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Indications: Asthma; Conjunctivitis, allergic
Pregnancy Category B
FDA Approved 1992 Dec
DRUG CLASS: Mast cell stabilizers
BRAND NAMES: Alocril (US);
Mireze (Canada); Telavist (France,
Israel); Tilade (US); Tilade Mint
(Hong-Kong);
(International brand names outside U.S. in italics)
COST OF THERAPY: $ 39.14 (Asthma; Tilade
Inhaler; 1.75 mg/inh; 16 g; 8 inhalations/day; 13 days)
Nedocromil Sodium (Inhalation)
DESCRIPTION:
Note: The trade names have been used throughout this monograph for clarity.
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.
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 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.
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·h/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 6 hours of dosing.
In a multiple dose study, 6 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 7 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 1 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·h/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 3 times a day for 7 days) showed an absolute bioavailability of less than 2%. In a radiolabeled (14C) nedocromil intravenous study involving 2 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 6-11 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 comprises 6469 patients, including 993 pediatric patients 6-11 years of age. Studies have been conducted both at twice daily and at 4 times daily dosage regimens. Evidence from these studies indicates that the 4 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 4 times daily regimen. (See DOSAGE AND ADMINISTRATION.)
Adult Studies
Tilade vs Placebo
The effectiveness of Tilade given 4 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 4 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.
The FEV1 percentage change relative to baseline favored Tilade over placebo throughout the study, with an effect seen first at the 2 week measurement.
| 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† (L) | Week 2 | 2.69 | 2.18 |
| FEV1† (L) | Week 6 | 2.65 | 2.15 |
| FEV1† (L) | Week 10 | 2.55 | 2.15 |
| FEV1† (L) | Week 14 | 2.59 | 2.10 |
| * Tilade significantly better than placebo, p <0.05. | |||
| † Tilade significantly better than placebo, p <0.01. | |||
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 2 weeks.
Tilade vs Cromolyn Sodium vs Placebo
The effectiveness of Tilade was compared to cromolyn sodium and placebo in an 8 week, double-blind, parallel-group, 12-center trial during which medication was given 4 times daily. Three hundred and six (306) 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 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 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 6-11 years of age with mild seasonal ragweed-induced asthma was examined in an 8 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 4 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 2 week baseline, patients were randomized to 8 weeks of double-blind treatment. The results of these evaluations are shown in TABLE 3.
| Variable | Time Period | Tilade Mean | Vehicle Placebo Mean |
|---|---|---|---|
| Summary symptom score*ठ| Weeks 3-8 | 1.38 | 1.99 |
| Bronchodilator use†‡§ | Weeks 3-8 | 0.43 | 0.84 |
| Parent's opinion§ | Week 8 | 2.13 | 2.75 |
| Clinician's opinion§ | Week 8 | 2.16 | 2.74 |
| * Daytime asthma, daytime cough, and sleep disturbance due to asthma (0-15). | |||
| † One unit every 2 inhalations. | |||
| ‡ Adjusted for baseline. | |||
| § Tilade significantly better than placebo, p <0.05. | |||
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.
Tilade Inhaler is indicated for maintenance therapy in the management of adult and pediatric patients 6 years and older with mild to moderate asthma.
Tilade is not indicated for the reversal of acute bronchospasm.
Non-FDA Approved Indications
Although not approved by the FDA, nedocromil is effective in preventing exercise-induced bronchospasm.
Tilade Inhaler is contraindicated in patients who have shown hypersensitivity to nedocromil sodium or other ingredients in this preparation.
Tilade Inhaler is not a bronchodilator and, therefore, should not be used for the reversal of acute bronchospasm, particularly status asthmaticus. Tilade 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 should be discontinued and alternative therapy instituted.
The role of Tilade 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, careful monitoring is necessary.
Information for the Patient
Patients should be told that:
Tilade must be taken regularly to achieve benefit, even during symptom-free
periods.
Tilade 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 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 Inhaler pack.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
A 2 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 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 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 US clinical trials and 192 children from foreign clinical trials (total = 503) of 4-12 weeks duration. An additional 225 children received Tilade for 40 weeks and 24 received Tilade for 52 weeks.
The safety and effectiveness of Tilade in children ages 6-11 have been established in adequate and well-controlled clinical trials. (See CLINICAL STUDIES, Pediatric Studies.) Use of Tilade in children ages 6-11 years is also supported by evidence from adequate and well-controlled studies of Tilade in adults.
The safety and effectiveness of Tilade in patients below the age of 6 years have not been established.
In clinical studies, Tilade has been co-administered with other anti-asthma medications, including inhaled and oral bronchodilators, and inhaled corticosteroids, with no evidence of increased frequency of adverse events or laboratory abnormalities. No formal drug-drug interaction studies, however, have been conducted.
Tilade is generally well tolerated. Adverse event information was derived from 6469 patients receiving Tilade in controlled and open-label clinical trials of 1-52 weeks in duration. A total of 4400 patients received 2 inhalations 4 times a day. An additional 2069 patients received 2 inhalations twice daily or another dose regimen. Seventy-seven percent (77%) of patients were treated with Tilade for 8 weeks or longer.
Of the 4400 patients who received 2 inhalations of Tilade 4 times a day, 2632 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 2446 patients who received placebo.
The reasons for withdrawal were generally similar in the Tilade and placebo-treated groups, except that patients withdrew due to bad taste statistically more frequently on Tilade than on placebo. Headache reported as severe or very severe, some with nausea and ill feeling, was experienced by 1.0% of Tilade 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 or placebo at 2 inhalations 4 times daily.
The adverse event profile observed in children ages 6-11 was similar to that observed in adults.
See TABLE 4.
| % Experienceing AE | % Withdrawing | ||||
|---|---|---|---|---|---|
| Tilade | Placebo | Tilade | Placebo | ||
| Adverse Event (AE) | (n=2632) | (n=2402) | |||
| 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 p <0.05. | |||||
| † Statistically significant higher frequency on placebo p <0.05. | |||||
Other adverse events present at less than the 1% level of occurrence, but that might be related to Tilade administration, include arthritis, tremor, and a sensation of warmth. In clinical trials with 2632 patients receiving Tilade, 2 patients (0.08%) developed neutropenia and 3 patients (0.11%) developed leukopenia. Although it is unclear if these reactions were caused by Tilade, in several cases these abnormal laboratory tests returned to normal when Tilade was discontinued.
There have been reports of clinically significant elevation of hepatic transaminases (ALT and AST greater than 10 times the upper limit of the normal reference range in 1 patient) associated with the administration of Tilade. It is unclear if these abnormal laboratory tests in asymptomatic patients were caused by Tilade.
Cases of bronchospasm immediately following dosing with Tilade have been reported from postmarketing experience. (See WARNINGS.) Isolated cases of pneumonitis with eosinophilia (PIE syndrome) and anaphylaxis have also been reported in which a relationship to drug is undetermined.
There is no experience to date with overdose of Tilade in humans. There were no deaths in rodents at an oral dose of 4000 mg/kg (approximately 690 times (for mice) and 1370 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 2000 and 4000 mg/kg (approximately 690 and 1370 times, respectively, the maximum recommended human daily inhalation dose on a mg/m2 basis). No deaths occurred in mice at a subcutaneous dose of 4000 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 2000 and 4000 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 3 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.
The recommended dosage for adult and pediatric patients 6 years of age and older is 2 inhalations 4 times a day at regular intervals, which provides a dose of 14 mg/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 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 Inhaler may be added to the patient's existing treatment regimen (e.g., bronchodilators). When a clinical response to Tilade 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 therapy depends upon its administration at regular intervals, even during symptom-free periods.
HOW SUPPLIED:
Tilade Inhaler is available in 16.2 g canisters providing at least 104 metered
inhalations. Each Tilade 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 logo. The Tilade canister
is to be used only with the Tilade Inhaler mouthpiece. The Tilade mouthpiece
should not be used with other aerosol medications and 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.
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.
Storage: Store between 2-30°C (36-86°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 "Information For
The Patient" leaflet that is distributed with the prescription 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.
Nedocromil Sodium (Ophthalmic)
DESCRIPTION:
Note: The trade names have been used throughout this monograph for clarity.
Alocril (nedocromil sodium ophthalmic solution) 2% is a clear, yellow, sterile solution for topical ophthalmic use.
Nedocromil sodium has the chemical formula C19H15NNa2O7, and a molecular weight of 415.30.
Chemical Name: 4H-Pyrano[3,2-g] quinoline-2, 8-dicarboxylic acid, 9-ethyl-6,9-dihydro-4, 6-dioxo-10-propyl-, disodium salt.
Each ml Contains:
Active: Nedocromil sodium 20 mg (2%); Preservative: Benzalkonium
chloride 0.01%; Inactives: Sodium chloride 0.5%, edetate disodium 0.05%
and purified water. It has a pH of 4.0-5.5.
CLINICAL PHARMACOLOGY:
Nedocromil sodium is a mast cell stabilizer. Nedocromil sodium inhibits the release of mediators from cells involved in hypersensitivity reactions. Decreased chemotaxis and decreased activation of eosinophils have also been demonstrated.
In vitro studies with adult human bronchoalveolar cells showed that nedocromil sodium inhibits histamine release from a population of mast cells having been defined as belonging to the mucosal subtype and beta-glucuronidase release from macrophages.
Pharmacokinetics and Bioavailability
Nedocromil sodium exhibits low systemic absorption. When administered as a 2% ophthalmic solution in adult human volunteers, less than 4% of the total dose was systemically absorbed following multiple dosing. Absorption is mainly through the nasolacrimal duct rather than through the conjunctiva. It is not metabolized and is eliminated primarily unchanged in urine (70%) and feces (30%).
Alocril is indicated for the treatment of itching associated with allergic conjunctivitis.
Alocril is contraindicated in those patients who have shown hypersensitivity to nedocromil sodium or to any of the other ingredients.
PRECAUTIONS:
Information for the Patient
Patients should be advised to follow the patient instructions listed on the Information for Patients sheet that is distributed with the prescription.
Users of contact lenses should refrain from wearing lenses while exhibiting the signs and symptoms of allergic conjunctivitis.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
A 2 year inhalation carcinogenicity study of nedocromil sodium at a dose of 24 mg/kg/day (approximately 400 times the maximum recommended human daily ocular dose on a mg/kg basis) in Wistar rats 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 (more than 1600 times the maximum recommended human daily ocular dose).
Pregnancy, Teratogenic Effects, Pregnancy Category B
Reproduction studies performed in mice, rats and rabbits using a subcutaneous dose of 100 mg/kg/day (more than 1600 times the maximum human daily ocular dose on a mg/kg 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, Alocril should be used during pregnancy only if clearly needed.
Nursing Mothers
After intravenous administration to lactating rats, nedocromil was excreted in milk. 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 Alocril is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in children below the age of 3 years have not been established.
Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
The most frequently reported adverse experience was headache (∼40%).
Ocular burning, irritation and stinging, unpleasant taste, and nasal congestion have been reported to occur in 10-30% of patients. Other events occurring between 1-10% included asthma, conjunctivitis, eye redness, photophobia,and rhinitis.
Some of these events were similar to the underlying ocular disease being studied.
The recommended dosage is 1 or 2 drops in each eye twice a day.
Alocril should be used at regular intervals.
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), even when symptoms are absent.
HOW SUPPLIED:
Alocril (nedocromil sodium ophthalmic solution)
2% is supplied as 5 ml of solution in a natural, low-density polyethylene round
eye drop bottle with a controlled dropper tip, and a natural polypropylene cap.
Storage: Store between 2-25°C (36-77°F). Keep tightly closed and out of
the reach of children.
| HOW SUPPLIED - EQUIVALENTS NOT
AVAILABLE: |
||||||
| Aerosol with Adapter -- Inhalation -- 1.75 mg/inh | ||||||
| 16 gm | $42.72 | Tilade | Aventis Pharmaceuticals | 00585-0685-02 | ||
| 16.20 gm | $30.05 | Tilade | Aventis Pharmaceuticals | 00075-0685-02 | ||
| Solution -- Ophthalmic -- 2% | ||||||
| 5 ml | $60.96 | Alocril | Allergan Inc | 00023-8842-05 | ||