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Nasacort AQ

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Nasacort AQ

CLINICAL PHARMACOLOGY

Mechanism of Action

Triamcinolone acetonide is a synthetic fluorinated corticosteroid with approximately 8 times the potency of prednisone in animal models of inflammation.

Although the precise mechanism of corticosteroid antiallergic action is unknown, corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

Pharmacodynamics

In order to determine if systemic absorption plays a role in the effect of NASACORT AQ Nasal Spray on allergic rhinitis symptoms, a two week double-blind, placebo-controlled clinical study was conducted comparing NASACORT AQ, orally ingested triamcinolone acetonide, and placebo in 297 adult patients with seasonal allergic rhinitis. The study demonstrated that the therapeutic efficacy of NASACORT AQ Nasal Spray can be attributed to the topical effects of triamcinolone acetonide.

Adrenal Function

In order to evaluate the effects of systemic absorption on the Hypothalamic-Pituitary-Adrenal (HPA) axis, 4 clinical studies, one each in adults and in children 6-12 years of age, 2-5 years of age, and 2-11 years of age, were conducted.

The adult clinical study compared 220 mcg or 440 mcg NASACORT AQ per day, or 10 mg prednisone per day with placebo for 42 days. Adrenal response to a six-hour 250 mcg cosyntropin stimulation test showed that NASACORT AQ administered at doses of 220 mcg and 440 mcg had no statistically significant effect on HPA activity versus placebo. Conversely, oral prednisone at 10 mg/day significantly reduced the response to ACTH.

A study evaluating plasma cortisol response thirty and sixty minutes after 250 mcg cosyntropin stimulation in 80 pediatric patients 6 to 12 years of age who received 220 mcg or 440 mcg (twice the maximum recommended daily dose) daily for six weeks was conducted. No abnormal response to cosyntropin infusion (peak serum cortisol < 18 mcg/dL) was observed in any pediatric patient after six weeks of dosing with NASACORT AQ at 440 mcg per day.

In pediatric patients 2 to 5 years of age (n = 61) receiving Nasacort AQ 110 mcg per day intranasally, HPA axis function was assessed by cosyntropin stimulation test; however, the results were inconclusive.

An effect of Nasacort AQ Nasal Spray on adrenal function in children 2 to 5 years of age cannot be ruled out.

In a 6-week trial in 140 children 2 to 11 years of age with allergic rhinitis, a daily dose of 110 or 220 mcg of NASACORT AQ Nasal Spray was compared to placebo nasal spray. A subset of 24 children 6 to 11 years of age received a higher dose of 220 mcg of NASACORT AQ Nasal Spray. A positive control was not included in this trial. Adrenal function was assessed by measurement of 24 hour serum cortisol levels before and after the treatment. The difference from placebo in the change from baseline in LS mean serum cortisol AUC (0-24 hr) at the end of week 6 for the NASACORT AQ Nasal Spray treatment groups (110 mcg and 220 mcg) was -4.2 mcg•hour/dL (95% CI: -14.7, 6.4).

Pharmacokinetics

Based upon intravenous dosing of triamcinolone acetonide phosphate ester in adults, 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.

Pharmacokinetic characterization of the NASACORT AQ Nasal Spray formulation was determined in both normal adult subjects and patients with allergic rhinitis. Single dose intranasal administration of 220 mcg of NASACORT AQ Nasal Spray in normal adult subjects and patients demonstrated minimal absorption of triamcinolone acetonide. The mean peak plasma concentration was approximately 0.5 ng/mL (range: 0.1 to 1.0 ng/mL) and occurred at 1.5 hours post dose. The mean plasma drug concentration was less than 0.06 ng/mL at 12 hours, and below the assay detection limit (the minimum LOQ of the assay was 0.025 ng/ml) at 24 hours. The average terminal half-life was 3.1 hours. The range of mean AUC0–∞ values was 1.4 ng•hr/mL to 4.7 ng•hr/mL between doses of 110 mcg to 440 mcg in both patients and healthy volunteers. Dose proportionality was demonstrated in both normal adult subjects and in allergic rhinitis patients following single intranasal doses of 110 mcg or 220 mcg NASACORT AQ Nasal Spray. The Cmax and AUC0-∞ of the 440 mcg dose increased less than proportionally when compared to 110 and 220 mcg doses.

Following multiple dose administration of NASACORT AQ 440 mcg once daily in pediatric patients 6 to 12 years of age, plasma drug concentrations, AUC0-∞, Cmax and Tmax were similar to those values observed in adult patients receiving the same dose. Intranasal administration of NASACORT AQ 110 mcg once daily in pediatric patients 2 to 5 years of age exhibited similar systemic exposure to that achieved in adult patients 20 to 49 years of age with intranasal administration of NASACORT AQ at a dose of 220 mcg once daily. Based on the population pharmacokinetic modeling, the apparent clearance and volume of distribution following intranasal administration of NASACORT AQ in pediatric patients 2 to 5 years of age were found to be approximately half of that in adults.

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.

Animal Toxicology and/or Pharmacology

Triamcinolone acetonide was teratogenic in rats, rabbits, and monkeys. In rats, triamcinolone acetonide was teratogenic at an inhalation dose of 20 mcg/kg and above (approximately 7/10 of the maximum recommended daily intranasal dose in adults on a mcg/m² basis). In rabbits, triamcinolone acetonide was teratogenic at inhalation doses of 20 mcg/kg and above (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m² basis). In monkeys, triamcinolone acetonide was teratogenic at an inhalation dose of 500 mcg/kg (approximately 37 times the maximum recommended daily intranasal dose in adults on a mcg/m² basis). Dose-related teratogenic effects in rats and rabbits included cleft palate and/or internal hydrocephaly and axial skeletal defects, whereas the effects observed in the monkey were cranial malformations.

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.

Clinical Studies

The safety and efficacy of NASACORT AQ Nasal Spray have been evaluated in 10 double-blind, placebo-controlled clinical studies of two-to four-weeks duration in adults and children 12 years and older with seasonal or perennial allergic rhinitis. The number of patients treated with NASACORT AQ Nasal Spray in these studies was 1266; of these patients, 675 were males and 591 were females.

Overall, the results of these clinical studies in adults and children 12 years and older demonstrated that NASACORT AQ Nasal Spray 220 mcg once daily (2 sprays in each nostril), when compared to placebo, provides statistically significant relief of nasal symptoms of seasonal or perennial allergic rhinitis including sneezing, stuffiness, discharge, and itching.

The safety and efficacy of NASACORT AQ Nasal Spray, at doses of 110 mcg or 220 mcg once daily, have also been adequately studied in two double-blind, placebo-controlled studies of two-and twelve-weeks duration in children ages 6 through 12 years with seasonal and perennial allergic rhinitis. These studies included 341 males and 177 females. NASACORT AQ administered at either dose resulted in statistically significant reductions in the severity of nasal symptoms of allergic rhinitis.

The safety and efficacy of NASACORT AQ Nasal Spray in children 2 to 5 years of age with perennial allergic rhinitis with or without seasonal allergic rhinitis was studied in a single 4 week double blind, placebo controlled clinical study with a 24 week open label extension conducted in the United States. The study included 464 patients (266 males and 198 females) 2 to 5 years of age who received at least one dose of study medication (233 placebo, 231 NASACORT AQ 110 mcg once daily). Efficacy was determined over a four-week double-blind, placebo-controlled treatment period and was based on patient's parent or guardian recording of four nasal symptoms (total nasal symptom score, TNSS), congestion, itching, rhinorrhea, and sneezing on a 0-3 categorical severity scale (0=absent, 1=mild, 2=moderate, and 3=severe) once daily. Reflective scoring (rTNSS) required recording symptom severity over the previous 24 hours; the instantaneous scoring (iTNSS) required recording symptom severity at the time just prior to dosing. Baseline symptom severity was comparable between NASACORT AQ and placebo respectively, for iTNSS (7.52, 7.61) and rTNSS (7.96, 7.87). While the 24-hour iTNSS over the 4-week double-blind period was numerically improved with NASACORT AQ (-2.28) vs. placebo (-1.92), the difference was not statistically significant (difference from placebo -0.36; 95% CI [-0.77, 0.06]; p value = 0.095). For the 24-hour rTNSS over the 4 week double-blind treatment period, NASACORT A Q 110 mcg once daily provided statistically significantly greater improvement from baseline (-2.31) versus placebo (-1.87) (difference from placebo 0.44; 95% CI [-0.84, -0.04]; p value = 0.033).

Last reviewed on RxList: 7/22/2013
This monograph has been modified to include the generic and brand name in many instances.

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