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Azmacort Inhalation (Triamcinolone Acetonide Inhalation) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Triamcinolone acetonide, USP, the active ingredient in Azmacort® Inhalation Aerosol, is a corticosteroid with a molecular weight of 434.5 and with the chemical designation 9-Fluoro-11(beta),16(alpha),17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. (C24 H31 FO6).

Azmacort Inhalation Aerosol is a metered-dose aerosol unit containing a microcrystalline suspension of triamcinolone acetonide in the propellant dichlorodifluoromethane and dehydrated alcohol USP 1% w/w. Each canister contains 60 mg triamcinolone acetonide. The canister must be primed prior to the first use. After an initial priming of 2 actuations, each actuation delivers 200 mcg triamcinolone acetonide from the valve and 100 mcg from the spacer-mouthpiece under defined in vitro test conditions. The canister will remain primed for 3 days. If the canister is not used for more than 3 days, then it should be reprimed with 2 actuations. There are at least 240 actuations in one Azmacort Inhalation Aerosol canister. After 240 actuations, the amount delivered per actuation may not be consistent and the unit should be discarded.

CLINICAL PHARMACOLOGY

Triamcinolone acetonide is a more potent derivative of triamcinolone. Although triamcinolone itself is approximately one to two times as potent as prednisone in animal models of inflammation, triamcinolone acetonide is approximately 8 times more potent than prednisone.

The precise mechanism of the action of glucocorticoids in asthma is unknown. However, the inhaled route makes it possible to provide effective local anti-inflammatory activity with reduced systemic corticosteroid effects. Though highly effective for asthma, glucocorticoids do not affect asthma symptoms immediately. While improvement in asthma may occur as soon as one week after initiation of Azmacort Inhalation Aerosol therapy, maximum improvement may not be achieved for 2 weeks or longer.

Based upon intravenous dosing of triamcinolone acetonide phosphate ester, the half-life of triamcinolone acetonide was reported to be 88 minutes. The volume of distribution (Vd) reported was 99.5 L (SD ± 27.5) and clearance was 45.2 L/hour (SD ± 9.1) for triamcinolone acetonide. The plasma half-life of glucocorticoids does not correlate well with the biologic half-life.

The pharmacokinetics of radiolabeled triamcinolone acetonide [14 C] were evaluated following a single oral dose of 800 mcg to healthy male volunteers. Radiolabeled triamcinolone acetonide was found to undergo relatively rapid absorption following oral administration with maximum plasma triamcinolone acetonide and [14 C]-derived radioactivity occurring between 1.5 and 2 hours. Plasma protein binding of triamcinolone acetonide appears to be relatively low and consistent over a wide plasma triamcinolone acetonide concentration range as a function of time. The overall mean percent fraction bound was approximately 68%.

The metabolism and excretion of triamcinolone acetonide were both rapid and extensive with no parent compound being detected in the plasma after 24 hours post-dose and a low ratio (10.6%) of parent compound AUC0-(infinity) to total [14 C] radioactivity AUC0-(infinity) . Greater than 90% of the oral [14 C]-radioactive dose was recovered within 5 days after administration in 5 out of the 6 subjects in the study. Of the recovered [14 C]-radioactivity, approximately 40% and 60% were found in the urine and feces, respectively.

Three metabolites of triamcinolone acetonide have been identified. They are 6(beta)-hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6(beta)-hydroxytriamcinolone acetonide. All three metabolites are expected to be substantially less active than the parent compound due to (a) the dependence of anti-inflammatory activity on the presence of a 21-hydroxyl group, (b) the decreased activity observed upon 6-hydroxylation, and (c) the markedly increased water solubility favoring rapid elimination. There appeared to be some quantitative differences in the metabolites among species. No differences were detected in metabolic pattern as a function of route of administration.

CLINICAL TRIALS

Double-blind, placebo controlled efficacy and safety studies have been conducted in asthma patients with a range of asthma severities, from those patients with mild disease to those with severe disease requiring oral steroid therapy.

The efficacy and safety of Azmacort Inhalation Aerosol given twice daily was demonstrated in two placebo-controlled clinical trials. In two separate studies, 222 asthmatic patients were randomized to receive either Azmacort Inhalation Aerosol 400 mcg twice daily or matching placebo for a treatment period of 6 weeks. Patients were adult asthmatics who were using inhaled beta2-agonists on more than an occasional basis (at least three times weekly), either without or with inhaled corticosteroids, for control of their asthma symptoms. For the combined studies, 48% (52/109) patients randomized to placebo and 41% (46/113) patients randomized to Azmacort Inhalation Aerosol treatment were previously treated with inhaled corticosteroids.

Results of weekly lung function tests (FEV1) from one of these trials is presented graphically below. Results of the second study are presented in tabular form as the changes in asthma measures from baseline to the end of the treatment period.

Mean Changes in Asthma Measures from Baseline
to Endpoint a
All-Treated Patients
Results from a Placebo-Controlled, 6 Week Study
Asthma Measure Placebo (N=61) Azmacort
400 mcg bid (N=60)
Percent Change in FEV1(%) 2.8% 17.5%
Increase in Morning Peak Flow Rate (L/min) 6.7    45.9   
Decrease in Albuterol Use (puffs/day) 0.6    3.4  
Decrease in Daily Asthma Symptom Score (units/day) b 0.5    2.3  
a Endpoint results are obtained from the last evaluable data, regardless of whether the patient completed 6 weeks of treatment.
b Scale (0-6) with 0 = no symptom: Maximum Score (AM + PM) = 12

In both studies, treatment with Azmacort Inhalation Aerosol (400 mcg twice daily) resulted in significant improvements in all clinical asthma measures (lung functions, asthma symptoms, use of as-needed beta2-agonist medications) when compared to placebo.

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