[Version 8.1, 1001/ ] ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

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1 [Version 8.1, 1001/ ] ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE VETERINARY MEDICINAL PRODUCT Caniphedrin 50 mg tablets for dogs (AT, SK, RO) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains: Active substance: Ephedrine hydrochloride (equivalent to 41.0 mg Ephedrine) 50 mg Excipients: For the full list of excipients, see section PHARMACEUTICAL FORM Tablets White tablets with score line. 4. CLINICAL PARTICULARS 4.1 Target species Dogs 4.2 Indications for use, specifying the target species For the ttreatment of urinary incontinence neurohormonally caused by dysfunction of the urethral sphincter mechanism incompetence, especially primarily urinary incontinence after spaying of thein ovariohysterectomised bitches. 4.3 Contraindications Do not use in dogs with cardiomyopathyorganic myocardial damage; tachycardic arrhythmias; hypertension; hyperthyroidism; diabetogenic diabetes metabolismmellitus; impaired renal function; glaucoma; anaesthesia with halogenated narcotics such as halothane or methoxyflurane. Do not use in food-producing animals. Do not use in case of hypersensitivity to the active substance or to any of the excipients. 4.4 Special warnings for each target species None. 4.5 Special precautions for use Special precautions for use in animals Not applicable.it is not appropriate to use the product for the behavioural cause of inappropriate urination. In bitches less than 1 year old the possibility of anatomical disorders contributing to incontinence should be considered prior to treatment. It is important to identify any underlying disease causing Polyuria/Polydipsia (PU/PD) which may be falsely diagnosed as urinary incontinence. Adequate treatment should be initiated. 2

3 Special precautions to be taken by the person administering the veterinary medicinal product to animals In case of In the event ofaccidental ingestion, most importantly by children, seek medical advice immediately and show the package leaflet or the label to the physician. 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 to children. To avoid accidental ingestion, the product must be used and kept out of the reach of children. People with known hypersensitivity to ephedrine should avoid contact with the veterinary medicinal product. It is strongly recommended that pregnant women should wear gloves for administration. 4.6 Adverse reactions (frequency and seriousness) In rare cases iincreased pulse ratefrequency, ventricular arrhythmia and central nervous excitation have been observed (more than 1 but less than 10 animals in 10,000 animals treated).can occur in isolated cases. These symptoms disappear following doseagain after reducing reduction the dose or termination of treatment.discontinuing the medication. 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 This medicinal product should Do not be used in the pregnant and lactating bitches. 4.8 Interaction with other medicinal products and other forms of interaction The potency of the veterinary medicinal product andpotentiated effect or increased the risk of adverse reactions may be increased when with concomitant administratered iontogether with of methylxanthines, sympathomimetics drugs and medicinal products leading to urine alkalisation. There is a that cause alkalinisation of urine. rrisk of cardiac arrhythmia when combineds when given in combination with digitalis glycosides and halogenated narcotics. Sympatholytics may decrease the efficacy of the veterinary medicinal product. Attenuation by sympatholytic drugs. 4.9 Amounts to be administered and administration route For oral administration. The tablets can be divided into 2 or 4 equal parts to ensure accurate dosing. The recommended starting dose isunless otherwise prescribed, administer 2 mg ephedrine hydrochloride per kg bodyweight (BW), equivalent to 1 tablet per 25 kg BW, per day during the first 10 days of treatment;. Once the If the desired effect has beenis achieved, the dose can be reduced to one half or less. Based on the observed effect and taking into account the occurrence of adverse effects, the individual dose should be adjusted to find the lowest effective dose. The lowest effective dose should be maintained for long-term treatment. IThe reduced dose level is maintained for permanent therapy; in case of a relapse, the dose has to should be increased to 2 mg ephedrine hydrochloride per kg BW again. the effective dose has been established, dogs should still be monitored at regular intervals. 3

4 4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary Ephedrine has an adequate safety margin sufficient therapeutic index. Undesirable effects such as hyperexcitation, increased in blood pressure and tachycardia generally disappear following dose after reductionng or termination of treatment. the dose or discontinuing the medication. The following symptomatic treatment may be initiatedthe emergency procedures are symptomatic: - if necessary gastric lavage, if necessary - in case of strong severe hyperexcitation, administration of sedatives such as diazepam or neuroleptics - in case of tachyarrhythmia, administration of Beta-Blockers -blocking substances - acceleration accelerated of eliminationexcretion by acidification of the urine and enhanced diuresis 4.11 Withdrawal period(s) Not applicable. 5. PHARMACOLOGICAL PROPERTIES Pharmacotherapeutic group: urologicals, ephedrine ATCvet code: QG04BX Pharmacodynamic properties The active substance ephedrine contained in Caniphedrin 50 mg tablets is an indirect sympathomimetic drug that works by increasing the level of noradrenalin in the synaptic cleft of sympathetic neurons. Owing to its structure, ephedrine also has a direct effect on -adrenergic receptors. Ephedrine thus has adrenalin-like effects that are less potent but more prolonged than under adrenalin. The sympathetic stimulation causes an increase in blood pressure through -mimetic vasoconstriction and a 1 -mimetic increase in the cardiac output, which is accompanied by a decrease in pulse owing to reflexive counterregulation of the heart at therapeutic doses. Tachycardia and tachycardic arrhythmia only occur at high doses. In organs with smooth muscles, ephedrine causes a decrease in muscle tone which leads to a reduced intestinal peristaltic activity and relaxation of the uterus and bronchial muscles. In sphincters, on the other hand, the muscle tone is increased. This increase in muscle tone also occurs in the urethral sphincter and leads to closure of the urethra when the tone of the bladder muscles is reduced at the same time. These effects can be taken advantage of in the treatment of urinary incontinence. In At the eye, mydriasis occurs while the pupillary reflex is maintainedwith a preserved reaction to light. Unlike adrenalin, ephedrine can cross the blood-brain barrier to a limited extent and cause excitatory effects at high doses, such as stimulation of breathing and psychomotor restlessness, in the CNS. Following repeated administration of high doses, a rapid attenuation of the effect (tachyphylaxis) can occur due to emptying of the noradrenalin reservoirs, which affects the cardiovascular reactions in particular. However, at the low doses used in the treatment of urinary incontinence, this tachyphylaxis has no therapeutic significance and was not observed in clinical trials in bitches with urinary incontinence. When administered orally, ephedrine has mild acute toxicity. When administered intravenously, 75 mg/kg was established as a lethal dose in the dog. After oral administration, the toxicity in test laboratory animals was around eight times lower. Signs of chronic toxicity were not observed during long-term therapy in humans and animals. Owing to the rapid elimination, prolonged use of ephedrine at the recommended dosing regimen does not lead to accumulation. Side effects associated with the treatment with ephedrine in urinary incontinence are a result of the undesirable sympathomimetic effects such as a moderate increase in blood pressure, palpitations and extrasystoles as well as a reduced gastrointestinal tone. A clinically relevant potentiation of the sympathomimetic effects and central hyperexcitation occur only after marked overdose. In clinical trials, ephedrine was well tolerated in the bitch. Clinically relevant side effectsadverse reactions have not been observed. and, only in very rare cases, ccentral nervous symptoms were not have been rarely observed. 4

5 5.2 Pharmacokinetic particulars Ephedrine has similar pharmacokinetic properties in humans and animals. After oral administration it is rapidly and practically completely absorbed, whereby peak plasma levels are achieved after one hour. Ephedrine is rapidly distributed in all tissues and can also gradually penetrate the CNS. Ephedrine is not broken down by the metabolic pathways of thedegraded via the endogenous catecholamine pathwayss, which explains the oral and longer efficacyprolonged duration of activity compared to adrenaline. N- demethylation generates norephedrine as the major metabolite, a potent metabolite that is formed very rapidly in dogs and appears to contribute significantly to the effect of ephedrine. Elimination takes place via the kidneys and is nearly completed after 24 hours. The half-life is 3 to 6 hours. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Gelatine, potato starch, lactose monohydrate, talc, microcrystalline cellulose, glycerol 85 % 6.2 Incompatibilities None known. 6.3 Shelf life Shelf life of the veterinary medicinal product as packaged for sale: 3 years. Unused divided tablets should be returned to the blister and used in the subsequent dose.do not use this medicinal product after the expiry date which is stated on the blister and carton Special precautions for storage Store in a cool and dry place protected from light.keep out of the sight and reach of children. 6.5 Nature and composition of immediate packaging Heat-sealed blister pack, consisting of aluminium foil and a PVC foil with 10 tablets per blister. Cardboard box containing 10 blisters of 10 tablets each. 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 product should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Richter Pharma AG, Feldgasse 19, 4600 Wels, Austria 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: {DD month YYYY} 5

6 10 DATE OF REVISION OF THE TEXT {MM/YYYY} PROHIBITION OF SALE, SUPPLY AND/OR USE Not applicable. 6

7 ANNEX III LABELLING AND PACKAGE LEAFLET 7

8 A. LABELLING 8

9 PARTICULARS TO APPEAR ON THE OUTER PACKAGE Cardboard box 1. NAME OF THE VETERINARY MEDICINAL PRODUCT Caniphedrin 50 mg tablets for dogs (AT, SK, RO) Ephedrine hydrochloride 2. STATEMENT OF ACTIVE AND OTHER SUBSTANCES Each tablet contains: Ephedrine hydrochloride 50 mg (equivalent to 41.0 mg Ephedrine) 3. PHARMACEUTICAL FORM Tablets. 4. PACKAGE SIZE 100 tablets 5. TARGET SPECIES Dogs. 6. INDICATION(S) - 7. METHOD AND ROUTE(S) OF ADMINISTRATION Kommentiert [AW1]: Due to space restrictions because of multilingual package and since the pharmaceutical form and target species are mentioned in the name of the veterinary medicinal product the applicant grey shaded Tablets.. Formatiert: Hervorheben Kommentiert [AW2]: Due to space restrictions because of multilingual package and since the pharmaceutical form and target species are mentioned in the name of the veterinary medicinal product the applicant grey shaded Dogs.. Formatiert: Hervorheben For oral administration. Read the package leaflet before use. 8. WITHDRAWAL PERIOD(S) - 9. SPECIAL WARNING(S), IF NECESSARY Accidental ingestion is dangerous. Read the package leaflet before use. 10. EXPIRY DATE EXP {month/year} 11. SPECIAL STORAGE CONDITIONS 9

10 Store in a cool and dry place protected from light. Unused divided tablets should be returned to the blister and used in the subsequent dose. 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 Richter Pharma AG, 4600 Wels, Austria 16. MARKETING AUTHORISATION NUMBER(S) 17. MANUFACTURER S BATCH NUMBER Lot {number} 10

11 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS blister with 10 tablets 1. NAME OF THE VETERINARY MEDICINAL PRODUCT Caniphedrin 50 mg tablets for dogs (AT, SK, RO) Ephedrine hydrochloride 2. NAME OF THE MARKETING AUTHORISATION HOLDER Richter Pharma AG 3. EXPIRY DATE EXP {month/year} 4. BATCH NUMBER Lot {number} 5. THE WORDS FOR ANIMAL TREATMENT ONLY For animal treatment only. 11

12 B. PACKAGE LEAFLET 12

13 PACKAGE LEAFLET FOR: Caniphedrin 50 mg tablets for dogs (AT, SK, RO) 1. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AND OF THE MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE, IF DIFFERENT Marketing authorisation holder: Richter Pharma AG, Feldgasse 19, 4600 Wels, Austria Manufacturer responsible for batch release: Richter Pharma AG, Durisolstrasse 14, 4600 Wels, Austria 2. NAME OF THE VETERINARY MEDICINAL PRODUCT Caniphedrin 50 mg tablets for dogs Ephedrine hydrochloride 3. STATEMENT OF THE ACTIVE SUBSTANCE(S) AND OTHER INGREDIENT(S) Each tablet contains: Active substance: Ephedrine hydrochloride 50 mg (equivalent to 41.0 mg Ephedrine) White tablets with score line. 4. INDICATION(S) For the ttreatment of urinary incontinenceneurohormonally caused by dysfunction of the urethral sphincter mechanism incompetence, primarilyespecially urinary incontinence in ovariohysterectomisedafter spaying of the bitches. 5. CONTRAINDICATIONS Do not use in dogs with cardiomyopathyorganic myocardial damage; tachycardic arrhythmias; hypertension; hyperthyroidism; diabetes mellitusdiabetogenic metabolism; impaired renal function; glaucoma; anaesthesia with halogenated narcotics such as halothane or methoxyflurane. Do not use in food-producing animals. Do not use in case of hypersensitivity to the active substance or to any of the excipients. 6. ADVERSE REACTIONS In rare cases iincreased pulse frequencyrate, ventricular arrhythmia and central nervous excitation can occur have been observed. in isolated cases. These symptoms disappear following dose reductionagain after reducing the dose or termination of treatmentdiscontinuing the medication. 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 ) 13

14 - 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 serious side effects, even those not already listed in this package leaflet or you think that the medicine has not worked, or other effects not mentioned in this package leaflet, please inform your veterinary surgeon. 7. TARGET SPECIES Dogs 8. DOSAGE FOR EACH SPECIES, ROUTE(S) AND METHOD OF ADMINISTRATION For oral administration. The tablets can be divided into 2 or 4 equal parts to ensure accurate dosing. The recommended starting dose isunless otherwise prescribed, administer 2 mg ephedrine hydrochloride per kg bodyweight (BW), equivalent to 1 tablet per 25 kg BW, per day during the first 10 days of treatment; this is. Once theif the desired effect is has been achieved, the dose can be reduced to one half or less. Based on the observed effect and taking into account the occurrence of adverse effects, the individual dose should be adjusted to find the lowest effective dose. The lowest effective dose should be maintained for long-term treatment. IThe reduced dose level is maintained for permanent therapy; in case of a relapse, the dose should be increased to 2 mg ephedrine hydrochloride per kg BW again. Once the effective dose has been established, dogs should still be monitored at regular intervals. 9. ADVICE ON CORRECT ADMINISTRATION Tablets can be divided into 2 equal parts to ensure accurate dosing. Pregnant women should wear gloves. 10. WITHDRAWAL PERIOD Not applicable. 11. SPECIAL STORAGE PRECAUTIONS Keep out of the sight and reach of children. Store in a cool and dry place protected from light. Unused divided tablets should be returned to the blister and used in the subsequent dose. Do not use this veterinary medicinal product after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month. 12. SPECIAL WARNING(S) Special warnings for each target species: None. Special precautions for use in animals: It is not appropriate to use the product for the behavioural cause of inappropriate urination. In bitches less than 1 year old the possibility of anatomical disorders contributing to incontinence should be considered prior to treatment. 14

15 It is important to identify any underlying disease causing Polyuria/Polydipsia (PU/PD) which may be falsely diagnosed as urinary incontinence. Adequate treatment should be initiated. Not applicable. Special precautions to be taken by the person administering the veterinary medicinal product to animals: In case of accidental ingestion, most importantly by children, seek medical advice immediately and show the package leaflet or the label to the physician. 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 to children. To avoid accidental ingestion, the product must be used and kept out of the reach of children. People with known hypersensitivity to ephedrine should avoid contact with the veterinary medicinal product. It is strongly recommended that pregnant women should wear gloves for administration. In the event of accidental ingestion, most importantly by children, seek medical advice immediately and show the package leaflet or the label to the physician. Pregnancy and lactation: This medicinal product shoulddo not be used in the pregnant and lactating bitches. Interaction with other medicinal products and other forms of interaction: The potency of the veterinary medicinal product and thepotentiated effect or increased risk of adverse reactions may be increased when with concomitant administered together withration of methylxanthines, sympathomimetics drugs and medicinal products leading to urine alkalisation. There is a rthat cause alkalinisation of urine. Risk of cardiac arrhythmias when given in combinedation with digitalis glycosides and halogenated narcotics. Sympatholytics may decrease the efficacy of the veterinary medicinal productattenuation by sympatholytic drugs. Overdose (symptoms, emergency procedures, antidotes): Ephedrine has an adequate safety margin sufficient therapeutic index. Undesirable effects such as hyperexcitation, increased in blood pressure and tachycardia generally disappear after following dose reductiong or termination of treatment. the dose or discontinuing the medication. The following symptomatic treatment may be initiatedthe emergency procedures are symptomatic: - if necessary gastric lavage, if necessary - in case of strong severe hyperexcitation, administration of sedatives such as diazepam or neuroleptics - in case of tachyarrhythmia, administration of Beta-Blockers -blocking substances - accelerated excretionion of elimination by acidification of the urine and enhanced diuresis Incompatibilities: None known. 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 product should be disposed of in accordance with local requirements. 14. DATE ON WHICH THE PACKAGE LEAFLET WAS LAST APPROVED dd/mm/yyy 15

16 15. OTHER INFORMATION Package sizes: Cardboard box containing 10 blisters of 10 tablets each. For any information about this veterinary medicinal product, please contact the local representative of the marketing authorisation holder. 16