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Nasacort (Triamcinolone Acetonide Nasal) - Description and Clinical Pharmacology

 
 



NASACORT®
[na' za-cort]
(triamcinolone acetonide)
Nasal Inhaler

For Intranasal Use Only

Shake Well Before Using

DESCRIPTION

Triamcinolone acetonide, USP, the active ingredient in Nasacort ® Nasal Inhaler, is a glucocorticosteroid with a molecular weight of 434.5 and with the chemical designation 9-Fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. (C24H31FO6).

Nasacort Nasal Inhaler is a metered-dose aerosol unit containing a microcrystalline suspension of triamcinolone acetonide in dichlorodifluoromethane and dehydrated alcohol USP 0.7% w/w. Each canister contains 15 mg triamcinolone acetonide. Each actuation delivers 55 mcg triamcinolone acetonide from the nasal actuator to the patient (estimated from in vitro testing). There are at least 100 actuations in one Nasacort Nasal Inhaler canister. After 100 actuations, the amount 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 Information for Patients tear-off sheet.

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.

Although the precise mechanism of corticosteroid antiallergic action is unknown, corticosteroids are very effective. However, they do not have an immediate effect on allergic signs and symptoms. When allergic symptoms are very severe, local treatment with recommended doses (microgram) of any available topical corticosteroids are not as effective as treatment with larger doses (milligram) of oral or parenteral formulations. When corticosteroids are prematurely discontinued, symptoms may not recur for several days.

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 corticosteroids does not correlate well with the biologic half-life.

When administered intranasally to man at 440 mcg/day dose, the peak plasma concentration was <1 ng/mL and occurred on average at 3.4 hours (range 0.5 to 8.0 hours) postdosing. The apparent half-life was 4.0 hours (range 1.0 to 7.0 hours); however, this value probably reflects lingering absorption. Intranasal doses below 440 mcg/day gave sparse data and did not allow for the calculation of meaningful pharmacokinetic parameters.

In animal studies using rats and dogs, three metabolites of triamcinolone acetonide have been identified. They are 6β-hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6β-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

In double-blind, parallel, placebo-controlled clinical trials of seasonal and perennial allergic rhinitis, in adults and adolescents in fixed total daily doses of 110, 220 and 440 mcg per day, the responses to aerosolized triamcinolone acetonide demonstrated a statistically significant improvement over placebo. In open label trials where the doses were sometimes adjusted according to patients' signs and symptoms, the daily doses and regimens varied. The most commonly used dose was 110 mcg per day.

Nasacort Nasal Inhaler, at a dose of 220 mcg once daily, has also been studied in two double-blind, placebo-controlled trials of two and four weeks duration in children ages 6 through 11 years with seasonal and perennial allergic rhinitis. These trials included 162 males and 91 females. Nasacort administered at a fixed dose of 220 mcg once daily resulted in consistent and statistically significant reductions of allergic rhinitis symptoms over vehicle placebo.

In attempting to determine if systemic absorption played a role in the response to Nasacort, a clinical study comparing intranasal and depot intramuscular triamcinolone acetonide was conducted. The doses used were based on bioavailability studies of each formulation. The final doses of Nasacort 440 mcg once a day and Kenalog®-40, 4 mg intramuscularly once a week, were chosen to deliver comparable total amounts of weekly triamcinolone acetonide. However, the weekly injection yielded sustained plasma levels throughout the dosing interval while the daily Nasacort application resulted in daily peak and trough concentrations, the mean of which was 3.5 times below the Kenalog plasma levels. Both topical Nasacort and intramuscular Kenalog-40 were clinically effective. In addition, in some studies there was evidence of improvement of eye symptoms. This suggests that Nasacort, at least to some degree is acting by a systemic mechanism.

In order to evaluate the effects of systemic absorption on the Hypothalamic-Pituitary-Adrenal (HPA) axis, Nasacort administered to adults in doses of 440 mcg once a day was compared to placebo and 42 days of a single morning dose of prednisone 10 mg. Adrenal response to a six-hour cosyntropin stimulation test suggests that intranasal Nasacort 440 mcg/day for six weeks did not measurably affect adrenal activity. Conversely, oral prednisone at 10 mg/day significantly reduced the response to ACTH.

No evidence of adrenal axis suppression was observed in 26 pediatric patients exposed for 6 weeks to systemic levels of triamcinolone acetonide higher than the systemic levels observed following administration of the maximum recommended dose of Nasacort Nasal Inhaler.

INDIVIDUALIZATION OF DOSAGE

Individual patients will experience a variable time to onset and degree of symptom relief when using Nasacort. It is recommended that dosing be started at 220 mcg once a day and the effect be assessed in four to seven days.

Adults and Children 12 years of age and older

Some relief can be expected in approximately two-thirds of patients within four to seven days. If greater effect is desired an increase of dose to 440 mcg once a day can be tried. If adequate relief has not been obtained by the third week of Nasacort treatment, alternate forms of treatment should be considered.

A dose-response between 110 mcg/day (one spray/nostril/day) and 440 mcg/day (four sprays/nostril/day) is not clearly discernible. In general, in the clinical trials the highest dose tended to provide relief sooner. This suggests an alternative approach to starting therapy with Nasacort, e.g., starting treatment with 440 mcg (four sprays/nostril/day) and then, depending on the patient's response, decreasing the dose by one spray per day every four to seven days. Although Nasacort may be used at 220 mcg/day or 440 mcg/day divided into two or four times a day, the degree of relief does not seem to be significantly different compared to once-a-day dosing. As with other nasal corticosteroids, the vehicle used to deliver the corticosteroid, may cause symptoms that are difficult to distinguish from the patient's rhinitis symptoms. Thus, depending upon the balance between these vehicle side effects and the benefits of treatment, in determining the optimal dose for the relief of symptoms, individual patients may need to have a trial of high and low doses.

Children 6 through 11 years of age

In children 6 through 11 years of age, it is recommended that dosing be started at 220 mcg given as two sprays (55 mcg/spray) in each nostril once a day. In clinical trials, significant relief of rhinitis symptoms in children was observed as early as the fourth day of treatment and generally, it took one to two weeks to achieve maximum benefit. If adequate relief has not been obtained by the third week of Nasacort treatment, alternate forms of treatment should be considered.

In general, it is always desirable to titrate an individual patient to the minimum effective dose to reduce the possibility of side effects. In clinical trials, after symptoms have been brought under control at the recommended starting doses, reducing the daily dose to 110 mcg (one spray in each nostril once per day) has been shown to be effective in controlling symptoms in approximately one-half of adult patients being treated long-term for allergic rhinitis. (See PRECAUTIONS, WARNINGS, Information for Patients and ADVERSE REACTIONS sections).

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