Aservo EquiHaler: Product Information (Page 2 of 3)

Information for Horse Owners:

Please review the User Manual with horse owners to ensure they understand the entire contents. The User Manual includes important instructions regarding the proper handling and use of ASERVO EQUIHALER. Demonstration of the activation, administration and storage of ASERVO EQUIHALER with the horse owner is highly recommended.

Clinical Pharmacology:

Pharmacokinetics: A four period pharmacokinetic study was conducted using 6 average weight horses and 6 light weight horses. Each horse received the following dosing regimens:

Period 1: 12 actuations (4116 mcg ciclesonide/horse) as a single inhalation administration,

Period 2: 16 actuations (5488 mcg ciclesonide/horse) as a single inhalation administration,

Period 3: 8 actuations (2744 mcg ciclesonide/horse) twice a day for 4 consecutive days and once on the fifth day,

Period 4: 8 actuations (2744 mcg ciclesonide/horse) twice a day for 5 consecutive days followed by 12 actuations (4116 mcg/horse) once a day for 5 days.

Blood samples were collected at pre-dose, 0 minutes, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours after a single inhalation administration of 2744, 4116, and 5488 mcg in periods 1, 2, 3, and after multiple doses of 2744 and 4116 mcg in Periods 3 and 4.

Urine samples were collected at 24 and 48 hours in Period 4. Plasma and urine samples were analyzed for ciclesonide and des-ciclesonide concentrations using validated liquid chromatograph/ mass spectrometry methods.

Ciclesonide was rapidly metabolized to des-ciclesonide; there were quantifiable concentrations of des-ciclesonide in most horses at 5 minutes post-dose. Urine concentrations of ciclesonide and des-ciclesonide were below the limit of quantification at 24 and 48 hours after inhalation administration of 2744 mcg twice a day for 5 days followed by 4116 mcg once a day for 5 days. Table 3 summarizes the results of the pharmacokinetic analysis for des-ciclesonide in average and light weight horses (adjusted for body weight) after inhalations of 2744 mcg ciclesonide twice a day for 5 days followed by inhalations of 4116 mcg ciclesonide once a day for 5 days.

Table 3: Mean (± standard deviation; SD) pharmacokinetic parameters of des-ciclesonide after inhalations of 2744 mcg ciclesonide twice a day for 5 days followed by inhalations of 4116 mcg ciclesonide once a day for 5 days

Parameter

Dose (mcg)

Average Horse

Light Horse

Cmax (pg/mL)

2744

232.67 (40.89)

297.00 (92.0)

Tmax (hrs)†

2744

0.50 (0.5-0.5)

0.50 (0.25-1.0)

AUClast (hr*pg/mL)

2744

824.26 (81.77)

1087.07 (137.85)

t ½ (hrs)

2744

5.00 (1.06)

5.94 (2.12)

Cmax (pg/mL)

4116

297.50 (104.62)

493.00 (248.27)

Tmax (hrs)†

4116

0.50 (0.5-1.0)

0.50 (0.5-1.0)

AUClast (hr*pg/mL)

4116

1011.39 (291.72)

1550.31 (690.02)

t ½ (hrs)

4116

6.08 (2.42)

9.75 (4.20)

Cmax = maximum plasma concentration
†Tmax = time to maximum concentration; median (range)
AUClast = area under the concentration vs time curve to the last quantifiable concentration
t ½ = half-life

The drug exposure of des-ciclesonide was higher and more variable in the light weight horses compared to the average weight horses. For des-ciclesonide in both average and light weight horses, there was a greater than dose proportional increase in Cmax and AUClast with an increase in dose from 2744 to 4166 mcg, after a single dose. There was minimal accumulation of des-ciclesonide after inhalations of 2744 mcg ciclesonide twice a day for 5 days followed by inhalations of 4116 mcg ciclesonide once a day for 5 days.

Mode of Action: The affinity of des-ciclesonide to human and rat lung glucocorticoid receptors is 120 times greater than the parent compound’s affinity and 12 times greater than dexamethasone’s affinity. Des-ciclesonide’s anti-inflammatory properties are exerted via a wide range of inhibitory activities against cell types including mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils as well as against pro-inflammatory mediators such as histamine, eicosanoids, leukotrienes, and cytokines.

Effectiveness:

In a multi-center, vehicle-controlled, randomized, double-blind, field study, 320 horses were randomly allocated to receive either ASERVO EQUIHALER, the investigational veterinary product containing the active ingredient ciclesonide, or the control product, consisting of an identical inhaler device containing the vehicle with no ciclesonide. The study consisted of two phases, and 108 of the 320 enrolled horses participated in both Phase 1 and Phase 2 of the study.

Phase 1 of the study consisted of a double-blind, 10-day evaluation of the effectiveness and safety of ASERVO EQUIHALER compared to vehicle control for the management of clinical signs associated with severe equine asthma in both client- and university-owned horses under field conditions. Modifications of the horse’s environment were not allowed during Phase 1. Following completion of Phase 1, 108 horses participated in the 90-day open-label Phase 2 to evaluate the safety of ASERVO EQUIHALER during repeated use.

In Phase 1, a weighted clinical score (WCS) was calculated to assess both eligibility at study enrollment and treatment success at the conclusion of the study.

The WCS was comprised of nine clinical parameters (respiratory rate, nasal discharge, nasal flaring, abdominal lift, tracheal sounds, bronchial tones, crackles, wheeze, and cough) with a maximum score of 23. In order to enroll, horses were to have a WCS ≥11 (see Table 4), weigh at least 200 kg, have a diagnosis of severe equine asthma with observation of at least one clinical sign for 14 days or more prior to enrollment, have history of at least two previous episodes of labored breathing at rest, and have history of improvement with appropriate treatment (for example, glucocorticoid administration, bronchodilator administration, and/or change in environment). Two hundred fifty-eight horses (134 ASERVO EQUIHALER and 124 control) were included in the effectiveness analysis. Horses that were not fully dosed after enrollment due to the horse’s refusal to accept the device were included in the analysis as treatment failures.

Table 4: Weighted Clinical Score

Parameter Score: Description

Respiratory rate (breaths/minute)

0: <16 bpm

1: 16-20 bpm

2: 21-25 bpm

3: 26-30 bpm

4: >30 bpm

Nasal Discharge

0: None

1: Serous

2: Mucous

3: Mucopurulent

Nasal Flaring

0: None

1: Present

Abdominal Lift

0: None

1: Mild movement of abdomen and/or thorax and/or anus (with or without perceptible heaves line)

3: Pronounced movement of abdomen and/or thorax and/or anus (with or without perceptible heaves line)

Tracheal Sounds

0: Normal

1: Increase in intensity

3: Mucus Movement

Bronchial Tones

0: Normal

2: Audible ventral and/or dorsal sounds

Crackles

0: None

2: Present

Wheezes

0: None

2: Present

Cough

0: None

1: Inducible by moderate pressure signal on larynx (only to be checked in the absence of intermittent or paroxysmal cough)

2: Intermittent

3: Paroxysmal

A horse was considered a treatment success if there was a reduction in the WCS by at least 30% between Day 0/1 and Day 10, and had a Day 10 WCS ≤ 14. In this study, 52% of horses treated with ASERVO EQUIHALER vs. 33% of the horses treated with vehicle control had treatment success (p=0.0187), demonstrating the ASERVO EQUIHALER (ciclesonide inhalation spray) is effective for the management of clinical signs associated with severe equine asthma in horses.

Phase 2 provided field safety and use information for repeated 10-day courses of treatment under conditions of use, including use with other appropriate treatment strategies. During Phase 2, 88 horses completed the full 100-day study. The most common reason for early withdrawal was perceived lack of effectiveness (n=7). Horses were to be prescribed a 10-day course of the ASERVO EQUIHALER when the WCS was ≥9. Eight out of 108 did not receive additional inhaler devices. Of the 100 horses who qualified for retreatment, 52 (52%) qualified for one to three additional courses of treatment. Two horses that were in the ASERVO EQUIHALER group during Phase 1 received nine additional courses of treatment in Phase 2, resulting in 100 days of exposure to ASERVO EQUIHALER. Twenty-three (23%) horses received seven to nine courses of treatment during Phase 2. Concomitant medications and environmental changes intended for the overall management of severe equine asthma were allowed in Phase 2. The most commonly prescribed concomitant medications included bronchodilators and antihistamines. Systemic antimicrobials were prescribed in six horses where the clinical signs of severe equine asthma were not adequately controlled, clinical signs worsened despite continued administration of ASERVO EQUIHALER, or clinical signs of infection developed.

Two horses received dexamethasone at early study withdrawal because their disease was insufficiently controlled.

The most common environmental changes implemented during Phase 2 included soaking or steaming the hay, changing the forage source to either hay cubes or silage, changing the hay source (including stopping access to round bales), and increasing time out on pasture compared to time spent in the barn.

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