Prescription Drugs

CLINICAL PHARMACOLOGY General: Nedocromil sodium has been shown to inhibit the in vitro activation of, and mediator release from, a variety of inflammatory cell types associated with asthma, including eosinophils, neutrophils, macrophages, mast cells, monocytes, and platelets. In vitro studies on cells obtained by bronchoalveolar lavage from antigen-sensitized macaque monkeys show that nedocromil sodium inhibits the release of mediators including histamine, leukotriene C4, and prostaglandin D2. Similar studies with human bronchoalveolar cells showed inhibition of histamine release from mast cells and beta-glucuronidase release from macrophages. Nedocromil sodium has been tested in experimental models of asthma using allergic animals and shown to inhibit the development of early and late bronchoconstriction responses to inhaled antigen. The development of airway hyper-responsiveness to nonspecific bronchoconstrictors was also inhibited. Nedocromil sodium reduced antigen-induced increases in airway microvasculature leakage when administered intravenously in a model system. In humans, nedocromil sodium has been shown to inhibit acutely the bronchoconstrictor response to several kinds of challenge. Pretreatment with single doses of nedocromil sodium inhibited the bronchoconstriction caused by sulfur dioxide, inhaled neurokinin A, various antigens, exercise, cold air, fog, and adenosine monophosphate. Nedocromil sodium has no bronchodilator, antihistamine, or corticosteroid activity. Nedocromil sodium, when delivered by inhalation at the recommended dose, has no known systemic activity. Pharmacokinetics and Bioavailability: Systemic bioavailability of nedocromil sodium administered as an inhaled aerosol is low. In a single dose study involving 20 healthy adult subjects who were administered a 3.5 mg dose of nedocromil sodium (2 actuations of 1.75 mg each), the mean AUC was 5.0 ng·hr/mL and the mean Cmax was 1.6 ng/mL attained about 28 minutes after dosing. The mean half-life was 3.3 hours. Urinary excretion over 12 hours averaged 3.4% of the administered dose, of which approximately 75% was excreted in the first six hours of dosing. In a multiple dose study, six healthy adult volunteers (3 males and 3 females) received a 3.5 mg single dose followed by 3.5 mg four times a day for seven consecutive days. Accumulation of the drug was not observed. Following single and multiple dose inhalations, urinary excretion of nedocromil accounted for 5.6% and 12% of the drug administered, respectively. After intravenous administration to healthy adults, urinary excretion of nedocromil was approximately 70%. The absolute bioavailability of nedocromil was thus 8% (5.6/70) for single and 17% (12/70) for multiple inhaled doses. Similarly, in a multiple dose study of 12 asthmatic adult patients, each given a 3.5 mg single dose followed by 3.5 mg four times a day for one month, both single dose and multiple dose inhalations gave a mean high plasma concentration of 2.8 ng/mL between 5 and 90 minutes, mean AUC of 5.6 ng-hr/mL, and a mean terminal half-life of 1.5 hours. The mean 24-hour urinary excretion after either single or multiple dose administration represented approximately 5% of the administered dose. Studies involving very high oral doses of nedocromil (600 mg single dose, and subsequently 200 mg three times a day for seven days) showed an absolute bioavailability of less than 2%. In a radiolabeled (14C) nedocromil intravenous study involving two healthy adult males, urinary excretion accounted for 64% of the dose, fecal excretion for 36%. Although minimal pharmacokinetic data are available in children between the ages of 6 and 11 years, the nedocromil sodium levels obtained at 1 hour after chronic dosing in this age group appear to be similar to those observed in adults. Protein Binding: Nedocromil is approximately 89% protein bound in human plasma over a concentration range of 0.5 to 50 µg/mL. This binding is reversible. Metabolism: Nedocromil is not metabolized after IV administration and is excreted unchanged. Clinical Studies The worldwide clinical trial experience with Tilade (nedocromil inhalation aerosol) comprises 6,469 patients, including 993 pediatric patients 6 through 11 years of age. Studies have been conducted both at twice daily and at four times daily dosage regimens. Evidence from these studies indicates that the four times daily regimen has been more effective than the twice daily regimen. Less frequent administration can be considered in patients under good control on the four times daily regimen. (See DOSAGE AND ADMINISTRATION.) Adult Studies: Tilade (nedocromil inhalation aerosol) vs. Placebo: The effectiveness of Tilade (nedocromil inhalation aerosol) given four times daily was examined in a 14-week, double-blind, placebo-controlled, parallel-group trial in five centers in 120 patients (60/treatment). To be eligible for entry, the asthmatic patients had to be controlled using only sustained-release theophylline (SRT) and beta2-agonists. Two weeks after the test therapies were begun the SRT was discontinued and four weeks after that oral beta2-agonists were stopped. Beta2-agonist metered dose inhalers could still be used after 6 weeks. Efficacy was assessed by symptom scores recorded on diary cards completed on a daily basis by the patients. Each morning the patient recorded nighttime asthma on a 0-2 scale, (0=slept well, no asthma; 1=woke once because of asthma; 2=woke more than once because of asthma). Before bedtime the patients recorded daytime asthma and cough on a 0-5 scale (0=no symptoms of asthma/cough today; 5=asthma/cough symptoms were noticed most of the day and caused a lot of trouble). At the end of the treatment phase, patients and clinicians were asked for their opinions on the effectiveness of the treatment based on a five point scale (1=very effective; 5=made condition worse). The results of these evaluations are shown in Table 1; Tilade (nedocromil inhalation aerosol) was significantly superior to placebo for all measurements. Table 1 Variable Time Period Tilade Mean Placebo Mean Daytime Asthma1 Weeks 7-14 1.26 2.08 Nighttime Asthma2 Weeks 7-14 0.67 0.96 Cough1 Weeks 7-14 0.68 1.49 Patient's Opinion2 Week 14 2.27 3.55 Clinician's Opinion2 Week 14 2.13 3.48 FEV12 (liters) Week 2 2.69 2.18 FEV12(liters) Week 6 2.65 2.15 FEV12(liters) Week 10 2.55 2.15 FEV12 (liters) Week 14 2.59 2.10 1Tilade (nedocromil inhalation aerosol) significantly better than Placebo, p

Tilade® Inhaler (nedocromil sodium) Inhalation Aerosol DESCRIPTION Tilade (nedocromil sodium) is an inhaled anti-inflammatory agent for the preventive management of asthma. Nedocromil sodium is a pyranoquinoline with the chemical name 4H-Pyrano[3,2-g]quinoline-2,8-dicarboxylic acid, 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-, disodium salt, and it has a molecular weight of 415.3. The empirical formula is C19H15NNa2O7. Nedocromil sodium, a yellow powder, is soluble in water. The molecular structure of nedocromil sodium is: Chemical Class: Pyranoquinoline Tilade Inhaler (nedocromil sodium inhalation aerosol) is a pressurized metered-dose aerosol suspension for oral inhalation containing micronized nedocromil sodium and sorbitan trioleate, as well as dichlorotetrafluoroethane and dichlorodifluoromethane as propellants. Each Tilade canister contains 210 mg nedocromil sodium. Each actuation meters 2.00 mg nedocromil sodium from the valve and delivers 1.75 mg nedocromil sodium from the mouthpiece. Each 16.2 g canister provides at least 104 metered actuations. After 104 metered actuations, the amount delivered per actuation may not be consistent and the unit should be discarded. Each Tilade (nedocromil inhalation aerosol) Inhaler canister must be primed with 3 actuations prior to the first use. If a canister remains unused for more than 7 days, then it should be reprimed with 3 actuations.

INDICATIONS Tilade (nedocromil inhalation aerosol) Inhaler is indicated for maintenance therapy in the management of adult and pediatric patients 6 years and older with mild to moderate asthma. Tilade (nedocromil inhalation aerosol) is not indicated for the reversal of acute bronchospasm. DOSAGE AND ADMINISTRATION The recommended dosage for adult and pediatric patients 6 years of age and older is two inhalations four times a day at regular intervals, which provides a dose of 14 mg per day. In patients whose asthma is well controlled on this dosage (e.g., patients who only need occasional inhaled or oral beta2-agonists and who are not experiencing serious exacerbations), less frequent administration may be effective. Each Tilade (nedocromil inhalation aerosol) Inhaler canister must be primed with 3 actuations prior to the first use. If a canister remains unused for more than 7 days, then it should be reprimed with 3 actuations. Tilade (nedocromil inhalation aerosol) Inhaler may be added to the patient's existing treatment regimen (e.g., bronchodilators). When a clinical response to Tilade (nedocromil inhalation aerosol) Inhaler is evident and if the patient's asthma is under good control, an attempt may be made to decrease concomitant medication usage gradually. Proper inhalational technique is essential (see Patient Instructions for Use). Patients should be advised that the optimal effect of Tilade (nedocromil inhalation aerosol) therapy depends upon its administration at regular intervals, even during symptom-free periods. HOW SUPPLIED Tilade (nedocromil inhalation aerosol) Inhaler is available in 16.2 g canisters providing at least 104 metered inhalations. Each Tilade (nedocromil inhalation aerosol) canister contains 210 mg nedocromil sodium. Each pack is supplied with patient instructions, a tan-colored rubber valve cover, and white plastic mouthpiece and cover, bearing the Tilade (nedocromil inhalation aerosol) logo. The Tilade (nedocromil inhalation aerosol) mouthpiece should not be used with other aerosol medications and the Tilade (nedocromil inhalation aerosol) canister should not be used with other mouthpieces. Each actuation meters 2.00 mg nedocromil sodium from the valve and delivers 1.75 mg nedocromil sodium from the mouthpiece. NDC 0585-0685-02 One 16.2 g Canister (104 Metered Inhalations) The canister should be discarded after the labeled number of actuations have been used. The amount of medication in each actuation cannot be assured after this point. Store between 2 to 30°C (36 to 86°F). Do not freeze. Avoid spraying in eyes. Contents under pressure. Do not puncture, incinerate, place near sources of heat, or use with other mouthpieces. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire or incinerator. Keep out of the reach of children. For best results, the canister should be at room temperature before use. Shake well before using. Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs). WARNING: Contains CFC-12 and CFC-114, substances which harm public health and the 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 insert under the Environmental Protection Agency's (EPA's) regulations. The patient's warning states that the patient should consult his or her physician if there are questions about alternatives. Distributed by: King Pharmaceuticals™, Inc. Bristol, TN 37620. Manufactured by: Aventis Pharma LTD, Holmes Chape,l Cheshire CW48B3, United Kingdom. FDA rev date:

PATIENT INFORMATION Tilade® INHALER (NEDOCROMIL SODIUM INHALATION AEROSOL) Metered-Dose Inhaler This leaflet does not contain the complete information about your medication. If you have any further questions, or are not sure about something, you should ask your doctor or pharmacist. You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished this canister. TELL YOUR DOCTOR BEFORE STARTING TO TAKE THIS MEDICINE: if you are pregnant (or intending to become pregnant), if you are breast-feeding a baby, if you are allergic to Tilade (nedocromil inhalation aerosol) , or any other components of the drug product. In some circumstances, this medication may not be suitable and your doctor may wish to give you a different medicine. Make sure that your doctor knows what other medicines you are taking. DO NOT use after the date shown as "EXP" on the label or box. INSTRUCTIONS FOR USE The following is one of several acceptable inhalation techniques. If your physician has suggested another method, you should use that method. 1. To use the Tilade (nedocromil inhalation aerosol) Inhaler, remove the Mouthpiece Cover and make sure the metal Canister is fully and firmly inserted into the plastic Mouthpiece. Do not remove the Valve Cover from the metal Canister (Figures 1a & 1b). 2. To prepare your Tilade (nedocromil inhalation aerosol) Inhaler for use, the Inhaler must be primed prior to the first use. To prime, hold the Inhaler upright, with the Mouthpiece facing away from you. Shake the Inhaler, then press firmly downward on the Canister. Repeat this procedure again until a total of three (3) sprays are released. Your Tilade (nedocromil inhalation aerosol) Inhaler is now ready for use. Repriming is only necessary when your Inhaler remains unused for more than 7 days. To reprime, shake the Inhaler and release one spray. Repeat this procedure until a total of three (3) sprays are released. 3. Hold the Inhaler (as illustrated in Figure 2) and shake well before each use. The Mouthpiece should be inspected for the presence of foreign objects before use. For optimal results, the Canister should be at room temperature before use. 4. Avoid spraying in eyes. 5. Hold the Inhaler away from your mouth, as shown, and exhale slowly. Do not breathe into the Inhaler as moisture could cause it to clog (Figure 3). 6. Place the Mouthpiece in your mouth and close your lips around it. Tilt your head back, keeping your tongue below the opening of the Inhaler (Figure 4). 7. Press the top of the Canister down firmly at exactly the same time as you begin to inhale. Keep the Canister depressed as you continue to inhale slowly through your mouth until you have taken a full breath (Figure 5). After you have finished your full breath, release the pressure of your finger from the top of the Canister. 8. Remove the Inhaler from your mouth, and hold your breath as long as comfortably possible before breathing out slowly. This step is very important because it allows the medication to spread throughout your lungs. 9. Repeat Steps 3-8; then replace the Mouthpiece Cover. 10. Keeping the plastic Mouthpiece clean is extremely important to prevent medication buildup and blockage. To clean, simply remove the Canister and Mouthpiece Cover, and wash the Mouthpiece through the top and bottom in HOT water (Figures 6 & 7). Never immerse the metal Canister in water. The Mouthpiece can be washed every day, and should be washed at least twice a week. To dry, shake off excess water and let the Mouthpiece air dry in a warm place overnight. When the Mouthpiece is completely dry, replace the Canister and Mouthpiece Cover. FOR BEST RESULTS Use the Inhaler every day, as directed by your physician. Do not stop the treatment, or even reduce the dosage during symptom-free periods, without your physician's permission. Remember, your Tilade (nedocromil inhalation aerosol) Inhaler must be primed prior to the first use. Repriming is only necessary when the Inhaler remains unused for more than 7 days. Do not reprime between more frequent usage. (See Step 2 under INSTRUCTIONS FOR USE.) Note: The Valve Cover should not be removed from the Canister (see Step 1 under INSTRUCTIONS FOR USE). It is essential that the Canister be pressed at exactly the same time as you inhale. It is well worth your time to review this technique with your physician. The dose delivered from the Inhaler can be seen as a fine mist. If you notice this mist escaping from your mouth or nose, you may not be breathing in at the exact moment the Canister is being pressed (see Steps 6 & 7 under INSTRUCTIONS FOR USE). Keep the Mouthpiece Cover on the Inhaler when not in use so that dirt can't get into it. Keep a record of the number of sprays used and discard the Canister after 104 sprays. The amount of medication in each spray cannot be assured after 104 sprays. Please note that the Canister has been filled with extra suspension to accommodate the initial priming activity. The Tilade (nedocromil inhalation aerosol) Canister is to be used only with the Tilade (nedocromil inhalation aerosol) Inhaler Mouthpiece and should not be used with other mouthpieces. In addition, the Tilade (nedocromil inhalation aerosol) Mouthpiece should not be used with canisters of other inhaled medications. While taking Tilade (nedocromil inhalation aerosol) Inhaler, other inhaled drugs should be taken only as directed by your physician. PRODUCT UTILIZATION For the treatment of mild to moderate asthma in patients 6 years of age and older, the recommended dosage is two (2) inhalations four times a day at regular intervals. For maintenance therapy, daily dosing frequency will depend upon your physician's assessment of your asthma and may be four times a day or less at regular intervals. With regular use, Tilade (nedocromil inhalation aerosol) will decrease asthma symptoms. However, Tilade (nedocromil inhalation aerosol) will not relieve the symptoms of an asthma attack once the attack has started. It is important that you follow your physician's daily dosing instructions - even during symptom-free periods - to achieve optimal benefit from this medication. Please note that Tilade (nedocromil inhalation aerosol) is not a steroid medication. Benefits which may be achieved from regular use of Tilade (nedocromil inhalation aerosol) include: Prevention or reduction of asthma symptoms such as wheezing, chest tightness, cough, and shortness of breath. Treatment of the bronchial inflammation that causes asthma. Tilade (nedocromil inhalation aerosol) Canisters should only be used with the Tilade (nedocromil inhalation aerosol) Inhaler Mouthpiece. The Tilade (nedocromil inhalation aerosol) Mouthpiece should not be used with canisters of other inhaled medications. Tilade (nedocromil inhalation aerosol) Inhaler will provide at least 104 metered sprays. However, after 104 sprays, the amount of drug delivered per spray may not be consistent. You should keep track of the number of sprays used from each Canister of Tilade (nedocromil inhalation aerosol) Inhaler and discard the Canister after 104 sprays. HOW TO CHECK CONTENTS OF YOUR CANISTER Shaking the Canister will NOT give you a good estimate of how much medication is left. We have included a convenient check-off chart to assist you in keeping track of medication inhalations used. This will help assure that you receive the labeled number of inhalations present. Please note that the Canister has been filled with extra suspension to accommodate the initial priming activity. - Retain with medication or affix to convenient location. - Starting with inhalation #1, check off one circle for each inhalation used. - DISCARD MEDICATION AFTER THE LABELED NUMBER OF INHALATIONS HAVE BEEN USED. - NEVER IMMERSE THE METAL CANISTER IN WATER. STORAGE The contents of Tilade (nedocromil inhalation aerosol) Inhaler are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures over 120°F may cause bursting. Never throw the Canister into a fire or incinerator. Keep out of the reach of children. Store at room temperature. Avoid excessive humidity. Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs). 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.

OVERDOSE There is no experience to date with overdose of Tilade (nedocromil inhalation aerosol) in humans. There were no deaths in rodents at an oral dose of 4,000 mg/kg (approximately 690 times [for mice] and 1,370 times [for rats] the maximum recommended human daily inhalation dose on a mg/m2 basis). The subcutaneous or intravenous lethal dose in rats was between 2,000 and 4,000 mg/kg (approximately 690 and 1,370 times, respectively, the maximum recommended human daily inhalation dose on a mg/m2 basis). No deaths occurred in mice at a subcutaneous dose of 4,000 mg/kg (approximately 690 times the maximum recommended human daily inhalation dose on a mg/m2 basis), and the intravenous lethal dose in mice was between 2,000 and 4,000 mg/kg (approximately 345 and 690 times, respectively, the maximum recommended human daily inhalation dose on a mg/m2 basis). An intravenous dose of 240 mg/kg (approximately 110 times the maximum recommended human daily inhalation dose on a mg/m2 basis) did not produce any deaths in cats. Head shaking/tremor and salivation were observed in beagle dogs following daily inhalation doses of 5 mg/kg (approximately 6 times the maximum recommended human daily inhalation dose on a mg/m2 basis) and transient hypotension was detected following daily subcutaneous doses of 8 mg/kg (approximately 9 times the maximum recommended human daily inhalation dose on a mg/m2 basis). In addition, clonic convulsions were observed in dogs following daily inhalation doses of 20 mg/kg plus subcutaneous doses of 20 mg/kg giving peak plasma nedocromil levels of 7.6 µg/mL, some three orders of magnitude greater than peak plasma levels (2.5 ng/mL) of the maximum recommended human daily inhalation dose. Specific tests designed to evaluate CNS activity demonstrated no effects due to nedocromil sodium, and nedocromil sodium does not pass the blood brain barrier. Therefore, overdosage is unlikely to result in clinical manifestations requiring more than observation and discontinuation of the drug where appropriate. CONTRAINDICATIONS Tilade (nedocromil inhalation aerosol) Inhaler is contraindicated in patients who have shown hypersensitivity to nedocromil sodium or other ingredients in this preparation.

SIDE EFFECTS Tilade (nedocromil inhalation aerosol) is generally well tolerated. Adverse event information was derived from 6,469 patients receiving Tilade (nedocromil inhalation aerosol) in controlled and open-label clinical trials of 1-52 weeks in duration. A total of 4,400 patients received two inhalations four times a day. An additional 2,069 patients received two inhalations twice daily or another dose regimen. Seventy-seven percent of patients were treated with Tilade (nedocromil inhalation aerosol) for eight weeks or longer. Of the 4,400 patients who received two inhalations of Tilade (nedocromil inhalation aerosol) four times a day, 2,632 were in placebo-controlled, parallel trials and of these 6.0% withdrew from the trials due to adverse events, compared to 5.7% of the 2,446 patients who received placebo. The reasons for withdrawal were generally similar in the Tilade (nedocromil inhalation aerosol) and placebo-treated groups, except that patients withdrew due to bad taste statistically more frequently on Tilade (nedocromil inhalation aerosol) than on placebo. Headache reported as severe or very severe, some with nausea and ill feeling, was experienced by 1.0% of Tilade (nedocromil inhalation aerosol) patients and 0.7% of placebo patients. The events reported with a frequency of 1% or greater across all placebo-controlled studies are displayed for all patients ages 6 years and older who received Tilade (nedocromil inhalation aerosol) or placebo at two inhalations four times daily. The adverse event profile observed in children ages 6 through 11 was similar to that observed in adults. % Experiencing AE % Withdrawing ADVERSE EVENT (AE) Tilade (N=2632) Placebo (N=2402) Tilade Placebo Special Senses Unpleasant Taste* 11.6% 3.1% 1.6% 0.0% Respiratory System Disorders Coughing 8.9% 10.2% 1.1% 1.2% Pharyngitis 7.6% 7.5% 0.5% 0.4% Rhinitis* 7.3% 6.0% 0.1% 0.1% Upper Respiratory Infection 6.7% 6.3% 0.1% 0.2% Sputum Increased 1.5% 1.4% 0.1% 0.2% Bronchitis 1.1% 1.5% 0.1% 0.1% Dyspnea 2.5% 3.3% 0.8% 1.0% Bronchospasm** 8.4% 11.8% 1.4% 2.0% Sinusitis 3.3% 4.1% 1.1% 0.0% Respiratory Disorder 0.8% 1.1% 0.0% 0.0% Gastrointestinal Tract Nausea* 3.9% 2.3% 1.1% 0.5% Vomiting* 2.5% 1.6% 0.2% 0.3% Dyspepsia 1.5% 1.1% 0.1% 0.1% Diarrhea 1.3% 1.2% 0.1% 0.0% Abdominal Pain* 1.9% 1.3% 0.2% 0.1% Central and Peripheral Nervous System Dizziness 0.8% 1.3% 0.1% 0.2% Body as a Whole Headache 8.1% 7.5% 0.4% 0.2% Chest Pain 3.6% 3.8% 0.7% 0.5% Fatigue 1.0% 0.8% 0.2% 0.0% Fever 3.1% 3.7% 0.1% 0.1% Resistance Mechanism Disorders Infection Viral 2.4% 3.2% 0.1% 0.1% Vision Disorders Conjunctivitis 1.1% 0.7% 0.0% 0.1% Skin and Appendages Disorders Rash** 0.5% 1.2% 0.1% 0.0% * Statistically significant higher frequency on Tilade (nedocromil inhalation aerosol) , p

WARNINGS Tilade® Inhaler (nedocromil inhalation aerosol) (nedocromil sodium inhalation aerosol) is not a bronchodilator and, therefore, should not be used for the reversal of acute bronchospasm, particularly status asthmaticus. Tilade (nedocromil inhalation aerosol) should ordinarily be continued during acute exacerbations, unless the patient becomes intolerant to the use of inhaled dosage forms. As with other inhaled asthma medications, bronchospasm, which can be life-threatening, may occur immediately after administration. If this occurs, Tilade (nedocromil inhalation aerosol) should be discontinued and alternative therapy instituted. PRECAUTIONS General: The role of Tilade (nedocromil inhalation aerosol) as a corticosteroid-sparing agent in patients receiving oral or inhaled corticosteroids remains to be defined. If systemic or inhaled corticosteroid therapy is reduced in patients receiving Tilade (nedocromil inhalation aerosol) , careful monitoring is necessary. Information for Patients: Patients should be told that: Tilade (nedocromil inhalation aerosol) must be taken regularly to achieve benefit, even during symptom-free periods. Tilade (nedocromil inhalation aerosol) is not meant to relieve acute asthma symptoms. If symptoms do not improve or the patient's condition worsens, the patient should not increase the dosage but should notify the physician immediately. They should not decrease the dose without the physician's knowledge. The recommended dose should not be exceeded. The full therapeutic effect of Tilade (nedocromil inhalation aerosol) may not be obtained for 1 week or longer after initiating treatment. Because the therapeutic effect depends upon local delivery to the lungs, it is essential that patients be properly instructed in the correct method of use (see Patient Instructions for Use). An illustrated leaflet for the patient is included in each Tilade (nedocromil inhalation aerosol) Inhaler pack. Carcinogenesis, Mutagenesis, Impairment of Fertility: A two-year inhalation carcinogenicity study of nedocromil sodium at a dose of 24 mg/kg/day (approximately 8 times the maximum recommended human daily inhalation dose on a mg/m2 basis) in Wistar rats showed no carcinogenic potential. A 21-month oral dietary carcinogenicity study of nedocromil sodium performed in B6C3F1 mice with doses up to 180 mg/kg/day (approximately 30 times the maximum recommended human daily inhalation dose on a mg/m2 basis) showed no carcinogenic potential. Nedocromil sodium showed no mutagenic potential in the Ames Salmonella/microsome plate assay, mitotic gene conversion in Saccharomyces cerevisiae, mouse lymphoma forward mutation, and mouse micronucleus assays. Reproduction and fertility studies in mice and rats showed no effects on male and female fertility at a subcutaneous dose of 100 mg/kg/day (approximately 30 times and 60 times, respectively, the maximum recommended human daily inhalation dose on a mg/m2 basis). Pregnancy: Pregnancy Category B: Reproduction studies performed in mice, rats, and rabbits using a subcutaneous dose of 100 mg/kg/day (approximately 30 times, 60 times, and 116 times, respectively, the maximum recommended human daily inhalation dose on a mg/m2 basis) revealed no evidence of teratogenicity or harm to the fetus due to nedocromil sodium. 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: 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 Tilade (nedocromil inhalation aerosol) is administered to a nursing woman. Pediatric Use: Safety data in normal volunteers and asthmatic patients between the ages of 6 and 11 years are available on a total of 311 children from U.S. clinical trials and 192 children from foreign clinical trials (total = 503) of 4-12 weeks duration. An additional 225 children received Tilade (nedocromil inhalation aerosol) for 40 weeks and 24 received Tilade (nedocromil inhalation aerosol) for 52 weeks. The safety and effectiveness of Tilade (nedocromil inhalation aerosol) in children ages 6 through 11 have been established in adequate and well-controlled clinical trials. (See Clinical Studies: Pediatric Studies.) Use of Tilade (nedocromil inhalation aerosol) in children ages 6 through 11 years is also supported by evidence from adequate and well-controlled studies of Tilade (nedocromil inhalation aerosol) in adults. The safety and effectiveness of Tilade (nedocromil inhalation aerosol) in patients below the age of 6 years have not been established. Geriatric Use: Clinical studies of Tilade (nedocromil inhalation aerosol) 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.