Tilade

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 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 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).

Patientsshould be advised that the optimal effect of Tilade therapy depends upon its administration at regular intervals, even during symptom-free periods.

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 mouthpiece should not be used with other aerosol medications and the Tilade 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 60793-120-01 ........................ 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.

Rx only

Prescribing Information as of September 2005.

Distributed by: King Pharmaceuticals, Inc., Bristol, TN 37620

Manufactured by: Aventis Pharma LTD, Holmes Chapel CW48BE, United Kingdom

Made in United Kingdom

Tilade® Inhaler (NEDOCROMIL SODIUM INHALATION AEROSOL)

Metered-Dose Inhaler

Rx Only

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, 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.