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Zetonna

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Zetonna

CLINICAL PHARMACOLOGY

Mechanism of Action

Ciclesonide is a pro-drug that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following intranasal application. Des-ciclesonide has anti-inflammatory activity with affinity for the glucocorticoid receptor that is 120 times higher than the parent compound.

The precise mechanism through which ciclesonide affects allergic rhinitis symptoms 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 allergic inflammation.

Pharmacodynamics

Adrenal Function

In a 6-week, randomized, double-blind, placebo-controlled, parallel-group trial in adolescents and adults 12-73 years of age with perennial allergic rhinitis, daily doses of 148 mcg and 282 mcg of ZETONNA Nasal Aerosol were compared to placebo nasal aerosol. Dexamethasone 6 mg was used as an active control during the last 4 days of the trial. Adrenal function was assessed by 24-hr serum cortisol AUC before and after the treatment. At the end of 6 weeks of treatment, the mean (SE) change from baseline in serum cortisol AUC(0-24) was -5.0 (4.6) mcg*hour/dL, -2.6 (4.6) mcg*hour/dL, and -4.6 (5.0) mcg*hour/dL for placebo (n=57), 148 mcg ZETONNA Nasal Aerosol (n=60), and 282 mcg ZETONNA Nasal Aerosol (n=50), respectively. The difference from placebo for the change from baseline in serum cortisol AUC(0-24) was -2.4 mcg^hour/dL (95% CI: -15.1, 10.2) and -0.5 mcg^hour/dL (95% CI: -13.9, 13.0) for 148 mcg/day and 282 mcg/day treatments, respectively. The effects observed with the active control (dexamethasone, n=18) validate the sensitivity of the study to assess the effect of ciclesonide on the HPA axis.

Pharmacokinetics

Absorption

Ciclesonide and des-ciclesonide have negligible oral bioavailability (both less than 1%) due to low gastrointestinal absorption and high first-pass metabolism. The intranasal administration of ciclesonide at recommended doses results in negligible serum concentrations of ciclesonide. However, the known active metabolite (des-ciclesonide) is detected in the serum of some patients after nasal inhalation of ciclesonide. The bioanalytical assay used has a lower limit of quantification of 10 pg/mL, for both ciclesonide and des-ciclesonide, respectively.

The low systemic exposure of des-ciclesonide following ciclesonide nasal aerosol administration was confirmed in a crossover trial in 29 healthy adults. The median Cmax of des-ciclesonide was 59 pg/mL following a single dose of ciclesonide nasal aerosol (296 mcg) compared to 602 pg/mL following a single dose of orally inhaled ciclesonide (320 mcg) and 12 pg/mL following a single dose of ciclesonide aqueous nasal spray (300 mcg). The pharmacokinetics of intranasally administered ciclesonide have been assessed in perennial allergic rhinitis patients resulting in similar exposure compared to healthy subjects.

Distribution

Following intravenous administration of 800 mcg of ciclesonide, the volumes of distribution of ciclesonide and des-ciclesonide were approximately 2.9 L/kg and 12.1 L/kg, respectively. The percentage of ciclesonide and des-ciclesonide bound to human plasma proteins averaged > 99% each, with < 1% of unbound drug detected in the systemic circulation. Des-ciclesonide is not significantly bound to human transcortin.

Metabolism

Ciclesonide is hydrolyzed to a biologically active metabolite, des-ciclesonide, by esterases. Des-ciclesonide undergoes further metabolism in the liver to additional metabolites mainly by the cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by CYP 2D6. The full range of potentially active metabolites of ciclesonide has not been characterized. After intravenous administration of 14C-ciclesonide, 19.3% of the resulting radioactivity in the plasma is accounted for by ciclesonide or des-ciclesonide; the remainder may be a result of other, as yet, unidentified multiple metabolites.

Elimination

Following intravenous administration of 800 mcg of ciclesonide, the clearance values of ciclesonide and des-ciclesonide were high (approximately 152 L/hr and 228 L/hr, respectively). 14C-ciclesonide was predominantly excreted via the feces after intravenous administration (66%) indicating that excretion through bile is the major route of elimination. Approximately 20% or less of drug related radioactivity was excreted in the urine.

Special Populations

Hepatic Impairment: Compared to healthy subjects, the systemic exposure (Cmax and AUC) in patients with liver impairment increased in the range of 1.4 to 2.7-fold after ex-actuator administration of 1280 mcg ciclesonide via oral inhalation. Dose adjustment in liver impairment is not necessary.

Renal Impairment: Trials in renally-impaired patients were not conducted since renal excretion of des-ciclesonide is a minor route of elimination ( < 20%).

Drug-Drug Interactions

Ciclesonide inhibited human recombinant cytochrome P450 enzymes at high concentration (3 microM) in vitro, but clinically relevant metabolic interactions are not anticipated. Based on in vitro studies in human liver microsomes, ciclesonide and des-ciclesonide appear to have no inhibitory or induction potential on the metabolism of other drugs metabolized by cytochrome P450 enzymes. In vitro studies demonstrated that the plasma protein binding of des-ciclesonide was not affected by warfarin or salicylic acid, indicating no potential for protein binding-based drug interactions.

In a drug interaction study, co-administration of orally inhaled ciclesonide and oral ketoconazole, a strong inhibitor of cytochrome P450 3A4, increased the exposure (AUC) of the active metabolite of ciclesonide, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged.

In another drug interaction study, co-administration of orally inhaled ciclesonide and oral erythromycin, a moderate inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin.

Clinical Studies

Seasonal and Perennial Allergic Rhinitis

Adults and Adolescent Patients 12 Years of Age and Older

The efficacy of ZETONNA Nasal Aerosol was evaluated in one randomized, double-blind, parallel-group, multicenter, placebo-controlled dose-ranging trial (74 mcg, 148 mcg, and 282 mcg once daily) and 3 confirmatory trials (74 mcg and 148 mcg once daily) in adolescents and adults with allergic rhinitis. Efficacy endpoints were evaluated at 2 weeks for the two seasonal allergic rhinitis trials and at 6 weeks for the perennial allergic rhinitis trial. These trials were all conducted in the United States. A total of 3001 patients were included in these 4 trials. The dose-ranging trial included a total of 513 patients [193 males (37.6%) and 320 females (62.4%)], of whom 65 (12.7%) were adolescents. The three confirmatory trials included a total of 2488 patients (905 males and 1583 females) of whom 170 were adolescents, ages 12 to 18 years. Patients enrolled in the trials were 12 to 81 years of age with a history of seasonal or perennial allergic rhinitis, a positive skin test to at least one relevant allergen, and active symptoms of allergic rhinitis at study entry. Assessment of efficacy in these trials was based on patient recording of four nasal symptoms (runny nose, nasal itching, sneezing, and nasal congestion) on a 0-3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, and 3 = severe) as reflective or instantaneous total nasal symptom scores (rTNSS and iTNSS respectively). Reflective scoring required the patients to record symptom severity over the previous 12 hours; the instantaneous scoring required patients to record symptom severity over the previous 10 minutes.

Additional secondary efficacy variables were assessed, including the total ocular symptom score (TOSS) in the seasonal allergic rhinitis trials and the Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities [RQLQ(S)] in both seasonal and perennial allergic rhinitis trials. TOSS is calculated as the sum of the patients' scoring of the three individual ocular symptoms (itching, tearing, and redness) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTOSS) or instantaneous (iTOSS) scores. To assess efficacy, rTOSS and iTOSS were evaluated as described above for the TNSS. Patients perceptions of disease specific quality of life were evaluated through the use of the RQLQ(S), which assesses the impact of allergic rhinitis symptoms and treatment through 28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) on a 7-point scale where 0 = not troubled and 6 = extremely troubled. An overall RQLQ(S) score is calculated from the average of the domain scores. An absolute difference of > 0.5 in mean change from baseline over placebo is considered the minimally clinically important difference (MCID) for the RQLQ(S).

Dose-Ranging Trial: There was a 2-week placebo-controlled, double-blind, dose-ranging trial that evaluated efficacy of three doses of ZETONNA Nasal Aerosol (74 mcg, 148 mcg, and 282 mcg once daily) in patients with seasonal allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average of morning and evening reflective total nasal symptom score (rTNSS) averaged over the 2-week treatment period. The rTNSS showed a statistically significant estimated treatment difference from placebo of 0.81 (95% CI: 0.32, 1.29); 0.90 (95% CI: 0.40, 1.39); and 0.66 (95% CI: 0.16, 1.16) for 282 mcg, 148 mcg and 74 mcg, respectively.

Confirmatory Seasonal Allergic Rhinitis Trials

There were two 2-week placebo-controlled, double-blind confirmatory trials that evaluated efficacy of two doses of ZETONNA Nasal Aerosol (74 mcg and 148 mcg once daily) in patients with seasonal allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average of morning and evening rTNSS averaged over the 2-week treatment period. Table 2 displays the efficacy results from one of these trials in patients with seasonal allergic rhinitis. The other trial showed similar results. In these trials, ZETONNA Nasal Aerosol 74 mcg once daily was statistically significantly different from placebo. Statistically significant differences in the morning pre-dose iTNSS indicate that the effect was maintained over the full 24-hour dosing interval. ZETONNA Nasal Aerosol 74 mcg demonstrated a statistically significant decrease from baseline in the rTOSS compared to placebo. Similarly, a clinically significant decrease ( > 0.5) from baseline compared to placebo for the RQLQ(S) was also shown. ZETONNA Nasal Aerosol 148 mcg once daily did not provide an efficacy benefit over the 74 mcg once daily dose.

Confirmatory Perennial Allergic Rhinitis Trial

There was one 26-week placebo-controlled, double-blind trial that evaluated efficacy of two doses of ZETONNA Nasal Aerosol (74 mcg and 148 mcg once daily) in patients with perennial allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average of morning and evening rTNSS averaged over the first 6 weeks of treatment. In this trial, ZETONNA Nasal Aerosol 74 mcg once daily was statistically significantly different from placebo (Table 2) in decreasing nasal symptom scores. Statistically significant differences in the morning pre-dose instantaneous total nasal symptom score indicate that the effect was maintained over the full 24-hour dosing interval. ZETONNA Nasal Aerosol 74 mcg did not demonstrate a clinically significant change from baseline in the overall RQLQ(S) compared to placebo. TOSS was not evaluated in this trial. ZETONNA Nasal Aerosol 148 mcg once daily did not provide an efficacy benefit over the 74 mcg once daily dose.

Table 2: Mean Changes in Efficacy Variables in Adult and Adolescent Patients With Seasonal or Perennial Allergic Rhinitis

Treatment N Mean Baselinea LS Mean Change from Baseline Difference from Placebob
Estimate (LS Mean) 95% CI p-valuec
Seasonal Allergic Rhinitis
Reflective Total Nasal Symptom Score
Ciclesonide 74 mcg 237 9.3 -1.5 0.9 0.6, 1.3 <0.001
Placebo 235 9.1 -0.5
Instantaneous Total Nasal Symptom Score
Ciclesonide 74 mcg 237 8.7 -1.3 0.9 0.5, 1.3 <0.001
Placebo 235 8.6 -0.5
Reflective Total Ocular Symptom Score
Ciclesonide 74 mcg 237 5.8 -0.8 0.5 0.3, 0.8 0.001
Placebo 235 5.7 -0.2
Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities
Ciclesonide 74 mcg 237 4 -0.8 0.6 0.4, 0.8 >0.001
Placebo 234 4 -0.2
Perennial Allergic Rhinitis
Reflective Total Nasal Symptom Score
Ciclesonide 74 mcg 298 8.5 -2 0.7 0.4, 1.0 <0.001
Placebo 307 8.6 -1.3
Instantaneous Total Nasal Symptom Score
Ciclesonide 74 mcg 298 7.7 -1.8 0.6 0.3, 0.9 <0.001
Placebo 307 7.7 -1.2
a Baseline for rTNSS, iTNSS, and rTOSS are averages of the AM and PM responses obtained during the Run-in Period up to 6 days prior to randomization and includes AM score prior to randomization. Baseline for morning iTNSS is the average of the AM responses obtained during the Run-in Period up to 6 days prior to randomization and includes the AM score prior to randomization. Baseline RQLQ(S) is from the randomization visit assessment.
b Estimates (LS Mean), 95% Confidence Intervals, and p-values were obtained from ANCOVA analyses with treatment and center as fixed effects and baseline as covariate in the model.
c P-values are significant at the 0.025 level based on Bonferroni correction.

Onset of Action: Onset of action was evaluated in both 2-week seasonal and one 6-week perennial allergic rhinitis trials by frequent recording of instantaneous symptom score. In these trials, onset of effect was seen after 36 hours following the first dose. Maximum benefit is usually achieved within 1 to 2 weeks after initiation of dosing.

Pediatric Patients Aged 11 Years and Younger

Efficacy of ZETONNA Nasal Aerosol in patients 11 years of age and younger has not been established [see Use In Specific Populations].

Last reviewed on RxList: 2/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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