Nasacort HFA

NASACORT HFA- triamcinolone acetonide aerosol, metered
Aventis Pharmaceuticals Inc.

For Intranasal Use Only

DESCRIPTION

Triamcinolone acetonide, USP, the active ingredient in Nasacort® HFA Nasal Aerosol, is a glucocorticosteroid with a molecular weight of 434.5, the chemical designation 9-Fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone (C24 H31 FO6 ), and the following chemical structure:

Image from Drug Label Content

Triamcinolone acetonide is a white to cream-colored crystalline powder, practically insoluble in water, very soluble in dehydrated alcohol, chloroform, and methyl alcohol.

Nasacort HFA Nasal Aerosol is a metered-dose aerosol unit containing a microcrystalline suspension of triamcinolone acetonide in tetrafluoroethane (HFA-134a) and dehydrated alcohol USP 0.7% w/w. Each canister contains 15 mg of triamcinolone acetonide.

The canister must be primed with 3 actuations prior to the first use or after a period of non-use (3 days). After priming, each actuation meters 100 mcg of triamcinolone acetonide in 65 mg of suspension from the valve and delivers 55 mcg of triamcinolone acetonide from the nasal actuator to the patient. If the product is not used for more than 3 days, it should be re-primed with 3 actuations.

Each 9.3 g canister of Nasacort HFA Nasal Aerosol provides 100 metered sprays. After 100 metered sprays, this amount of medication delivered per actuation may not be consistent and the unit should be discarded. Patients are provided with a check-off card to track usage as part of the PATIENT’S INSTRUCTIONS FOR USE tear-off sheet.

CLINICAL PHARMACOLOGY

Triamcinolone acetonide, a synthetic glucocorticosteroid, is a more potent derivative of triamcinolone. Although triamcinolone itself is approximately 1 to 2 times as potent as prednisone in animal models of inflammation, triamcinolone acetonide is approximately 8 times more potent than prednisone. The clinical relevance of in vitro or animal models of potency comparison is unknown.

The precise mechanism of corticosteroid action on allergic rhinitis is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. Nasacort HFA Nasal Aerosol, like other corticosteroids, does not have an immediate effect on allergic rhinitis signs and symptoms. When corticosteroids are discontinued, symptoms may not recur for several days.

Pharmacokinetics

Absorption

Triamcinolone acetonide is absorbed into the systemic circulation in humans following intranasal administration. In a study involving 24 patients with allergic rhinitis and 24 healthy subjects, absorption of triamcinolone from the nasal mucosa was similar. Following a single intranasal administration of 440 mcg of Nasacort HFA Nasal Aerosol to healthy subjects, the mean maximum triamcinolone acetonide plasma concentration of 0.2 (SD ± 0.1) ng/mL was observed at 3.8 (SD ± 2.4) hours postdosing.

Distribution

Based on an intravenous dose of 2 mg of triamcinolone acetonide phosphate ester in 12 healthy subjects, the mean volume of distribution (Vd) was 103.4 L (SD ± 58.7). The binding of triamcinolone acetonide to plasma proteins is relatively low, and remains consistent over a wide plasma triamcinolone acetonide concentration range (0.03 – 3.2 ng/mL). Based on an ex vivo study, the overall mean percent bound to plasma protein was approximately 68% (SD ± 4.3%).

Metabolism

The metabolism and excretion of triamcinolone acetonide were both rapid and extensive with no parent compound being detected in plasma after 24 hours post oral [14 C]-triamcinolone radiolabeled dose.

The disposition and metabolic profile of [14 C]-triamcinolone acetonide in human plasma, urine, and feces was evaluated in 6 healthy male subjects. Three major metabolites in plasma were 6β-hydroxytriamcinolone acetonide, triamcinolone acetonide-21-oic acid, and 6β-hydroxytriamcinolone acetonide-21-oic acid. Two major metabolites in the urine were 6β-hydroxytriamcinolone acetonide and its derivative following further oxidation (possibly 6-oxo-triamcinolone acetonide or 11-oxo-triamcinolone acetonide). A trace amount of triamcinolone acetonide-21-oic acid was also found in urine. Primary metabolites in the feces were the same as those in plasma. All three major metabolites in the plasma had no activity as determined by in vitro studies.

Elimination

Based on an intravenous dose of 2 mg of triamcinolone acetonide phosphate ester in 12 healthy subjects, the mean half-life of triamcinolone acetonide was 2 hours (SD ± 0.7), and the mean clearance was 37.3 L/hour (SD ± 12.8). Following a single intranasal administration of 440 mcg of triamcinolone acetonide in 24 healthy subjects, the mean half-life was 5.4 hours (SD ± 4.1). However, this value probably reflects lingering absorption of triamcinolone acetonide.

Following a single 800 mcg oral dose of radiolabeled [14 C]-triamcinolone acetonide in 6 healthy subjects, urinary and fecal excretion accounted for approximately 90% of the oral [14 C]-radiolabeled dose. Of the recovered [14 C]-radioactivity, approximately 40% and 60% were found in the urine and feces, respectively. Urinary excretion of [14 C]-radioactivity was essentially complete within 24 hours post-dose with most of the fecal elimination completed between 48 and 96 hours post-dose. The plasma half-life of corticosteroids does not correlate well with the duration of the drug’s activity.

Special Populations

Formal pharmacokinetic studies using intranasal triamcinolone acetonide were not carried out in any special populations. The effects of renal impairment, hepatic impairment, age, or gender on the pharmacokinetics of triamcinolone acetonide following intranasal administration have not been investigated.

Pharmacodynamics

Several studies were performed to determine if systemic absorption played a role in the response to triamcinolone acetonide in the treatment of allergic rhinitis. An open-label, multiple-dose study was conducted comparing intranasal CFC and depot intramuscular formulations of triamcinolone acetonide in 25 adult patients with seasonal or perennial allergic rhinitis. The doses used were based on bioavailability studies of each formulation. The intranasal CFC formulation was administered at a dose of 440 mcg once daily for 42 days, and the 4 mg depot intramuscular formulation was administered once a week for 42 days. Weekly injection yielded sustained plasma levels throughout the dosing interval while daily intranasal administration resulted in daily peak and trough concentrations, the mean of which was 3.5 times below the mean plasma levels achieved with intramuscular administration. Both intranasal and intramuscular triamcinolone acetonide were clinically effective on allergic rhinitis symptoms. This suggests that triamcinolone acetonide is both systemically and topically active.

The potential systemic effects of triamcinolone acetonide aqueous formulation (Nasacort AQ Nasal Spray) on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 64 patients with allergic rhinitis. Nasacort AQ Nasal Spray administered to adults at doses of 220 or 440 mcg once daily was compared to placebo or 10 mg prednisone administered as oral capsules for 42 days. Plasma cortisol concentrations were not affected in patients treated with either placebo or Nasacort AQ Nasal Spray in response to a 6-hour cosyntropin stimulation test, while oral prednisone significantly reduced the response to cosyntropin.

In another trial, the potential systemic effects of triamcinolone acetonide CFC formulation (Nasacort Nasal Inhaler) on the HPA axis were studied in 64 patients with allergic rhinitis. Nasacort Nasal Inhaler administered to adults at doses of 220 or 440 mcg once daily was compared to placebo or 10 mg prednisone once daily administered as oral capsules for 42 days. Plasma cortisol concentrations, 24-hour urinary 17-OHCS, and 24-hour urinary free cortisol concentrations were not affected in patients treated with either placebo or Nasacort Nasal Inhaler in response to a 6-hour cosyntropin stimulation test, while oral prednisone significantly reduced the response to cosyntropin for plasma cortisol concentrations and 24-hour urinary 17-OHCS concentrations.

A study was conducted evaluating plasma cortisol response 30 and 60 minutes after cosyntropin stimulation in 80 pediatric patients aged 6 to 12 years with allergic rhinitis who received 220 mcg or 440 mcg (twice the maximum recommended daily dose) of Nasacort AQ Nasal Spray daily for 6 weeks. No abnormal response to cosyntropin infusion (peak serum cortisol <18 mcg/dL) was observed after 6 weeks of dosing at 440 mcg per day.

Clinical Trials

The determination of efficacy and safety of Nasacort HFA Nasal Aerosol is based on the clinical program linking Nasacort HFA Nasal Aerosol to Nasacort Nasal Inhaler (triamcinolone acetonide CFC formulation), and by extrapolation from the known efficacy and safety of the Nasacort Nasal Inhaler. The clinical program of Nasacort HFA Nasal Aerosol included 2 studies conducted in the United States involving 1176 patients 12 to 83 years of age with allergic rhinitis, of whom 729 patients were treated with Nasacort HFA Nasal Aerosol. One study was a 2-week, double-blind, parallel-group, placebo-controlled trial comparing Nasacort HFA Nasal Aerosol to Nasacort Nasal Inhaler (triamcinolone acetonide CFC formulation) in 780 patients 18 years of age and older with seasonal allergic rhinitis. The design incorporated 2 doses of Nasacort Nasal Inhaler that were known to be effective (110 mcg and 440 mcg once daily), and 2 doses of Nasacort HFA Nasal Aerosol (110 mcg and 440 mcg once daily). Another study was a 12-month, open-label safety study in 396 patients 12 years of age and older with perennial allergic rhinitis. The dose of Nasacort HFA Nasal Aerosol was 220 mcg once daily for the first 2 weeks and 440 mcg once daily for the remainder of the study.

In the 2-week, double-blind study, Nasacort HFA Nasal Aerosol and Nasacort Nasal Inhaler (triamcinolone acetonide CFC formulation) were comparable, and both formulations showed a significant reduction in symptoms of allergic rhinitis (see table below). There were no significant differences in the effectiveness of Nasacort HFA Nasal Aerosol across subgroups of patients defined by gender, age, or race.

Effect of Nasacort HFA Nasal Aerosol on Total Symptom Score in a 2-Week Clinical Trial in Patients with Seasonal Allergic Rhinitis.
Treatment Group (n) Baseline Mean Score (SEM)* Mean Change From Baseline (SEM) Placebo Comparison (p-value)
*
Baseline score was an average of the morning and evening scores of 3 symptoms of allergic rhinitis (nasal discharge, nasal stuffiness, and sneezing) for 3 days preceding randomization and the morning of randomization. Each symptom was scored by patients 2 times a day by reflection over the preceding 12 hours on a scale of 0 to 3 where 0=no symptom and 3=severe symptoms.
Changes were averaged over the 2-week treatment period compared to the baseline. Symptom scoring during treatment period was the same as that for the baseline.
Nasacort HFA 440 mcgOnce Daily (111) 6.78 (0.1) -2.64 (0.18) < 0.05
Nasacort HFA 110 mcgOnce Daily (105) 6.41 (0.1) -2.29 (0.18) < 0.05
Placebo (109) 6.75 (0.1) -1.39 (0.18)
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