Tilade (Nedocromil Sodium)

TILADE®

Rh´ne-Poulenc Rorer

Nedocromil Sodium

Bronchial Anti-inflammatory Agent

Action and Clinical Uses:

Nedocromil sodium is a new chemical entity that inhibits the release of inflammatory mediators from a variety of cell types occurring in the lumen and in the mucosa of the bronchial tree. When it is administered topically to the bronchi, it displays specific anti-inflammatory properties. Laboratory experiments have shown that nedocromil sodium prevents the release of inflammatory chemotactic and smooth muscle contracting mediators, which are preformed or derived from arachidonic acid metabolism by both the lipoxygenase and cyclo-oxygenase pathways, in a range of human and animal leukocytes. Nedocromil sodium prevents the release of mediators, such as, histamine, leukotriene C 4 (LTC 4) and prostaglandin D 2 (PGD 2) from the cellular population of the chronically inflamed bronchus, especially from mast cells of the mucosal type. There is growing evidence that these mediators are important in human lung disease, and nedocromil sodium may, therefore, be expected to have more scope in the management of chronic reversible obstructive airways disease in which allergy, inflammation and bronchial hyper-responsiveness are significant pathophysiological factors.

After inhalation, nedocromil sodium is deposited throughout the respiratory tract where about 5% of the dose is absorbed. Because nedocromil sodium is inhaled, much of the delivered dose is either swallowed directly or subsequently due to mucociliary clearance from the large airways. A small amount of nedocromil sodium (2 to 3%) is then absorbed from the gastrointestinal tract. Since the absorption rate constant from the respiratory tract is lower than the elimination rate constant in bile and urine, the terminal half-life (1.5 to 2 hours) reflects the absorption rate of the lungs. The drug is cleared rapidly enough from the circulation so that successive doses in the recommended dosing regimen do not accumulate.

Nedocromil sodium is bound reversibly (80%) to human plasma proteins and to a lesser extent in animals. It is not metabolized in man or in animals. In man it is excreted unchanged in the urine (approximately 70%) and in feces (approximately 30%). While the plasma concentration falls rapidly (i.e., to 10% of peak levels in 8 hours) and urinary excretion is 90% complete within 12 hours, fecal elimination may take up to 3 days to be completed.

The pharmacokinetic profile of nedocromil sodium is similar in healthy volunteers and in patients with reversible obstructive airways disease. In challenge studies, a single dose of nedocromil provided protection against bronchospasm provoked by stimulants such as, inhaled allergens, cold air, exercise and atmospheric pollutants.

There is limited data on the pharmacokinetic profile of nedocromil sodium in children.

Indications And Clinical Uses:

As an adjunctive in the treatment of mild to moderate reversible obstructive airways disease, including bronchial asthma and bronchitis, particularly where allergic factors may be present.

Nedocromil sodium can also be used on a maintenance or on an occasional basis in the prevention of bronchospasm provoked by stimulants, such as, inhaled allergens, cold air, exercise and atmospheric pollutants.

Nedocromil sodium may be used safely with other antiasthma drugs. The addition of nedocromil sodium may permit reduction of concomitant therapy.

Contra-Indications:

Known hypersensitivity to nedocromil sodium, to sorbitan trioleate or to propellants, such as, dichlorotetrafluoroethane and dichlorodifluoromethane.

Warnings in Clinical States:

Nedocromil sodium should not be used for the relief of an acute attack of bronchospasm.

Precautions:

In the treatment of asthma, nedocromil sodium should not be used as an alternative to bronchodilators. However, addition of nedocromil sodium to the treatment regimen can reduce the need for concomitant medications. This reduction should be done slowly and under close supervision. The requirements for the reduction of corticosteroids have not been established.:

To ensure optimal delivery to the bronchial tree patients should be carefully instructed in the proper use of the inhaler. For maximum benefit, patients should be reminded of the necessity to take nedocromil sodium regularly, as prescribed.

Physicians should advise patients that to relieve or prevent throat irritation and the unpleasant taste caused by nedocromil sodium, they may gargle or rinse their mouth after use.

Abuse of fluorocarbon propellants may be hazardous. Deliberate inhalation of propellants in high concentrations, particularly under conditions of hypoxia, has resulted in toxic cardiovascular effects, severe CNS disturbances, and death. Acute toxic effects of nedocromil sodium would be restricted to propellant overdose or to aerosol-induced bronchoconstriction. Nedocromil sodium itself has an extremely low acute toxicity.

Pregnancy: Safety in human pregnancy and the absence of adverse effects on the human reproductive process have not been established. Small amounts are known to cross the placenta but without effect in animals. In fact, in reproductive studies, nedocromil sodium at up to 100 mg/kg (more than 800 times the human maintenance dose) has shown no teratogenic or embryotoxic effects, nor has it interfered with reproductive performance, gestation, parturition, or suckling. Nedocromil sodium did not affect male or female fertility nor did it alter the development of progeny.

Although there is no reason to suspect that nedocromil sodium affects the fetus or mother, as with any drug, caution must be exercised. The benefits of treatment to the mother must be weighed against the potential risk to the fetus before proposing its use.

Lactation: Safety in breast-fed infants has not been established. Animal studies have indicated no toxicity of nedocromil sodium in suckling newborns receiving drug from the parent or directly by injection. The concentrations of nedocromil sodium in milk of animals were very low but have not been measured in human milk. The benefits of treating a nursing mother must be weighed against potential risk to the infant.

Children: The safety and efficacy in children under 6 years of age has not yet been established.

Drug Interactions :

Nedocromil sodium has been used in association with other antiasthmatic drugs in man including b-adrenergic agonists, inhaled and oral corticosteroids, theophylline and other methylxanthines and, with ipratropium bromide. No drug-drug interactions have been observed in humans or in animals.

Children: There is limited data on drug interactions with nedocromil sodium use in children under 12 years of age.

Adverse Reactions:

Few side effects have been reported, principally headache and upper gastrointestinal tract symptoms, (nausea, vomiting, dyspepsia and abdominal pain). These have been mild and transient and insufficient to require discontinuation of treatment in nearly all cases. Some patients have reported an unpleasant taste. In common with other inhaled medications nedocromil sodium may produce cough or bronchospasm. There have been reports of a generalized sensation of warmth with nedocromil sodium use.

Specific side effects and their frequencies of occurrence with chronic dosing are unpleasant taste (12.2%), headache (5.98%), nausea (3.77%), vomiting (1.77%), dyspepsia (1.21%) and abdominal pain (0.94%).

In pediatric clinical trials, specific side effects and their occurrence were unpleasant taste (5.86%), headache (12.02%), nausea (1.69%), vomiting (2.93%) and abdominal pain (3.08%).

Symptoms And Treatment Of Overdose :

OverdoseThere have been no reported cases of overdose in humans. Animal studies have not shown evidence of toxic effects of nedocromil sodium, even at high dosage. If overdosage is suspected, treatment should be supportive and directed to the control of the relevant symptoms.:

Dosage And Administration:

Nedocromil sodium is intended for regular daily usage and should not be used for relief of symptoms during an acute attack.

The therapeutic benefits of repeated doses will be apparent in most patients within 1 week of starting treatment, but it may take longer on occasion.

Adults and children over 6 years of age: In initial and maintenance therapy, 2 actuations (4 mg of nedocromil sodium) 4 times daily. In patients under good control on 4 times daily dosing, a lower dose of nedocromil sodium can be tried. This reduction should first be to 3 times daily. Then, after several weeks of continued good control, administration can be changed to twice daily dosing. Data on the effectiveness of 2 actuations twice daily is limited in patients under 12 years of age.

Nedocromil sodium in a single dose of 2 actuations (4 mg) up to 30 minutes before exposure may provide protection against bronchospasm provoked by stimulants, such as, inhaled allergens, cold air, exercise and atmospheric pollutants.

It is essential that patients be properly instructed in the use of the inhaler, and that the correct method be reinforced periodically.

Availability And Storage:

Each metered actuation contains: nedocromil sodium 2 mg. Nonmedicinal ingredients: dichlorodifluoromethane, dichlorotetrafluoroethane and sorbitan trioleate. Pressurized, aluminum canisters of 17 mL. Units are filled with material to provide a minimum of 112 metered actuations. The pack consists of an aerosol canister with a plastic adapter and a patient instruction sheet. Store at 15 to 30°C. Contents under pressure. Do not place in hot water or near radiators, stoves or other sources of heat. Do not puncture or incinerate container even when empty. Do not store at temperatures over 30°C.

TILADE® Rh´ne-Poulenc Rorer Nedocromil Sodium Bronchial Anti-inflammatory Agent

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