister and rinsing the plastic mouthpiece in warm water.

    Before using the Inhaler for the first time, or if it has not been used for a while, it's a good idea to test it. Just give the canister one press.

    It is essential that the canister be pressed at exactly the same time as you breathe in, so it's worth some time practicing this.

    The dose delivered from the Inhaler can be seen as a fine white mist. If any of this can be seen escaping from your mouth or nose, then you are not using the Inhaler correctly.

    To keep your Inhaler in good working order, do not exhale into the mouthpiece.

Important: Remember--a little time spent taking cromolyn sodium correctly and regularly can save you from countless attacks of asthma and the upheaval they cause.

It must be used everyday as directed by your doctor. Do not stop the treatment or even reduce the dose without consulting your doctor.

Dosage: For management of bronchial asthma in adults and children, the usual starting dosage is two metered inhalations four times a day at regular intervals. When asthma symptoms are well controlled, your doctor may reduce the dose to three times a day, and sometimes two times a day.

For the prevention of acute bronchospasm which follows exercise, exposure to cold dry air, or environmental agents, the usual dosage is two metered inhalations shortly before exposure to the offending factor.

Use as directed by your physician.

Cleaning: Twice a week, remove the metal canister from the plastic mouthpiece. Wash the mouthpiece in warm water and dry thoroughly before replacing the metal canister. Never immerse the metal canister in water.

Storage: Store between 15°-30°C (59°- 86°F). Contents under pressure. Do not puncture, incinerate, or place near sources of heat. Keep out of the reach of children.

Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's).

This product contains CFC-12 and CFC-114, substances which harm the environment by destroying ozone in the upper atmosphere.

Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.

Nasal Solution: 40 mg/ml

How to Use Your Nasalmatic Unit

    Remove the clear plastic Dust Cap from the Tip.

    Remove the yellow Safety Clip beneath the Finger Rests.

    Holding the Unit, place your index and second finger on either side of the Finger Rests and your thumb underneath the Unit.

    Press the Finger Rests down firmly and allow to returnuntil a single spray is delivered. It is only necessary to do this the first time you use the Unit.

    Place the Tip into one nostril and inhale deeply as you press the Finger Rests down firmly. This will release one dose of medication. NOTE: Dose only as directed by your physician.

    Repeat the process in your other nostril.

    Replace Dust Cap and Safety Clip before storing.

Special Tips

    Clear nasal passages before using your Nasalmatic Unit. Your doctor will instruct you if any other medication is required.

    Keep out of the reach of children

CLINICAL PHARMACOLOGY

Gelatin Capsules

In vitro and in vivo animal studies have shown that cromolyn sodium inhibits the release of mediators from sensitized mast cells. Cromolyn sodium acts by inhibiting the release of histamine and leukotrienes (SRS-A) from the mast cell.

Cromolyn sodium has no intrinsic vasoconstrictor, antihistaminic or anti-inflammatory activity.

Cromolyn sodium is poorly absorbed from the gastrointestinal tract. No more than 1% of an administered dose is absorbed by humans after oral administration, the remainder being excreted in the feces. Very little absorption of cromolyn sodium was seen after oral administration of 500 mg by mouth to each of 12 volunteers. From 0.28 to 0.50% of the administered dose was recovered in the first 24 hours of urinary excretion in 3 subjects. The mean urinary excretion of an administered dose over 24 hours in the remaining 9 subjects was 0.45%.

Capsules for Inhalation, Inhalation Aerosol, and Inhalation Solution

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.

Cromolyn 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 pollutants, at least in some patients - (Inhalation Aerosol).

Cromolyn sodium has no intrinsic bronchodilator or antihistaminic 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.

Nasal Solution

In vitro and in vivo animal studies have shown that cromolyn sodium inhibits the degranulation of sensitized mast cells which occurs after exposure to specific antigens. Cromolyn sodium inhibits the release of histamine and SRS-A (the slow-acting substance of anaphylaxis). Rhinitis induced by the inhalation of specific antigens can be inhibited to varying degrees by pretreatment with cromolyn sodium nasal solution.

Another activity demonstrated in vitrois the capacity of cromolyn sodium to inhibit the degranulation of non-sensitized rat mast cells by phospholipase A and the subsequent release of chemical mediators. An additional in vitro study showed that cromolyn sodium did not inhibit the enzymatic activity of released phospholipase A on its specific substrate.

Cromolyn sodium has no intrinsic bronchodilator, antihistaminic or anti-inflammatory activity.

Cromolyn sodium is poorly absorbed from the gastrointestinal tract. After instillation of cromolyn sodium nasal solution, less than 7% of the total dose administered is absorbed and is rapidly excreted unchanged in the bile and urine. The remainder of the dose is expelled from the nose, or swallowed and excreted via the alimentary tract.

SIDE EFFECTS

Gelatin Capsules

Most of the adverse events reported in mastocytosis patients have been transient and could represent symptoms of the disease. The most frequently reported adverse events in mastocytosis patients who have received oral cromolyn sodium capsules during clinical studies were headache and diarrhea. Each occurred in 4 of the 87 patients. Pruritus, nausea, and myalgia were each reported in 3 patients and abdominal pain, rash, and irritability in 2 patients each. One report of malaise was also recorded.

A generally similar profile of adverse events has been reported during studies in other clinical conditions. Additional reports which have been received during the course of these studies and spontaneous reports during foreign marketing include: flushing, urticaria/angioedema, arthralgia, dizziness, fatigue, paresthesia, taste perversion, migraine, psychosis, anxiety, depression, insomnia, behavior change, esophagospasm, flatulence, dysphagia, hepatic function test abnormal, edema, dyspnea, polycythemia, neutropenia, dysuria, hallucinations, skin erythema and burning, burning mouth and throat, stiffness and weakness of the legs, and postprandial lightheadedness and lethargy. These events are infrequent, the majority representing only a single report, and in many cases the causal relationship to oral cromolyn sodium capsules is uncertain.

Capsules for Inhalation

Clinical experience with the use of cromolyn sodium suggests that adverse reactions are rare events. 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.

Inhalation Solution

Clinical experience with the use of cromolyn sodium suggests that adverse reactions are rare events. The following adverse reactions have been associated with cromolyn sodium inhalation solution: cough, nasal congestion, nausea, sneezing, and wheezing.

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.

In addition, adverse reactions have been reported with cromolyn sodium capsules for inhalation. 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.

Capsules for Inhalation and Inhalation Solution

Information on the incidence of adverse reactions to cromolyn sodium has been derived from U.S. postmarketing surveillance experience. The following adverse reactions attributed to cromolyn sodium, 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 lacrimation.

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 and vertigo.

Capsules for Inhalation

The following adverse effects have been reported in less than 1 in 10,000 patients, and are a consequence of the Spinhaler delivery system: inhalation of (capsule) gelatin particles and inhalation of mouthpiece or propeller.

Inhalation Aerosol

In controlled clinical studies of cromolyn sodium inhaler, the most frequently reported adverse reactions attributed to cromolyn sodium treatment were: Throat irritation or dryness, Bad taste, Cough, Wheeze, Nausea.

The most frequently reported adverse reactions attributed to other forms of cromolyn sodium (on the basis of recurrence following readministration) involve the respiratory tract and are: bronchospasm [sometimes severe, associated with a precipitous fall in pulmonary function (FEV1)], cough, laryngeal edema (rare), nasal congestion (sometimes severe), pharyngeal irritation, and wheezing.

Adverse reactions which occur infrequently and are associated with administration of the drug are: anaphylaxis, angioedema, dizziness, dysuria and urinary frequency, joint swelling and pain, lacrimation, nausea and headache, rash, swollen parotid gland, urticaria, pulmonary infiltrates with eosinophilia, substernal burning, and myopathy.

The following adverse reactions have been reported as rare events and it is unclear whether they are attributable to the drug: anemia, exfoliative dermatitis, hemoptysis, hoarseness, myalgia, nephrosis, periarteritic vasculitis, pericarditis, peripheral neuritis, photodermatitis, sneezing, drowsiness, nasal itching, nasal bleeding, nasal burning, serum sickness, stomach ache, polymyositis, vertigo, and liver disease.

Nasal Solution

The most frequent adverse reactions occurring in the 430 patients included in the clinical trials with cromolyn sodium nasal solution were sneezing (1 in 10 patients), nasal stinging (1 in 20), nasal burning (1 in 25), and nasal irritation (1 in 40). Headaches and bad taste were reported in about 1 in 50 patients. Epistaxis, postnasal drip, and rash were reported in less than one percent of the patients. One patient in the clinical trials developed anaphylaxis.

Adverse reactions which have occurred in the use of other cromolyn sodium formulations for inhalation include angioedema, joint pain and swelling, urticaria, cough, and wheezing. Other reactions reported rarely are serum sickness, periarteritic vasculitis, polymyositis, pericarditis, photodermatitis, exfoliative dermatitis, peripheral neuritis, and nephrosis.

DRUG INTERACTIONS

Drug Interaction During Pregnancy

Cromolyn sodium and isoproterenol were studied following subcutaneous injections in pregnant mice. Cromolyn sodium alone in doses of 60 to 540 mg/kg (38 to 338 times the human dose) did not cause significant increases in resorptions or major malformations. Isoproterenol alone at a dose of 2.7 mg/kg (90 times the human dose) increased both resorptions and malformations. The addition of cromolyn sodium (338 times the human dose) to isoproterenol (90 times the human dose) appears to have increased the incidence of both resorptions and malformations.

WARNINGS

Gelatin Capsules: The recommended dosage should be decreased in patients with decreased renal or hepatic function. Severe anaphylactic reactions may occur rarely in association with cromolyn sodium administration.

Capsules for Inhalation and Inhalation Solution: Cromolyn sodium has no role in the treatment of status asthmaticus.

Inhalation Aerosol: Cromolyn sodium inhaler has no role in the treatment of an acute attack of asthma, especially status asthmaticus. Severe anaphylactic reactions can occur after cromolyn sodium administration. The recommended dosage should be decreased in patients with decreased renal or hepatic function. Cromolyn sodium inhaler should be discontinued if the patient develops eosinophilic pneumonia (or pulmonary infiltrates with eosinophilia). Because of the propellants in this preparation, it should be used with caution in patients with coronary artery disease or a history of cardiac arrhythmias.

PRECAUTIONS

General

Gelatin Capsules: In view of the biliary and renal routes of excretion of cromolyn sodium, consideration should be given to decreasing the dosage of the drug in patients with impaired renal or hepatic function.

Inhalation Aerosol and Nasal Solution: In view of the biliary and renal routes of excretion for cromolyn sodium, consideration should be given to decreasing the dosage or discontinuing the administration of the drug in patients with impaired renal or hepatic function.

Capsules for Inhalation, Inhalation Aerosol, and Inhalation Solution: Occasionally, patients may experience cough and/or bronchospasm following cromolyn sodium inhalation. At times, patients who develop bronchospasm may not be able to continue cromolyn sodium administration despite prior bronchodilator administration. Rarely, very severe bronchospasm has been encountered.

Capsules for Inhalation and Inhalation Solution: Symptoms of asthma may recur if cromolyn sodium is reduced below the recommended dosage or discontinued.

Nasal Solution: Some patients may experience transient nasal stinging and/or sneezing immediately following instillation of cromolyn sodium nasal solution. Except in rare occurrences, these experiences have not caused discontinuation of therapy.

Information for the Patient

Capsules for Inhalation and Inhalation Solution: Cromolyn sodium 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.

Capsules for Inhalation: Patients may experience irritation of the throat or coughing after inhalation of the powder. In some cases, rinsing the mouth or taking a drink of water immediately before and/or after using the Spinhaler will eliminate the throat irritation or cough.

If the patient experiences difficulty in emptying the capsule, which may require several deep inhalations, check to make certain the patient is following the directions carefully. A light dusting of powder remaining in the capsule is normal, and is not an indication that the Spinhaler or capsule is faulty or that the proper dose was not delivered. The Spinhaler should be washed in clean, warm water at least once a week, and dried thoroughly before use.

Inhalation Solution: Cromolyn sodium inhalation solution should be used in a power-driven nebulizer with an adequate airflow rate equipped with a suitable face mask or mouthpiece.

For additional information, see the accompanying leaflet entitled "Living a Full Life with Asthma."

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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 no neoplastic effect of cromolyn sodium.

No evidence of chromosomal damage or cytotoxicity was obtained in various mutagenesis studies.

No evidence of impaired fertility was shown in laboratory animal reproduction studies.

Pregnancy

Pregnancy Category B

Reproduction studies with cromolyn sodium administered parenterally to pregnant mice, rats, and rabbits in doses up to 338 times the human clinical dose produced no evidence of fetal malformations. 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. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Gelatin Capsules, Capsules for Inhalation, Inhalation Solution, and Nasal Solution: 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 cromolyn sodium is administered to a nursing woman.

Inhalation Aerosol: It is not known whether this drug is excreted in human milk, therefore, caution should be exercised when cromolyn sodium inhaler is administered to a nursing woman and the attending physician must make a benefit/risk assessment in regard to its use in this situation.

Pediatric Use

Gelatin Capsules: Animal studies suggest increased risk of toxicity in premature animals when given doses much higher than clinically recommended. In term infants up to six months of age, available clinical data suggest that the dose should not exceed 20 mg/kg/day. The use of this product in children less than two years should be reserved for patients with severe disease in which the potential benefits clearly outweigh the risks.

Capsules for Inhalation: Safety and effectiveness in children below the age of 2 years have not been established. For young children unable to utilize the Spinhaler, cromolyn sodium inhalation solution is recommended.

Inhalation Aerosol: Safety and effectiveness in children below the age of 5 years have not been established. For young children unable to utilize the inhaler, cromolyn sodium inhalation solution is recommended. Because of the possibility that adverse effects of this drug could become apparent only after many years, a benefit/risk consideration of the long-term use of cromolyn sodium inhaler is particularly important in pediatric patients.

Inhalation Solution: Safety and effectiveness in children below the age of 2 years have not been established.

Nasal Solution: Safety and effectiveness in children below the age of 6 years have not been established.

OVERDOSE

There is no clinical syndrome associated with an overdosage of cromolyn sodium. Acute toxicity testing in a wide variety of species has demonstrated an extremely low order of toxicity for cromolyn sodium, regardless of whether administration was parenteral, oral or by inhalation. Parenteral administration in mice, rats, guinea pigs, hamsters and rabbits demonstrated an LD50 in the region of 4000 mg/kg. Intravenous administration in monkeys also indicated a similar order of toxicity. The highest dose administered by the oral route in rats and mice was 8000 mg/kg 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.

CONTRAINDICATIONS

Gelatin Capsules and Inhalation Solution: Capsules and Inhalation Solution are contraindicated in those patients who have shown hypersensitivity to cromolyn sodium.

Capsules for Inhalation: Cromolyn sodium is contraindicated in those patients who have shown hypersensitivity to cromolyn sodium or to lactose.

Inhalation Aerosol: Cromolyn sodium inhaler is contraindicated in those patients who have shown hypersensitivity to cromolyn sodium or other ingredients in this preparation.

Nasal Solution: Cromolyn sodium nasal solution is contraindicated in those patients who have shown hypersensitivity to any of the ingredients.