Prescription Drug Information: Zetonna (Page 3 of 5)

10 OVERDOSAGE

Chronic overdosage may result in signs or symptoms of hypercorticism [see Warnings and Precautions (5.5)]. There are no data on the effects of acute or chronic overdosage with ZETONNA.

11 DESCRIPTION

The active component of ZETONNA is ciclesonide, a non-halogenated glucocorticoid having the chemical name pregna -1,4-diene-3,20-dione, 16,17-[[R-cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)-,(11ß,16α)-. Ciclesonide is delivered as the R-epimer. The empirical formula is C32 H44 O7 and its molecular weight is 540.7. Its structural formula is as follows:

Structural Formula

Ciclesonide is a white to yellow-white powder. It is soluble in dehydrated alcohol, acetone, dichloromethane, and chloroform.

ZETONNA is comprised of a pressurized, metered-dose aerosol canister and actuator, which is fitted with a dose indicator. ZETONNA is intended for nasal use only. Each canister contains a solution of ciclesonide in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. After priming, ZETONNA delivers 50 mcg of ciclesonide from the valve and 37 mcg of ciclesonide from the actuator. This product delivers 50 microliters (59.3 milligrams) of solution as fine particle mist from the valve with each actuation.

12 CLINICAL PHARMACOLOGY

12.1 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 nasal 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.

12.2 Pharmacodynamics

Adrenal Function: In a 6-week, randomized, double-blind, placebo-controlled, parallel-group trial in adult and pediatric patients aged 12 to 73 years of age with perennial allergic rhinitis, daily doses of 148 mcg and 282 mcg of ZETONNA were compared to placebo. 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 LS means (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 (n=60), and 282 mcg ZETONNA (n=50), respectively. The LS means 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.

In a 6-week, randomized, double-blind, placebo-controlled, parallel-group trial in patients 6 to 11 years of age with perennial allergic rhinitis, a daily dose of 74 mcg of ZETONNA was compared to placebo. Adrenal function was assessed by 24-hr serum cortisol AUC before and after the treatment. At the end of 6 weeks of treatment, the LS means (SE) change from baseline in serum cortisol AUC(0-24) was 5.9 (5.6) mcg•hour/dL and 1.7 (5.2) mcg•hour/dL for placebo and ZETONNA, respectively. The LS means difference from placebo for the change from baseline in serum cortisol AUC(0-24) was 7.6 mcg•hour/dL (95% CI: -7.4, 22.6).

12.3 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 nasal 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 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 (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 nasally 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.

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). 14 C-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.

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 14 C-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.

Specific Populations

Patients with 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.

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

Drug Interaction Studies: 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies in B6C3F1 mice and Wistar rats were conducted to assess the carcinogenic potential of ciclesonide. Ciclesonide demonstrated no tumorigenic potential in a study with mice that received oral doses up to 900 mcg/kg/day (approximately 60 times the MRHDID in adult and pediatric patients ≥ 12 years of age on a mcg/m2 basis), and a study with rats that received inhalation doses up to 193 mcg/kg/day (approximately 25 times the MRHDID in adult and pediatric patients ≥ 12 years of age on a mcg/m2 basis).

Ciclesonide was not mutagenic in an Ames test or in the Chinese hamster lung V79 cell/hypoxanthine-guanine phosphoribosyl transferase (HGPRT) forward mutation assay and was not clastogenic in a human lymphocyte chromosomal aberration assay or in an in vitro micronucleus test. However, ciclesonide was clastogenic in an in vivo mouse micronucleus test. The concurrent reference corticosteroid (dexamethasone) in this study showed similar findings.

Fertility and reproductive performance were unaffected in male and female rats dosed by the oral route up to 900 mcg/kg/day (approximately 120 times the MRHDID in adults based on mcg/m2).

14 CLINICAL STUDIES

14.1 Seasonal and Perennial Allergic Rhinitis

Adults and Pediatric Patients 12 Years of Age and Older:

The efficacy of ZETONNA 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 adult and pediatric patients 12 years and older 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 pediatric patients 12 years and older. The three confirmatory trials included a total of 2488 patients (905 males and 1583 females) of whom 170 were pediatric patients, 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 to 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 (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 (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 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 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 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 (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 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 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 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 Pediatric Patients (12 years and older) With Seasonal or Perennial Allergic Rhinitis
Treatment N MeanBaselinea LS MeanChange from Baseline Difference from Placebob
Estimate (LS Mean) 95% CI p-value c
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.

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 Standardized Activities

Ciclesonide 74 mcg

237

4.0

-0.8

0.6

0.4, 0.8

<0.001

Placebo

234

4.0

-0.2

Perennial Allergic Rhinitis

Reflective Total Nasal Symptom Score

Ciclesonide 74 mcg

298

8.5

-2.0

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

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.

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