(NEDOCROMIL SODIUM INHALATION AEROSOL)
Tilade (nedocromil sodium) is an inhaled anti-inflammatory agent for the preventive management of asthma. Nedocromil sodium is a pyranoquinoline with the chemical name 4 H -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 dichlorotetrafluoro ethane 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 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.
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 50µg/mL. This binding is reversible.
Metabolism: Nedocromil is not metabolized after IV administration and is excreted unchanged.
The worldwide clinical trial experience with Tilade 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 vs. Placebo: The effectiveness of Tilade 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 was significantly superior to placebo for all measurements.
| 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|
|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|
|1 Tilade significantly better than Placebo, p<0.05|
|2 Tilade significantly better than Placebo, p<0.01|
The FEV1 percentage change relative to baseline is shown in Figure 1; these also favored Tilade over placebo throughout the study, with an effect seen first at the two week measurement.
This study shows that Tilade improves symptom control and pulmonary function when it is added to an as-needed inhaled beta2-adrenergic bronchodilator regimen and that a beneficial effect could be detected within two weeks.
Tilade vs. Cromolyn Sodium vs. Placebo: The effectiveness of Tilade 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/ Tilade; 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.
| Variable || Time Period || Tilade Mean || Placebo Mean || Cromolyn Sodium Mean |
|Summary Score1||Weeks 3–8||1.30||1.76||1.13|
|Daytime Asthma1||Weeks 3–8||1.59||2.05||1.41|
|Nighttime Asthma2||Weeks 3–8||0.91||1.23||0.77|
|Patient’s Opinion1||Week 8||2.54||3.39||2.22|
|Clinician’s Opinion1||Week 8||2.60||3.43||2.39|
|1 Tilade significantly better than Placebo, p<0.001|
|2 Tilade significantly better than Placebo, p<0.01, cromolyn sodium significantly better than Tilade, p<0.05|
|3 Tilade significantly better than Placebo, p<0.05|
This study corroborates the findings of the 14-week study, showing that Tilade is effective in the management of symptoms and pulmonary function in primarily atopic mild to moderate asthmatics. Both active treatments were statistically significantly better than placebo for the primary efficacy variable (summary symptom score); Tilade 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 allergic asthmatics who are well controlled on cromolyn sodium, there is no evidence that the substitution of Tilade for cromolyn sodium would confer additional benefit to the patient.
Available data on the relative efficacy of Tilade and cromolyn sodium are inconclusive and efficacy with one agent is not known to be predictive of efficacy with the other.
Pediatric Studies: Tilade vs. Placebo in Pediatric Patients: The effectiveness of Tilade in minimizing the anticipated seasonal increase in asthmatic symptoms in pediatric patients 6 through 11 years of age with mild seasonal ragweed-induced asthma was examined in an eight-week, double-blind, placebo-controlled, parallel-group trial in nine centers in 146 patients (75/ Tilade ; 71/placebo). These patients had a mean baseline FEV1 that was 85% of predicted normal and a mean baseline beta2-agonist requirement of less than 2 inhalations of albuterol from a metered dose inhaler per day. Study medication was given four times a day. Efficacy was assessed on the basis of diary card symptom scores (daytime asthma, sleep disturbance, daytime cough, and morning asthma, all rated on a six point scale: 0=no symptoms; 5=severe symptoms) and as-needed bronchodilator use. The primary efficacy variable was based on both the summary symptom score (total of daytime asthma, daytime cough, and sleep disturbance) and as-needed bronchodilator usage. At the end of the treatment phase, parents and clinicians assessed treatment effectiveness on a five-point scale: 1=very effective; 5=made condition worse. After a two-week baseline, patients were randomized to eight weeks of double-blind treatment. The results of these evaluations are shown in Table 3.
| Comparison of Scores for Tilade and Placebo During the Primary Time Period of Evaluation |
| Variable || Time Period || Tilade Mean || Vehicle Placebo Mean |
|Summary Symptom Score1,3,4 ||Weeks 3–8||1.38||1.99|
|Bronchodilator Use2,3,4||Weeks 3–8||0.43||0.84|
|Parent’s Opinion4||Week 8||2.13||2.75|
|Clinician’s Opinion4||Week 8||2.16||2.74|
|1 Daytime asthma, daytime cough, and sleep disturbance due to asthma (0–15) |
|2 One unit for every two inhalations |
|3 Adjusted for baseline |
|4 Tilade significantly better than Placebo, p<0.05|
The percentage change from baseline in summary symptom score by week is shown in Figure 2.
This study shows that Tilade, when used prophylactically in asthmatics with known seasonal exacerbations, can attenuate an increase in symptoms of asthma and reduce the need for rescue bronchodilator treatment.
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