ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Aservo EquiHaler 343 micrograms/actuation inhalation solution for horses

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each actuation (ex nostril adapter) contains:

Active substance:

Ciclesonide: 343 micrograms

Excipients:

Qualitative composition of excipients and other constituents	Quantitative composition if that information is essential for proper administration of the veterinary medicinal product
Ethanol	7.9 mg
Hydrochloric acid
Water, purified

Clear, colourless to yellowish solution.

3. CLINICAL INFORMATION

3.1 Target species

Horse

3.2 Indications for use of each the target species

For the alleviation of clinical signs of severe equine asthma (formerly known as Recurrent Airway Obstruction– (RAO), Summer Pasture Associated Recurrent Airway Obstruction – (SPA-RAO)).

3.3 Contraindications

Do not use in known cases of hypersensitivity to the active substance, to corticosteroids or to any of the excipients.

3.4 Special warnings

Special care should be taken when administering the veterinary medicinal product. To ensure an efficacious administration, the breath indicator in the chamber wall of the nostril adapter needs to be observed: when the horse inhales, the membrane of the breath indicator curves inwards. During exhalation, the membrane of the breath indicator curves outwards. The spray should be released at the beginning of inhalation, i.e. when the breath indicator starts curving into the chamber. If the movement of the breath indicator cannot be observed, assure the correct positioning of the nostril adapter. If movement of the breath indicator is still not visible or the movement is too rapid, the product should not be administered.

Efficacy of the product has not been established in horses with acute exacerbations (<14 days duration) of clinical signs.

3.5 Special precautions for use

Special precautions for safe use in the target species

Safety of the veterinary medicinal product has not been established in horses weighing less than 200 kg body weight, or in foals.

The prescribing veterinarian should assess if the horse has a temperament suitable for a safe and efficacious administration of the Aservo EquiHaler in agreement with good veterinary practice. Horses might not adapt to an easy and safe application of the Aservo EquiHaler within a couple of days. An alternative treatment should be considered if the horse does not adapt to the treatment with Aservo EquiHaler.

The onset of clinical improvement may take several days. The use of concomitant medication (such as bronchodilators) and environmental control may need to be considered in cases of severe clinical signs of respiratory obstruction, at the discretion of the attending veterinarian (see also section 3.8).

Special precautions to be taken by the person administering the veterinary medicinal product to animals

Follow closely the instructions for handling and use of the Aservo EquiHaler as provided in the package leaflet section “Other Information”.

A European survey showed that 16 out 84 horses could not be treated according to the product information due to horses not co-operating. In case a horse has a tendency towards defensive behavioural reactions, additional safety precautions could be considered (e.g. employ a second person to handle the horse). Acclimatising the horse with a training device prior to treatment start has in some cases shown to ease the administration of the veterinary medicinal product.

Administration of the product should take place in well ventilated surroundings.

People with known hypersensitivity to ciclesonide or any of the excipients should avoid contact with the veterinary medicinal product.

Inhalative or intranasal corticosteroids may cause rhinitis, nasal discomfort, nosebleed, upper respiratory tract infection and headache. An aerosol filtering mask must be worn during handling and administration. This prevents inadvertent inhalation in case of unintended release of actuations outside the nostril or without the nostril adapter.

The product can cause irritation to the eyes due to its ethanol content. Avoid contact with eyes. In case of accidental eye contact, rinse with large quantities of water.

In case of experiencing an adverse reaction due to accidental inhalation, and in case of eye irritation, seek medical advice and show the package leaflet or the label to the physician.

These precautions should be followed by the person administering the product and persons in close proximity to the horse’s head during administration.

The safety of ciclesonide after inhalatory exposure has not been established in pregnant women. In animal studies ciclesonide has been shown to induce malformations in foetuses (cleft palate, skeletal malformations). Pregnant women should therefore not administer the product.

If the Aservo EquiHaler is visually damaged it should not be used any more.

It is essential to keep the product out of reach for children.

Special precautions for the protection of the environment Not applicable.

3.6 Adverse events

Horse:

Common (1 to 10 animals / 100 animals treated):

Nasal discharge.*

* mild

Reporting adverse events is important. It allows continuous safety monitoring of a veterinary medicinal product. Reports should be sent, preferably via a veterinarian, to either the marketing authorisation holder or its local representative or the national competent authority via the national reporting system. See also the last section of the package leaflet for respective contact details.

3.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during pregnancy or lactation.

Use only according to the benefit/risk assessment by the responsible veterinarian.

The product was shown to be teratogenic following oral administration after high doses in rabbits but not in rats.

3.8 Interaction with other medicinal products and other forms of interaction

Concomitant use of clenbuterol in a field study in seven horses with severe equine asthma did not indicate any safety concerns.

3.9 Amounts to be administered and administration route

Inhalation use.

The number of actuations to be administered is the same for all horses. The total treatment duration is 10 days:

- Day 1 to 5:

8 actuations (corresponding to 2,744 µg ciclesonide) administered twice daily approximately 12 h apart

- Day 6 to 10:

12 actuations (corresponding to 4,116 µg ciclesonide) administered once daily approximately 24 h apart.

The onset of clinical improvement may take several days. The 10 days treatment schedule should normally be completed. In case of any concerns related to the treatment the responsible veterinarian should be consulted.

The Aservo EquiHaler contains sufficient inhalation solution for one horse for the entire treatment duration of the 10 days and an additional amount covering priming and potential losses during administration.

Treatment schedule for use:

Treatment days 1 to 5	Treatment days 6 to 10
8 actuations morning and evening approximately 12 h apart	12 actuations once daily approximately 24 h apart

The “Instructions for handling and use of the Aservo EquiHaler” is provided in section

“Other information“ of the package leaflet.

3.10 Symptoms of overdose (and where appplicable, emergency procedures and antidotes

After administration of the veterinary medicinal product at up to the 3-fold recommended dose for 3 times the recommended treatment duration no relevant clinical signs were observed.

3.11 Special restrictions for use and special conditions for use, including restrictions on the use of antimicrobial and antiparasitic veterinary medicinal products in order to limit the risk of development of resistance

Not applicable.

3.12 Withdrawal periods

Meat and offal: 18 days

Not authorised for use in horses producing milk for human consumption.

4. PHARMACOLOGICAL INFORMATION

4.1 ATCvet code:

QR03BA08

4.2 Pharmacodynamics

Ciclesonide is a prodrug which is enzymatically converted to the pharmacologically active metabolite desisobutyryl-ciclesonide (des-ciclesonide) following inhalation. The glucocorticoid-receptor affinity of des-ciclesonide was tested in rats and humans and demonstrated that the glucocorticoid-receptor affinity of des-ciclesonide is up to 120 times greater than the parent compound’s affinity and 12 times greater than dexamethasone’s affinity. Des-ciclesonide has anti-inflammatory properties which are exerted through a wide range of inhibitory activities.

In general, cortisol levels serve as a marker for suppression of the hypothalamic-pituitary-adrenal axis by systemic action of corticosteroids which could be associated with side effects.

No statistically significant suppression of cortisol levels was observed in horses with equine asthma at the recommended dosing regimen and in healthy horses with ciclesonide treatment up to three times the dose and three times the duration.

The pivotal field trial included horses (mean age 18.5 years) with severe equine asthma characterised by the following main criteria: clinical signs >14 days duration; horses that tolerated insertion of the nostril adapter; laboured breathing at rest; weighted clinical score ≥11/23. The weighted clinical score included the following parameters: coughing, nasal discharge, nasal flaring, laboured breathing at rest, respiratory rate, tracheal sounds and abnormal lung sounds. Clinical success was defined as an improvement of at least 30% in the weighted clinical score. In total, 73.4% of the ciclesonide group and 43.2% of the placebo group demonstrated treatment success, and the difference between the groups was statistically significant.

4.3 Pharmacokinetics

Absorption

Ciclesonide was rapidly absorbed after inhalation with a median T_max of about 5 minutes after the last actuation and rapidly converted to its active metabolite des-ciclesonide as shown by concentrations at the first sampling time, i.e. 5 minutes after the last actuation.

Distribution

The volume of distribution in horses is 25.7 l/kg, indicating that ciclesonide is distributed readily into the tissues.

Following inhalative administration in horses, the absolute systemic bioavailability of ciclesonide was very low and was not higher than 5% to 17%. The apparent systemic bioavailability of des-ciclesonide following administration of ciclesonide was in the range of 33.8% to 59.0%. The plasma exposure for ciclesonide and des-ciclesonide in terms of C_max and AUC_last increased with the dose. A slight trend to an increase of plasma exposure higher than the dose proportionality was observed.

In-vitro protein binding of des -ciclesonide was tested in the plasma from mice, rats, rabbits, dogs and humans (mouse plasma 98.9% to 99.1%; rat plasma 97.5% to 98.0%; rabbit plasma 99.1% to 99.2%; dog plasma 97.9% to 98.0%; human plasma 98.5% to 98.8%).

Metabolism

Ciclesonide is a pro-drug that is rapidly metabolized to the major active metabolite (des-ciclesonide) after inhalation. In vitro, three metabolites were reported as major metabolites. In vivo, only desciclesonide occurred whereas the other two metabolites could not be confirmed.

Elimination

The mean apparent harmonic terminal half-life after single inhalation administration was approximately 3-5 hours for ciclesonide and approximately 4-5 hours for des-ciclesonide. Elimination of ciclesonide and its active metabolite des-ciclesonide is principally via faeces.

5. PHARMACEUTICAL PARTICULARS

5.1 Major incompatibilities

Not applicable.

5.2 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 3 years Shelf life after first activation: 12 days.

5.3 Special precautions for storage

This veterinary medicinal product does not require any special storage conditions.

5.4 Nature and composition of immediate packaging

One Aservo EquiHaler with a polyurethane nostril adapter contains a pre-inserted cartridge. The cartridge consists of a polyethylene/polypropylene plastic container closed with a polypropylene cap and crimped in an aluminium cylinder. The cartridge contains sufficient inhalation solution for the entire treatment duration (140 treatment actuations). The cartridge also contains an additional amount covering priming and potential losses during administration within the 10 day treatment duration. Additionally, there is residual solution which cannot be delivered with the required accuracy, and should therefore not be administered.

The cartridge cannot be removed from the Aservo EquiHaler.

5.5 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products

Medicines should not be disposed of via wastewater or household waste.

Use take-back schemes for the disposal of any unused veterinary medicinal product or waste materials derived thereof in accordance with local requirements and with any national collection systems applicable to the veterinary medicinal product concerned.

The cartridge contains residual amount of the product at the end of the course of administration. This should be taken into account at disposal of the used veterinary medicinal product.

6. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Vetmedica GmbH

7. MARKETING AUTHORISATION NUMBER(S)

EU/2/19/249/001

8. DATE OF FIRST AUTHORISATION

Date of first authorisation: 28/01/2020

9. DATE OF THE LAST REVISION OF THE SUMMARY OF THE PRODUCT CHARACTERISTICS

DD/MM/YYYY

10. CLASSIFICATION OF VETERINARY MEDICINAL PRODUCTS

Veterinary medicinal product subject to prescription.

Detailed information on this veterinary medicinal product is available in the Union Product Database (https://medicines.health.europa.eu/veterinary).

ANNEX II

OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

None.

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

1.	NAME OF THE VETERINARY MEDICINAL PRODUCT

Aservo EquiHaler 343 micrograms/actuation inhalation solution

2.	STATEMENT OF ACTIVE SUBSTANCES

Ciclesonide: 343 micrograms/actuation.

3.	PACKAGE SIZE

1 inhaler contains 140 treatment actuations.

4.	TARGET SPECIES

Horse

5.	INDICATIONS

6.	ROUTE OF ADMINISTRATION

Inhalation use.

7.	WITHDRAWAL PERIOD

Withdrawal period:

Meat and offal: 18 days.

Not authorised for use in horses producing milk for human consumption.

8.	EXPIRY DATE

Exp. {mm/yyyy}

Once activated use within 12 days.

9.	SPECIAL STORAGE PRECAUTIONS

10.	THE WORDS “READ THE PACKAGE LEAFLET BEFORE USE”

Read the package leaflet before use.

11.	THE WORDS “FOR ANIMAL TREATMENT ONLY”

For animal treatment only.

12.	THE WORDS “KEEP OUT OF THE SIGHT AND REACH OF CHILDREN”

Keep out of the sight and reach of children.

13.	NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Vetmedica GmbH

14.	MARKETING AUTHORISATION NUMBER

EU/2/19/249/001

15.	BATCH NUMBER

Lot {number} info.equi-haler.com

1.	NAME OF THE VETERINARY MEDICINAL PRODUCT

Aservo EquiHaler 343 µg/actuation inhalation solution

2.	STATEMENT OF ACTIVE SUBSTANCES

Ciclesonide: 343 µg/actuation.

1 inhaler contains 140 treatment actuations.

3.	TARGET SPECIES

Horse

4.	ROUTE OF ADMINISTRATION

Inhalation use.

Read the package leaflet before use.

5.	WITHDRAWAL PERIODS

Withdrawal period:
Meat and offal: 18 days.
Not authorised for use in horses producing milk for human consumption.

6.	EXPIRY DATE

Exp. {mm/yyyy}

Once activated use within 12 days.

7.	SPECIAL STORAGE PRECAUTIONS

8.	NAME OF THE MARKETING AUTHORISATION HOLDER

9.	BATCH NUMBER

Lot {number}

B. PACKAGE LEAFLET

PACKAGE LEAFLET

1. Name of the veterinary medicinal product

Aservo EquiHaler 343 micrograms/actuation inhalation solution for horses

2. Composition

Each actuation (out of the nostril adapter) contains:

Active substance:

Ciclesonide 343 micrograms

Excipients:

Ethanol 7.9 mg

Clear, colourless to yellowish solution.

3. Target species

Horse

4. Indication for use

For the alleviation of clinical signs of severe equine asthma (formerly known as Recurrent Airway Obstruction– (RAO), Summer Pasture Associated Recurrent Airway Obstruction – (SPA-RAO)).

5. Contraindications

Do not use in known cases of hypersensitivity to the active substance, to corticosteroids or to any of the excipients.

6. Special warnings

Special care should be taken when administering the veterinary medicinal product. To ensure an efficacious administration, the breath indicator in the chamber wall of the nostril adapter needs to be observed: when the horse inhales, the membrane of the breath indicator curves inwards. During exhalation, the membrane of the breath indicatior curves outwards. The spray should be released at the beginning of inhalation, i.e. when the breath indicator starts curving into the chamber. If the movement of the breath indicator cannot be observed, assure the correct positioning of the nostril adapter. If movement of the breath indicator is still not visible or the movement is too rapid, the product should not be administered.

Efficacy of the product has not been established in horses with acute exacerbations (<14 days duration) of clinical signs.

Special precautions for safe use in the target species:

Safety of the veterinary medicinal product has not been established in horses weighing less than 200 kg body weight, or in foals.

The prescribing veterinarian should assess if the horse has a temperament suitable for a safe and efficacious administration of the Aservo EquiHaler in agreement with good veterinary practice.

Horses might not adapt to an easy and safe application of the Aservo EquiHaler within a couple of days. An alternative treatment should be considered if the horse does not adapt to the treatment with Aservo EquiHaler.

The onset of clinical improvement may take several days. The use of concomitant medication (such as bronchodilators) and environmental control may need to be considered in cases of severe clinical signs of respiratory obstruction, at the discretion of the attending veterinarian.

Special precautions to be taken by the person administering the veterinary medicinal product to animals:

Follow closely the instructions for handling and use of the Aservo EquiHaler as provided in the package leaflet section “Other Information”.

A European survey showed that 16 out 84 horses could not be treated according to the product information due to horses not co-operating. In case a horse has a tendency towards defensive behavioural reactions, additional safety precautions could be considered (e.g. employ a second person to handle the horse). Acclimatising the horse with a training device prior to treatment start has in some cases shown to ease the administration of the veterinary medicinal product.

Administration of the product should take place in well ventilated surroundings.

People with known hypersensitivity to ciclesonide or any of the excipients should avoid contact with the veterinary medicinal product.

Inhalative and intranasal corticosteroids may cause rhinitis, nasal discomfort, nosebleed, upper respiratory tract infection and headache. An aerosol filtering mask must be worn during handling and administration. This prevents inadvertent inhalation in case of unintended release of actuations outside the nostril or without the nostril adapter.

The product can cause irritation to the eyes due to its ethanol content. Avoid contact with eyes. In case of accidental eye contact, rinse with large quantities of water.

In case of experiencing an adverse reaction due to accidental inhalation, and in case of eye irritation, seek medical advice and show the package leaflet or the label to the physician.

These precautions should be followed by the person administering the product and persons in close proximity to the horse’s head during administration.

The safety of ciclesonide after inhalatory exposure has not been established in pregnant women. In animal studies ciclesonide has been shown to induce malformations in foetuses (cleft palate, skeletal malformations). Pregnant women should therefore not administer the product.

If the Aservo EquiHaler is visually damaged it should not be used any more.

It is essential to keep the product out of reach for children.

Pregnancy and lactation:

The safety of the veterinary medicinal product has not been established during pregnancy or lactation.

Use only according to the benefit/risk assessment by the responsible veterinarian.

The product was shown to be teratogenic following oral administration after high doses in rabbits but not in rats.

Interaction with other medicinal products and other forms of interaction:

Concomitant use of clenbuterol in a field study in seven horses with severe equine asthma did not indicate any safety concerns.

Overdose:

After administration of the veterinary medicinal product at up to the 3-fold recommended dose for 3 times the recommended treatment duration no relevant clinical signs could be observed.

7. Adverse events

Horse:

Common (1 to 10 animals / 100 animals treated):

Nasal discharge.*

* mild

Reporting adverse events is important. It allows continuous safety monitoring of a product. If you notice any side effects, even those not already listed in this package leaflet, or you think that the medicine has not worked, please contact, in the first instance, your veterinarian. You can also report any adverse events to the marketing authorisation holder or the local representative of the marketing authorisation holder using the contact details at the end of this leaflet, or via your national reporting system.

8. Dosage for each species, routes and method of administration

Inhalation use.

The number of actuations to be administered is the same for all horses. The total treatment duration is 10 days:

- Day 1 to 5:

8 actuations (corresponding to 2,744 µg ciclesonide) administered twice daily approximately 12 h apart

- Day 6 to 10:

12 actuations (corresponding to 4,116 µg ciclesonide) administered once daily approximately 24 h apart.

The onset of clinical improvement may take several days. The 10 days treatment schedule should normally be completed. In case of any concerns related to the treatment the responsible veterinarian should be consulted.

The Aservo EquiHaler contains sufficient inhalation solution for one horse for the entire treatment duration of the 10 days and an additional amount covering priming and potential losses during administration.

Treatment schedule for use:

Treatment days 1 to 5	Treatment days 6 to 10
8 actuations morning and evening approximately 12 h apart	12 actuations once daily approximately 24 h apart

9. Advice on correct administration

The “Instructions for handling and use of the Aservo EquiHaler” is provided in section “Other information” of this leaflet.

10. Withdrawal periods

Meat and offal: 18 days.

Not authorised for use in horses producing milk for human consumption.

11. Special storage precautions

Keep out of the sight and reach of children.

This veterinary medicinal product does not require any special storage conditions.

Shelf life after first activation: 12 days.

Do not use this veterinary medicinal product after the expiry date which is stated on the carton and the label after Exp. The expiry date refers to the last day of that month.

12. Special precautions for disposal

Medicines should not be disposed via wastewater or household waste.

Use take-back schemes for the disposal of any unused veterinary medicinal product or waste materials derived thereof in accordance with local requirements and with any applicable national collection systems. These measures should help to protect the environment.

Ask your veterinary surgeon or pharmacist how to dispose of medicines no longer required. The cartridge contains residual amount of the product at the end of the course of administration. This should be taken into account at disposal of the used veterinary medicinal product.

13. Classification of veterinary medicinal products

Veterinary medicinal product subject to prescription.

14. Marketing authorisation numbers and pack sizes

EU/2/19/249/001

One Aservo EquiHaler with a nostril adapter and a pre-inserted cartridge. The cartridge contains sufficient inhalation solution for the entire treatment duration (140 treatment actuations) and an additional amount covering priming and potential losses during administration within the 10 day treatment duration. Additionally there is residual solution which cannot be delivered with the required accuracy, and should therefore not be administered. The cartridge cannot be removed from the Aservo EquiHaler.

15. Date on which the package leaflet was last approved

DD/MM/YYYY

Detailed information on this veterinary medicinal product is available in the Union Product Database (https://medicines.health.europa.eu/veterinary).

16. Contact details

Marketing authorisation holder:

Boehringer Ingelheim Vetmedica GmbH

55216 Ingelheim/Rhein

Germany

Manufacturer responsible for batch release:

Fareva Amboise

Zone Industrielle

29 Route des Industries

37530 Pocé-sur-Cisse

France

Local representatives and contact details to report suspected adverse reactions:

België/Belgique/Belgien Lietuva

Boehringer Ingelheim Animal Boehringer Ingelheim RCV GmbH & Co KG

Health Belgium SA Lietuvos filialas

Avenue Arnaud Fraiteurlaan 15-23, Dr. Boehringer Gasse 5-11

1050 Bruxelles/Brussel/Brüssel A-1121 Vīne, Austrija Tél/Tel: + 32 2 773 34 56 Tel: +370 5 2595942

Република България Luxembourg/Luxemburg

Boehringer Ingelheim RCV GmbH & Co KG Boehringer Ingelheim Animal

Dr. Boehringer Gasse 5-11 Health Belgium SA

A-1121 Виена, Австрия Avenue Arnaud Fraiteurlaan 15-23,

Tel: +359 2 958 79 98 1050 Bruxelles/Brussel/Brüssel

Tél/Tel: + 32 2 773 34 56

Česká republika Magyarország

Boehringer Ingelheim spol. s r.o. Boehringer Ingelheim RCV GmbH & CoKG

Purkyňova 2121/3 Magyarországi Fióktelep CZ - 110 00, Praha 1 Lechner Ö. Fasor 10.

Tel: +420 234 655 111 H-1095 Budapest

Tel: +36 1 299 8900

Danmark Malta

Boehringer Ingelheim Animal Health Nordics Boehringer Ingelheim Vetmedica GmbH

A/S D-55216 Ingelheim/Rhein, il-Ġermanja

Weidekampsgade 14 Tel: +353 1 291 3985

DK-2300 København S

Tlf: + 45 3915 8888

Deutschland Nederland

Boehringer Ingelheim Vetmedica GmbH Boehringer Ingelheim Animal Health

55216 Ingelheim/Rhein Netherlands bv

Tel: 0800 290 0 270 Basisweg 10

1043 AP Amsterdam