Indications : Asthma Pregnancy Category B FDA Class 1S (“Standard Review”) FDA Approved 1992 Dec DRUG CLASS : : Antiasthmatics BRAND NAMES : Mireze (Canada); Telavist (France, Israel); Tilade (US); (International brand names outside U.S. in italics) DESCRIPTION : 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. Chemical Class : Pyranoquinoline. nedocromil sodium inhalation aerosol is a pressurized metered-dose aerosol suspension for oral inhalation containing micronized nedocromil sodium, sorbitan trioleate with dichlorotetrafluoroethane and dichlorodifluoromethane as propellants. Each actuation delivers from the mouthpiece 1.75 mg nedocromil sodium. Each 16.2 g canister provides at least 104 metered inhalations. CLINICAL PHARMACOLOGY : Cellular and Animal Studies : 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 the 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. Pharmacokinetics and Bioavailability : Systemic bioavailability of nedocromil sodium administered as an inhaled aerosol is low. In a single dose study involving 20 healthy 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 X 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 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, 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 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 inhalation gave a mean high plasma concentration of 2.8 ng/ml between 5 and 90 minutes, mean AUC of 5.6 ng X 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 study involving two healthy males, urinary excretion accounted for 64% of the dose, fecal excretion for 36%. Protein Binding : nedocromil is approximately 89% protein bound to human plasma over a concentration range of 0.5 to 50 mcg/ml. This binding is reversible. Metabolism : nedocromil is not metabolized after IV administration and is excreted unchanged. CLINICAL STUDIES : 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 intrinsic bronchodilator, antihistamine, or glucocorticoid activity. nedocromil sodium, when delivered by inhalation at the recommended dose, has no known therapeutic systemic activity. The worldwide clinical trial experience with nedocromil sodium comprises 5352 patients. 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. A lower dose (two or three times daily) can be considered in patients under good control on the four times daily regimen (see DOSAGE AND ADMINISTRATION.) nedocromil sodium vs. Placebo : The effectiveness of nedocromil sodium 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 beta-agonists. Two weeks after the test therapies were begun the SRT was discontinued and four weeks after that oral beta-agonists were stopped. Beta-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 or 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; nedocromil sodium was significantly superior to placebo for all measurements. TABLE 1 Variable Time Period Tilade Mean Placebo Mean Daytime Asthma* Weeks 7-14 1.26 2.08 Nighttime Asthma Weeks 7-14 0.67 0.96 Cough* Weeks 7-14 0.68 1.49 Patient’s Opinion Week 14 2.27 3.55 Clinician’s Opinion Week 14 2.13 3.48 FEV1 (liters) Week 2 2.69 2.18 FEV12 (liters) Week 6 2.65 2.15 FEV1 (liters) Week 10 2.55 2.15 FEV1 (liters) Week 14 2.59 2.10 * Tilade significantly better than placebo, p<0.05 Tilade significantly better than placebo, p<0.01 The FEV1 percentage change relative to baseline also favored nedocromil sodium over placebo throughout the study, with an effect seen first at the two week measurement. (For graphic representation of this data, please refer to manufacturer’s original package insert). This study shows that nedocromil sodium improves symptom control and pulmonary function when it is added to a prn inhaled beta-adrenergic bronchodilator regimen and that a beneficial effect could be detected within two weeks. nedocromil sodium vs. Cromolyn Sodium vs. Placebo : The effectiveness of nedocromil sodium was compared to cromolyn sodium and placebo in an eight week, double-blind, parallel group, 12 center trial during which medication was given four times daily. Three hundred and six patients were randomized to treatment (103/nedocromil sodium; 104/cromolyn sodium; 99/placebo). All patients were SRT dependent and this drug was stopped prior to starting the test treatment. Efficacy was assessed on the basis of diary card symptom scores and FEV1. The diary scores were the same as used in the 14 week study except that nighttime symptoms were recorded on a 0-3 scale. The primary efficacy variable was a summary symptom score derived by averaging the scores for daytime asthma, nighttime asthma and cough. The results of the study are shown in TABLE 2. TABLE 2 Variable Time Period Tilade Mean Placebo Mean Cromolyn Sodium Mean Summary Score* Weeks 3-8 1.30 1.76 1.13 Daytime Asthma* Weeks 3-8 1.59 2.05 1.41 Nighttime Asthma Weeks 3-8 0.91 1.23 0.77 Cough Weeks 3-8 1.11 1.58 0.93 FEV1 Weeks 3-8 2.46 2.23 2.56 Patient’s Opinion* Week 8 2.54 3.39 2.22 Clinician’s Opinion* Week 8 2.60 3.43 2.39 * Tilade significantly better than Placebo, p<0.001 Tilade significantly better than Placebo, p<0.01, cromolyn sodium significantly better than Tilade, p<0.05 Tilade significantly better than Placebo, p<0.05 This study corroborates the findings of the 14 week study, showing that nedocromil sodium is effective in the management of symptoms and pulmonary function in primary atopic mild to moderate asthmatics. Both active treatments were statistically significantly better than placebo for the primary efficacy variable (summary symptom score); nedocromil sodium and cromolyn sodium were not significantly different for this parameter. A statistically significant difference favoring cromolyn sodium was, however, seen for nighttime asthma and FEV1. In laboratory studies, pretreatment with nedocromil sodium before an anticipated challenge can prevent the bronchoconstriction associated with sulfur dioxide, cold air, fog, exercise, allergen challenge, adenosine monophosphate, and neurokinin A. Controlled studies have not been carried out to assess the clinical significance of these findings. In allergic asthmatics who are well controlled on cromolyn sodium, there is no evidence that the substitution of nedocromil sodium for cromolyn sodium would confer additional benefit to the patient. Efficacy with one agent is not known to be predictive of efficacy with the other. The presently available data on the relative efficacy of nedocromil sodium and cromolyn sodium are inconclusive. INDICATIONS AND USAGE : nedocromil sodium Inhaler is indicated for maintenance therapy in the management of patients with mild to moderate bronchial asthma. nedocromil sodium is not indicated for the reversal of acute bronchospasm. CONTRAINDICATIONS : nedocromil sodium inhaler is contraindicated in those patients who have shown hypersensitivity to nedocromil sodium or other ingredients in this preparation. WARNINGS : nedocromil sodium Inhaler is not a bronchodilator and, therefore, should not be used for the reversal of acute bronchospasm, particularly status asthmaticus. nedocromil sodium 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, paradoxical bronchospasm, which can be life-threatening, has been reported rarely in postmarketing experience. If it occurs, discontinue treatment with nedocromil sodium immediately and institute alternative therapy. PRECAUTIONS : General : If systemic or inhaled steroid therapy is at all reduced, patients must be monitored carefully. nedocromil sodium has not been shown to be able to substitute for the total dose of steroids. Information for the Patient : nedocromil sodium must be taken regularly to achieve benefit, even during symptom-free periods. Because the therapeutic effect depends upon topical application to the lungs, it is essential that patients be properly instructed in the correct method of use (see PATIENT PACKAGE INSERT.) An illustrated leaflet for the patient is included in each nedocromil sodium inhaler pack Carcinogenesis, Mutagenesis, and Impairment of Fertility : A two-year inhalation chronic/carcinogenicity study of nedocromil sodium in Wistar rats showed no carcinogenic potential. The maximum achievable daily dose of 24 mg/kg corresponded to 86 times the maximum human daily aerosol dose of 0.28 mg/kg (based on eight actuations of 1.75 mg to a 50 kg person). Assuming 5% systemic absorption in man, and comparing calculated exposure to measured exposure in rats, systemic exposure in rats in this study was about 40 times human exposure. A 21-month oral dietary carcinogenicity study of nedocromil sodium performed in B6C3F1 mice with daily doses up to 180 mg/kg showed no carcinogenic potential. Systemic exposure in the mouse, calculated as above for the rats, was about six times that in humans, or about 20 times that in humans based on free drug concentrations in plasma. The exposure of the GI tract in top dose animals corresponded to 643 times the human daily dose since, in man, most of an inhaled dose is subsequently swallowed. nedocromil sodium showed no mutagenic potential in the Ames Salmonella/microsome plate assay, mitotic gene conversion in S. cerevisiae, mouse lymphoma forward mutation and mouse micronucleus assays. Reproduction and fertility studies in mice and rats showed no effects on male or female fertility at subcutaneous doses of 100 mg/kg/day. Pregnancy Category B : Reproduction studies performed in mice, rats, and rabbits using subcutaneous doses of 100 mg/kg/day, revealed no evidence of impaired fertility 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 nedocromil sodium is administered to a nursing woman. Pediatric Use : Safety and effectiveness in children below the age of 12 years have not been established. DRUG INTERACTIONS : nedocromil sodium has been co-administered with other anti-asthma therapies including inhaled and oral bronchodilators and inhaled corticosteroids. There are no known adverse drug interactions. ADVERSE REACTIONS : nedocromil sodium is generally well tolerated. Adverse event information was derived from 5352 patients receiving nedocromil sodium in controlled and open-label clinical trials of 2-52 weeks in duration. A total of 3538 patients received two inhalations four times a day. An additional 1814 patients received two inhalations twice daily or some other dose regimen. Seventy-three percent of patients were exposed to study drug for eight weeks or longer. Of the 3538 patients who received two inhalations of nedocromil sodium four times a day, 2042 were in placebo-controlled trials and of these 7% withdrew from the trials due to adverse events, compared to 6% of the 1875 patients who received placebo. The reasons for withdrawal were generally similar in the nedocromil sodium and placebo-treated groups, except that patients withdrew due to bad taste statistically more frequently on nedocromil sodium than on placebo. Headache reported as severe or very severe was experienced by 1.2 percent of nedocromil sodium patients and 0.9 percent of placebo patients, some with nausea and ill feeling. The events reported with a frequency of 1% or greater across all placebo-controlled studies are displayed below (TABLE 3) for all patients who received nedocromil sodium or placebo at two inhalations four times daily. TABLE 3 % Experiencing AE % Withdrawing Tilade Placebo Tilade Placebo Adverse Event (n=2042) (n=1875) Special Senses Unpleasant Taste* 12.6% 3.6% 2.1% 0.4% Respiratory System Disorders Coughing 7.0 7.2 1.4 1.4 Pharyngitis 5.7 5.0 0.6 0.5 Rhinitis* 4.6 3.0 0.1 0.1 Upper Respiratory Tract Infection* 3.9 2.4 0.1 0.1 Sputum Increased 1.7 1.4 0.1 0.2 Bronchitis 1.2 1.3 0.1 0.1 Dyspnea 2.8 3.8 0.9 1.3 Bronchospasm 5.4 8.2 1.5 2.3 Gastro-Intestinal Tract Nausea* 4.0% 2.1% 1.3% 0.7% Vomiting* 1.7 0.9 0.2 0.4 Dyspepsia* 1.3 0.6 0.1 0.1 Mouth Dry 1.0 0.9 0.1 0.2 Diarrhea 0.9 0.6 0.1 0.0 Abdominal Pain* 1.2 0.5 0.2 0.1 Central and Peripheral Nervous System Dizziness 0.9 1.2 0.1 0.2 Dysphonia 1.0 0.6 0.1 0.1 Body as a Whole Headache 6.0 4.7 0.5 0.3 Chest Pain 4.0 3.9 0.9 0.6 Fatigue 1.1 0.7 0.2 0.1 Resistance Mechanism Disorders Infection Viral 2.4 3.4 0.1 0.1 * Statistically significant (p0.05) higher frequency of events on Tilade. Statistically significant (p0.05) higher frequency of events on Placebo. Table includes data from double-blind group comparative studies at four times per day dosing. Other adverse events present at less than the 1% level of occurrence, but that might be related to nedocromil sodium administration, include rash, arthritis, tremor and a sensation of warmth. Elevations of SGPT were noted in 3.3% of patients on nedocromil sodium vs. 1.7% on placebo. The average elevation over placebo was 10 I.U. with only two patients increasing by more than 100 I.U. and none becoming ill. The clinical significance of these elevations is unclear. Rare cases of paradoxical bronchospasm (see WARNINGS) have been reported from postmarketing experience. Isolated cases of pneumonitis with eosinophilia (PIE syndrome) and anaphylaxis have also been reported in which a relationship to drug is undetermined. OVERDOSAGE : There is no experience to date with overdose of nedocromil sodium in humans. Animal studies by several routes of administration (inhalation, oral, intravenous, subcutaneous) have demonstrated little potential for significant toxicity in humans from inhalation of high doses of nedocromil sodium. Head shaking/tremor and salivation were observed in beagle dogs following daily inhalation doses of 5 mg/kg and transient hypotension was detected following daily subcutaneous doses of 8 mg/kg. 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 levels of 7.6 mcg/ml, some three orders of magnitude greater than peak plasma levels (2.5 ng/ml) of the human daily 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. DOSAGE AND ADMINISTRATION : The recommended dosage for symptomatic adults and children (12 years of age and over) is two inhalations four times a day at regular intervals to provide 14 mg of nedocromil sodium per day. Maintenance therapy should be initiated at the same dose. In patients under good control on four times daily dosing (i.e., patients whose only medication need is occasional [not more than twice a week] inhaled or oral beta-agonists, and who have no serious exacerbations with respiratory infections) a lower dose can be tried. If use of lower doses is attempted, nedocromil sodium should first be reduced to a three times daily regimen (10.5 mg of nedocromil sodium per day) then, after several weeks on continued good control, to twice a day (7 mg of nedocromil sodium per day). nedocromil sodium inhaler should be added to the patient’s existing treatment regimen (e.g., bronchodilators). When a clinical response to nedocromil sodium Inhaler is evident and if the asthma is under good control, an attempt may be made to decrease concomitant medication usage gradually. Proper inhalational technique is essential (see PATIENT PACKAGE INSERT.) Patients should be advised that the optimal effect of nedocromil sodium therapy depends upon its administration at regular intervals, even during symptom-free periods. PATIENT PACKAGE INSERT : Metered-Dose Inhaler : The following is one of several acceptable inhalation techniques. If your physician has suggested another method, you should use that method. (For graphic representation of the following steps, please consult an original copy of the PATIENT PACKAGE INSERT.) 1. To use the nedocromil sodium Inhaler, remove the Mouthpiece Cover and make sure the metal Canister is firmly inserted into the plastic Mouthpiece. Do not remove the Valve Cover from the metal Cannister. 2. Shake the Inhaler. 3. Hold the Inhaler away from your mouth, and exhale slowly. Do not breathe into the Inhaler as moisture could cause it to clog. 4. 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. 5. 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. After you have finished your full breath, release the pressure of your finger from the top of the Canister. 6. Remove the Inhaler from your mouth, and hold your breath for several seconds before breathing out slowly. This step is very important because it allows the medication to spread throughout your lungs. 7. Repeat Steps 2-6; then replace the Mouthpiece Cover. 8. Keeping the plastic Mouthpiece clean is extremely important to prevent medication build-up and blockage. To clean, simply remove the Canister and Mouthpiece Cover, and wash the Mouthpiece through the top and bottom in HOT water. 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 Mouthpiece air dry in warm place overnight. When the Mouthpiece is completely dry, replace Canister and Mouthpiece Cover. Suggestions for Best Results 1. 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. 2. Before using the Inhaler for the very first time, or the first time in a while, shake the Inhaler and give it one press in the upright position to be sure it’s working properly. Note : The Valve Cover should not be removed from the Canister (see Step 1 under Instructions). 3. It is essential that the Canister be pressed at exactly the time as you inhale. It is well worth your time to review this technique with your physician. 4. 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 4 & 5 under Instructions). 5. Keep the Mouthpiece Cover on the Inhaler when not in use so that dirt can’t get into it. Dosage For the treatment of mild to moderate asthma in patients 12 years of age or 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 range from four times a day to twice a day at regular intervals. With regular use, nedocromil sodium will decrease asthma symptoms. However, nedocromil sodium 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 nedocromil sodium is not a steroid medication. Benefits which may be achieved from regular use of nedocromil sodium 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. Storage : Store the Inhaler between 2°-30°C (36°-86°F). Do not freeze. Contents under pressure. Do not puncture, incinerate, place near sources of heat, or use with other mouthpieces. 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. For further information about nedocromil sodium, please call our toll-free number: 1-800-2-ASTHMA (1-800-227-8462). HOW SUPPLIED : Tilade inhaler is available in 16.2 g canisters providing at least 104 metered inhalations. Available in single and double canister packs. Each pack is supplied with patient instructions and white plastic mouthpiece(s), one per canister, bearing the Tilade logo. One 16.2 g Canister: (104 Metered Inhalations) Two 16.2 g Canisters: (2 x 104 Metered Inhalations) Store between 2°-30°C (36°-86°F). Do not freeze. Contents under pressure. Do not puncture, incinerate, place near sources of heat or use with other mouthpieces. 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.