[Version 8.1,01/2017]

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT ENURACE 50, 50 mg tablets for dogs (UK, NL, IT, BE, DE, ES) ENURACE grand chien (FR)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains:

Active substance: 40.7 mg ephedrine equivalent to 50 mg ephedrine hydrochloride.

Excipients: For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Tablets. Round, white tablet with break line on one side and inscription ENURACE 50 on the other side. 4. CLINICAL PARTICULARS

4.1 Target species Dog (ovariohysterectomised female dogs).

4.2 Indications for use, specifying the target species Treatment of urinary incontinence caused by urethral sphincter mechanism incompetence in ovariohysterectomised female dogs.

4.3 Contraindications Do not use in dogs with glaucoma. Do not use in cases of hypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings for each target species This product is not suitable for treatment of inappropriate urination due to behaviour problems.

4.5 Special precautions for use Special precautions for use in animals Do not use the product in dogs under 20 kilogram of bodyweight. As ephedrine is an alpha- and beta-adrenergic receptor agonist, the product should be used with caution in dogs with cardiovascular disease and only after a comprehensive risk/benefit analysis by the attending veterinarian. The dog’s cardiovascular functionality should be carefully assessed before the start of the treatment with the product and it should be periodically monitored during the treatment.

In addition, a similar approach should be adopted in animals suffering from partial urethral obstruction, hypertension, diabetes mellitus, hyperadrenocorticism, hyperthyroidism or other metabolic disorders. It should be mentioned that the polyuria/polydipsia (PU/PD) frequently accompanying the aforementioned conditions may be falsely diagnosed as urinary incontinence. Special precautions to be taken by the person administering the veterinary medicinal product to animals Ephedrine hydrochloride could be toxic if ingested. Adverse effects may include insomnia and nervousness, dizziness, headache, increased blood pressure, increased sweating and nausea. Ingestion may be fatal, especially in children. To avoid accidental ingestion, the product must be used and kept out of the reach of children. Always replace the cap securely after use. In case of accidental ingestion, most importantly by children, seek medical advice immediately and show the package leaflet or the label to the physician. It is strongly recommended that pregnant women should wear gloves for administration. Wash hands after administration.

4.6 Adverse reactions (frequency and seriousness)

Cardiovascular effects like tachycardia, atrial fibrillation, stimulation of the heart activity; and vasoconstriction.

Stimulation of the central nervous system leading to sleeplessness, excitation, anxiety and muscle tremors.

Panting.

Mydriasis.

Cystitis.

Bronchodilatation and decrease of mucus release in the respiratory mucosal membranes.

Reduction of the motility and tone of the intestinal wall. Due to the nature of ephedrine the mentioned effects can occur at the recommended therapeutic dose, with anxiety and cardiovascular effects being the most prevalent. In 10% of the treatments, side effects have been observed in efficacy studies. Vomiting has been reported very rarely in spontaneous reports. The frequency of adverse reactions is defined using the following convention: - very common (more than 1 in 10 animals treated displaying adverse reaction(s)) - common (more than 1 but less than 10 animals in 100 animals treated) - uncommon (more than 1 but less than 10 animals in 1,000 animals treated) - rare (more than 1 but less than 10 animals in 10,000 animals treated) - very rare (less than 1 animal in 10,000 animals treated, including isolated reports).

4.7 Use during pregnancy, lactation or lay Not applicable.

4.8 Interaction with other medicinal products and other forms of interaction

Ephedrine may interact with other sympathomimetics.

Ephedrine may enhance glucocorticoid metabolism. Concomitant use with MAO-inhibitors may cause hypertension.

Ephedrine can enhance the activity of products of the same class as theophylline.

Volatile anaesthetics may enhance the sensitivity of the myocardium to the cardiovascular effects of ephedrine.

Concomitant use with cardiac glycosides, quinine and tricyclic antidepressants can cause arrhythmias.

Vascular constrictions can occur after concomitant treatment with ergot alkaloids and oxytocin.

Substances leading to an increase in pH of the urine are able to prolong the excretion of ephedrine, whereas substances leading to a decrease in pH of the urine are able to accelerate the excretion of ephedrine.

4.9 Amounts to be administered and administration route For oral administration only. A starting dose of 2 mg ephedrine HCl per kg of bodyweight per day, divided in two oral doses is recommended. Dogs can be dosed according to the following table:

Weight (kg)

Dose (mg/day)

Dose (Number of tablets)

per day 1st gift 2nd gift

20-30 50 1 ½ ½

31-40 75 1 ½ ½ 1

41-50 100 2 1 1

Desired therapeutic effect and occurrence of adverse effects have to be monitored approximately at 14 days, 1 month, 3 months and 6 months after the start. Based on the observed effect in comparison with the expected effect and taking into account the occurrence of adverse effects, the individual dose should be adjusted. The dose should be adjusted to find the lowest effective dose. Once the effective dose has been established, dogs should still be monitored at regular intervals, e.g. every six months. The product should be administered before meals in a piece of food. A maximum dose of 5 mg/ kg of bodyweight per day has to be respected.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary The signs of overdose resemble those of the adverse reactions as described in section 4.6. In case of overdose, it is useful to accelerate excretion of ephedrine by acidification of the urine and enhanced diuresis.

4.11 Withdrawal period(s) Not applicable.

5. PHARMACOLOGICAL PROPERTIES Pharmacotherapeutic group:urologicals. ATC vet code: QG04BX90.

5.1 Pharmacodynamic properties

Ephedrine directly stimulates alpha- and beta-adrenergic receptors, present in all organ systems. It also stimulates the release of catecholamines from sympathetic neurons. Since ephedrine passes the blood-brain barrier, it also induces effects that are mediated through the central nervous system. Ephedrine specifically causes a contraction of the internal urethral sphincter muscles and a relaxation of the bladder muscles through a sympathomimetic action on the adrenergic receptors.

5.2 Pharmacokinetic particulars Ephedrine is rapidly absorbed, and the bioavailability is high. Ephedrine is widely distributed over the body. Degradation by demethylation to norephedrine is the major metabolic pathway. Within 48 hours, urinary excretion accounts for elimination of 80 to 90 % of the administered dose, at high urinary acidity.

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Colloidal silica Lactose monohydrate Microcrystalline cellulose Magnesium stearate 6.2 Major incompatibilities None known.

6.3 Shelf life Shelf-life of the veterinary medicinal product as packaged for sale: 5 years.

6.4. Special precautions for storage Do not store above 25°C. Store in the original container. Divided tablets should be returned in the original package and used in the subsequent dose. Close the cap to the click. 6.5 Nature and composition of immediate packaging White polypropylene container containing 100 tablets, with child-resistant closure system, in a cardboard box. The packaging might also contain a polyurethane cover-up.

6.6 Special precautions for the disposal of unused veterinary medicinal product or waste

materials derived from the use of such products Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER Ecuphar NV Legeweg 157-i 8020 Oostkamp

Belgium

8. MARKETING AUTHORISATION NUMBER(S) To be completed nationally. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: to be completed nationally. Date of last renewal: to be completed nationally.

10 DATE OF REVISION OF THE TEXT

PROHIBITION OF SALE, SUPPLY AND/OR USE To be supplied only on veterinary prescription.

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGE

{CARDBOARD BOX}

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

ENURACE 50, 50 mg tablets for dogs (Ephedrine HCl)

2. STATEMENT OF ACTIVE SUBSTANCES

Per tablet 50 mg ephedrine HCl.

3. PHARMACEUTICAL FORM

Tablets.

4. PACKAGE SIZE

100 tablets.

5. TARGET SPECIES

Dog

6. INDICATION(S)

7. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral, with food. 1-3 mg/kg/day divided in 2 doses. Read the package leaflet before use.

8. WITHDRAWAL PERIOD(S)

9. SPECIAL WARNING(S), IF NECESSARY

Accidental ingestion by man, especially children, is dangerous. Read the package leaflet before use.

10. EXPIRY DATE

EXP month/year

11. SPECIAL STORAGE CONDITIONS

Do not store above 25°C. Store in the original package. Divided tablets should be returned in the original package and used in the subsequent dose. Close the cap to the click.

12. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR

WASTE MATERIALS, IF ANY

Disposal: read package leaflet.

13. THE WORDS “FOR ANIMAL TREATMENT ONLY” AND CONDITIONS OR

RESTRICTIONS REGARDING SUPPLY AND USE, IF APPLICABLE

For animal treatment only. To be supplied only on veterinary prescription.

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

Keep out of the sight and reach of children.

15. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Ecuphar NV Legeweg 157-i 8020 Oostkamp Belgium

16. MARKETING AUTHORISATION NUMBER(S)

To be completed nationally.

17. MANUFACTURER’S BATCH NUMBER

Lot

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGE

{POLYPROPYLENE CONTAINER}

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

ENURACE 50, 50 mg tablets for dogs (Ephedrine HCl)

2. STATEMENT OF ACTIVE SUBSTANCES

Per tablet 50 mg ephedrine HCl.

3. PHARMACEUTICAL FORM

Tablets.

4. PACKAGE SIZE

100 tablets

5. TARGET SPECIES

Dog

6. INDICATION(S)

7. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

8. WITHDRAWAL PERIOD(S)

9. SPECIAL WARNING(S), IF NECESSARY

Accidental ingestion by man, especially children, is dangerous. Close the cap to the click. Read the package leaflet before use.

10. EXPIRY DATE

EXP month/year

11. SPECIAL STORAGE CONDITIONS

Do not store above 25°C. Store in the original container.

12. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR WASTE MATERIALS, IF ANY

Disposal: read package leaflet.

13. THE WORDS “FOR ANIMAL TREATMENT ONLY” AND CONDITIONS OR

RESTRICTIONS REGARDING SUPPLY AND USE, IF APPLICABLE

For animal treatment only. To be supplied only on veterinary prescription.

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

Keep out of the sight and reach of children.

15. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Ecuphar NV Legeweg 157-i 8020 Oostkamp Belgium

16. MARKETING AUTHORISATION NUMBER(S)

To be completed nationally.

17. MANUFACTURER’S BATCH NUMBER

Lot

B. PACKAGE LEAFLET

PACKAGE LEAFLET:

ENURACE 50, 50 mg tablets for dogs

1. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AND OF

THE MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH

RELEASE, IF DIFFERENT Marketing authorisation holder: Ecuphar NV Legeweg 157-i 8020 Oostkamp Belgium Manufacturer responsible for batch release: Ecuphar NV Legeweg 157-i 8020 Oostkamp Belgium ACE Pharmaceuticals BV Schepenveld 41 3891 ZK Zeewolde The Netherlands

2. NAME OF THE VETERINARY MEDICINAL PRODUCT ENURACE 50, 50 mg tablets for dogs (Ephedrine HCl)

3. STATEMENT OF THE ACTIVE SUBSTANCE(S) AND OTHER INGREDIENT(S) The product contains 50 mg ephedrine HCl per tablet, corresponding with 40.7 mg ephedrine. The tablet can be divided in two equal parts, each part containing 25 mg ephedrine HCl.

4. INDICATION(S) Treatment of unwanted loss of urine (urinary incontinence) due to too low tension in the circular muscles closing the urethra (urethral sphincter mechanism incompetence) in ovariohysterectomised female dogs.

5. CONTRAINDICATIONS Do not use the product in dogs with increased pressure in the eye (glaucoma). Do not use in cases of hypersensitivity to the active substance or to any of the excipients.

6. ADVERSE REACTIONS Disorders of the heart and blood circulation (tachycardia, atrium fibrillation, stimulation of the

heart activity; vasoconstriction). Stimulation of the central nervous system, leading to sleeplessness, excitation, anxiety and

trembling of the muscles (muscle tremors). Panting.

Dilatation of the pupils (mydriasis). Bladder infection (cystitis). Relaxation of the muscles of the lungs (bronchodilatation) and decrease of mucus release in the

lungs (respiratory mucosal membranes). Reduction of the motion (motility) and tension (tone) of the intestinal wall. Due to the nature of ephedrine the above-mentioned effects can occur at the recommended therapeutic dose, with anxiety and cardiovascular effects being the most prevalent. In 10% of the treatments, side effects have been observed in efficacy studies. Vomiting has been reported very rarely in spontaneous reports. The frequency of adverse reactions is defined using the following convention: - very common (more than 1 in 10 animals treated displaying adverse reaction(s)) - common (more than 1 but less than 10 animals in 100 animals treated) - uncommon (more than 1 but less than 10 animals in 1,000 animals treated) - rare (more than 1 but less than 10 animals in 10,000 animals treated) - very rare (less than 1 animal in 10,000 animals treated, including isolated reports). 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 inform your veterinary surgeon.

7. TARGET SPECIES Ovariohysterectomised female dogs.

8. DOSAGE FOR EACH SPECIES, ROUTE(S) AND METHOD OF ADMINISTRATION For oral administration only. Give a starting dose of 2 mg ephedrine HCl / kg / day, divided in two oral doses. Dose according to the following dosing scheme:

Weight (kg)

Dose (mg/day)

Dose (Number of tablets)

per day 1st gift 2nd gift

20-30 50 1 ½ ½

31-40 75 1 ½ ½ 1

41-50 100 2 1 1

Desired therapeutic effect and occurrence of adverse effects have to be monitored approximately at 14 days, 1 month, 3 months and 6 months after the start. Based on the observed effect in comparison with the expected effect and taking into account the occurrence of adverse effects, the individual dose should be adjusted. The dose should be adjusted to find the lowest effective dose. Once the effective dose has been established, dogs should still be monitored at regular intervals, e.g. every six months. The product should be administered before meals in a piece of food. A maximum dose of 5 mg/ kg of bodyweight per day has to be respected.

9. ADVICE ON CORRECT ADMINISTRATION Pregnant women should wear gloves.

10. WITHDRAWAL PERIOD(S)

Not applicable.

11. SPECIAL STORAGE PRECAUTIONS Keep out of the sight and reach of children. Do not store above 25°C. Store in the original container. Return divided tablet in the original package and use this tablet in the subsequent dose. Close the cap to the click. Do not use this veterinary medicinal product after the expiry date which is stated on the label after “EXP”. The expiry date refers to the last day of that month.

12. SPECIAL WARNING(S) Special warnings for each target species: This product is not suitable for treatment of inappropriate urination due to behaviour problems. Special precautions for use in animals: Do not use the product in dogs under 20 kg bodyweight. As ephedrine is an alpha- and beta-adrenergic receptor agonist, the product should be used with caution in dogs with cardiovascular disease and only after a comprehensive risk/benefit analysis by the attending veterinarian. The dog’s cardiovascular functionality should be carefully assessed before the start of the treatment with the product and it should be periodically monitored during the treatment. In addition, a similar approach should be adopted in animals suffering from partial urethral obstruction, hypertension, diabetes mellitus, hyperadrenocorticism, hyperthyroidism or other metabolic disorders. It should be mentioned that the polyuria/polydipsia (PU/PD) frequently accompanying the aforementioned conditions may be falsely diagnosed as urinary incontinence. Special precautions to be taken by the person administering the veterinary medicinal product to animals: It is strongly recommended that pregnant women should wear gloves for administration. Wash hands after administration. Warnings on accidental ingestion Ephedrine hydrochloride could be toxic if ingested. Adverse effects may include insomnia and nervousness, dizziness, headache, increased blood pressure, increased sweating and nausea. Ingestion may be fatal, especially in children. To avoid accidental ingestion, the product must be used and kept out of the reach of children. Always replace the cap securely after use. In the event of accidental ingestion, most importantly by children, seek immediate medical attention showing the physician the package insert. Interaction with other medicinal products and other forms of interaction: Ephedrine may interact with other sympathomimetics. Ephedrine may enhance the metabolism of hormones of the pituitary gland (glucocorticoid

metabolism). Concomitant use with MAO-inhibitors (used for treatment of depression) may cause increased

blood pressure (hypertension). Ephedrine can enhance the activity of products of the same class as theophylline (used in treatment

of epilepsy). Volatile anaesthetics may enhance the sensitivity of the heart muscle (myocardium) to the effects

on heart and blood vessels (cardiovascular effects) of ephedrine.

Concomitant use with cardiac glycosides (used to increase the pump force of the heart), quinine (anti-infection) and tricyclic antidepressants (used for treatment of depressions) can cause disorders of the heart rhythm (arrhythmias).

Constrictions of the blood vessels (vascular constrictions) can occur after concomitant treatment with ergot alkaloids and oxytocin (both used for the induction of labour).

Substances leading to an increase in pH of the urine are able to prolong the excretion of ephedrine, whereas substances leading to a decrease in pH of the urine are able to accelerate the excretion of ephedrine.

Overdose (symptoms, emergency procedures, antidotes): The signs of overdose resemble those of the adverse reactions as described in section 6. In case of overdose, it is useful to accelerate excretion of ephedrine by acidification of the urine and enhanced diuresis.

13. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCT OR WASTE

MATERIALS, IF ANY Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

14. DATE ON WHICH THE PACKAGE LEAFLET WAS LAST APPROVED To be completed nationally.

15. OTHER INFORMATION For any information about this veterinary medicinal product, please contact the local representative of

the marketing authorisation holder.