1. NAME OF THE VETERINARY MEDICINAL PRODUCT

pecial precautions for use in animals

Kidney function and serum potassium levels should be evaluated before initiating combined treatment with spironolactone and Angiotensin Converting Enzyme (ACE) inhibitors. Unlike in humans, an increased incidence of hyperkalaemia was not observed in clinical trials performed in dogs with this combination. However, in dogs with renal impairment regular monitoring of renal function and serum potassium levels is recommended as there may be an increased risk of hyperkalaemia.

Dogs treated concomitantly with spironolactone and NSAIDs should be correctly hydrated.

Monitoring of their renal function and plasma potassium levels is recommended before initiation and during treatment with combined therapy (see section 4.3).

As spironolactone has an antiandrogenic effect, it is not recommended to administer the veterinary medicinal product to growing dogs.

As spironolactone undergoes extensive hepatic biotransformation, care should be taken when using veterinary medicinal product to treat dogs with hepatic dysfunction.

Special precautions to be taken by the person administering the veterinary medicin animals

May cause skin sensitisation: people with known hypersensitivity to spironolacto contact with the veterinary medicinal product. Wash hands after use.

In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.

• 4.6 Adverse reactions (frequency and seriousness)

  
  

A reversible prostatic atrophy is often observed in entire ma

• 4.7 Use during pregnancy, lactation or lay

Do not use during pregnancy and lactation, laboratory studies in species (rat, mouse, rabbit and monkey) have shown evidence of developmental toxic

4.8 Interaction with other medicinal products other forms of interaction

Furosemide and pimobendan have been used together with Spironolactone Ceva in dogs with heart failure without any clinical evidence of adverse reactions.

Spironolactone decreases digoxin elimination and hence raises digoxin plasma concentration. As the therapeutic index for digoxin is very narrow, it is advisable to monitor closely dogs receiving both digoxin and spironolactone.

The administration of either deoxycorticosterone or NSAIDs with spironolactone may lead to a moderate reduction of the natriuretic effects (reduction of urinary sodium excretion) of spironolactone. Concomitant administration of spironolactone with ACE-inhibitors and other potassium-sparing drugs (as angiotensin receptor blockers, ß-blockers, calcium channels blockers…etc) may potentially lead to hyperkalaemia (see section 4.5).

Spironolactone may cause both induction and inhibition of cytochrome P450 enzymes and could therefore affect the metabolism of other drugs utilizing these metabolic pathways.

• 4.9 Amounts to be administered and administration route

  Oral use.

  
  

/kg of body weight of spironolactone once daily. The veterinary medicinal product should be administered with food. The tablet can either be mixed with a small amount of food offered prior to the main meal, or administered directly into the mouth after feeding.

lets contain beef flavouring to improve palatability, and a study conducted in healthy dogs that they were voluntarily and fully consumed 75% of the time.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessaryto healthy dogs, dose-

After administration of up to 10 times the recommended dose dependent adverse effects were noted (see section 4.6).

In case of an accidental massive ingestion by a dog, there is n therefore recommended to induce vomiting, gastric lavage (depending on risk assessment) and monitor electrolytes. Symptomatic treatment, e.g., fluid therapy, should be provided.

• 4.11 Withdrawal period

  5. PHARMACOLO­GICAL

  
  

Not applicable.

Pharmacotherapeutic group: Aldosterone antagonist. ATCvet code: QC03DA01.

5.1 Pharmacodynamic properties

Spironolactone and its active metabolites (including 7a-thiomethyl-spironolactone and canrenone) act as specific antagonists of aldosterone, and exert their effects by binding competitively to the mineralocorticoid receptor located in the kidneys, heart and blood vessels.

Spironolactone is a natriuretic drug (historically described as a soft diuretic). In the kidney, spironolactone inhibits the aldosterone-induced sodium retention leading to increase in sodium and subsequently water excretion, and potassium retention.

The renal effects of spironolactone and its metabolites lead to a decrease in extracellular volume and consequently in a decrease of cardiac preload and left atrial pressure. The result is an improvement in heart function.

In the cardiovascular system, spironolactone prevents the detrimental effects of aldosterone. Although the precise mechanism of action is not yet clearly defined, aldosterone promotes myocardial fibrosis, myocardial and vascular remodelling and endothelial dysfunction.

In experimental models in dogs, it was shown that long term therapy with an aldosterone antagonist prevents progressive left ventricle dysfunction and attenuates left ventricle remodelling in dogs with chronic heart failure.

In a clinical study investigating the survival time in dogs with congestive heart failure, there was a 65% reduction in the relative risk of mortality at 15 months in dogs treated with spironolactone in combination with standard therapy compared to dogs treated with standard therapy alone. (Mortality was classified as death or euthanasia due to heart failure).

When used in combination with ACE-inhibitors, spironolactone may counteract the effects of “aldosterone escape”.

A slight increase in aldosterone blood levels may be observed in animals on treatment. This is thought to be due to activation of feedback mechanisms without adverse clinical consequence. There may be a dose related hypertrophy of the adrenal zona glomerulosa at high dose rates.

• 5.2 Pharmacokinetic particulars

The pharmacokinetics of spironolactone are based on its metabolites, as the parent compound is unstable at assay.

Absorption

After oral administration of spironolactone to dogs, it was demonstrated that the three metabolites achieved levels from 32 % to 49 % of the administered dose. Food increases the bioavailability from 80 % to 90 %. Following oral administration of 2 to 4 mg/kg, absorption increases linearly over the range. After multiple oral doses of 2 mg spironolactone/ kg for 10 consecutive days, no accumulation is observed. Mean Cmax of 382 jxg/l and 94 pg/l are achieved for the primary metabolites, 7a-thiomethyl-spironolactone and canrenone, after 2 and 4 hours, respectively. Steady-state conditions are reached by day 2.

Distribution

The mean volumes of distribution (Vss) of 7a-thiomethyl-spironolactone and canrenone are approximately 153 litres and 177 litres, respectively.

The mean residence time of the metabolites ranges from 9 to 14 hours and they are preferentially distributed to the gastro-intestinal tract, kidney, liver and adrenal glands.

Metabolism

Spironolactone is rapidly and completely metabolised by the liver into its active metabolites, 7a-thiomethyl-spironolactone and canrenone, which are the primary metabolites in the dog.

Elimination

Spironolactone is mainly excreted via its metabolites. Plasma clearance of canrenone is 1.45±0.39 l/h/kg and 7a-thiomethyl-spironolactone is 0.89±0.44 l/h/kg. After oral administration of radiolabelled spironolactone to the dog, 70 % of the dose is recovered in faeces and 20 % in the urine.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Lactose monohydrate

Cellulose, microcrystalline

Crospovidone

Povidone K30

Artificial beef flavour

Compressible sugar

Magnesium stearate

6.2 Incompati­bilities

Not applicable.

6.3 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 3 years

2 months after first opening the bottle.

X?

6.4. Special precautions for storage

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

Partially used tablets should be stored in the original bottle.

• 6.5 Nature and composition of immediate packaging

White HDPE bottle containing 30 tablets with a white polypropylene child-resistant tamper-evident screw cap fitted with a desiccant insert, packaged in a cardboard box.

Not all pack sizes may be marketed.

• 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

Ceva Santé Animale

10, av. de La Ballastière

33500 Libourne

France

8. MARKETING AUTHORISATION NUMBER(S)

EU/2/07/074/007–009

9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

Date of first authorisation: 20 June 2007

Date of last renewal: 22 May 2012

10 DATE OF REVISION OF THE TEXT

Detailed information on this veterinary medicinal product is available on the website of the European

Medicines Agency.

PROHIBITION OF SALE, SUPPLY AND/OR USE

Not applicable.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Spironolactone Ceva 10 mg contains 10 mg spironolactone

Spironolactone Ceva 40 mg contains 40 mg spironolactone

Spironolactone Ceva 80 mg contains 80 mg spironolactone

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS4.1 Target species

Dogs.

4.2 Indications for use, specifying the target species

pecial precautions for use in animals

Kidney function and serum potassium levels should be evaluated before initiating combined treatment with spironolactone and Angiotensin Converting Enzyme (ACE) inhibitors. Unlike in humans, an increased incidence of hyperkalaemia was not observed in clinical trials performed in dogs with this combination. However, in dogs with renal impairment regular monitoring of renal function and serum potassium levels is recommended as there may be an increased risk of hyperkalaemia.

Dogs treated concomitantly with spironolactone and NSAIDs should be correctly hydrated.

Monitoring of their renal function and plasma potassium levels is recommended before initiation and during treatment with combined therapy (see section 4.3).

As spironolactone has an antiandrogenic effect, it is not recommended to administer the veterinary medicinal product to growing dogs.

As spironolactone undergoes extensive hepatic biotransformation, care should be taken when using veterinary medicinal product to treat dogs with hepatic dysfunction.

Special precautions to be taken by the person administering the veterinary medicin animals

May cause skin sensitisation: people with known hypersensitivity to spironolacto contact with the veterinary medicinal product. Wash hands after use.

In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.

• 4.6 Adverse reactions (frequency and seriousness)

  
  

A reversible prostatic atrophy is often observed in entire ma

• 4.7 Use during pregnancy, lactation or lay

Do not use during pregnancy and lactation, laboratory studies in species (rat, mouse, rabbit and monkey) have shown evidence of developmental toxic

4.8 Interaction with other medicinal products other forms of interaction

Furosemide and pimobendan have been used together with Spironolactone Ceva in dogs with heart failure without any clinical evidence of adverse reactions.

Spironolactone decreases digoxin elimination and hence raises digoxin plasma concentration. As the therapeutic index for digoxin is very narrow, it is advisable to monitor closely dogs receiving both digoxin and spironolactone.

The administration of either deoxycorticosterone or NSAIDs with spironolactone may lead to a moderate reduction of the natriuretic effects (reduction of urinary sodium excretion) of spironolactone. Concomitant administration of spironolactone with ACE-inhibitors and other potassium-sparing drugs (as angiotensin receptor blockers, ß-blockers, calcium channels blockers…etc) may potentially lead to hyperkalaemia (see section 4.5).

Spironolactone may cause both induction and inhibition of cytochrome P450 enzymes and could therefore affect the metabolism of other drugs utilizing these metabolic pathways.

• 4.9 Amounts to be administered and administration route

  Oral use.

  
  

/kg of body weight of spironolactone once daily. The veterinary medicinal product should be administered with food. The tablet can either be mixed with a small amount of food offered prior to the main meal, or administered directly into the mouth after feeding.

lets contain beef flavouring to improve palatability, and a study conducted in healthy dogs that they were voluntarily and fully consumed 75% of the time.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessaryto healthy dogs, dose-

After administration of up to 10 times the recommended dose dependent adverse effects were noted (see section 4.6).

In case of an accidental massive ingestion by a dog, there is n therefore recommended to induce vomiting, gastric lavage (depending on risk assessment) and monitor electrolytes. Symptomatic treatment, e.g., fluid therapy, should be provided.

• 4.11 Withdrawal period

  5. PHARMACOLO­GICAL

  
  

Not applicable.

Pharmacotherapeutic group: Aldosterone antagonist. ATCvet code: QC03DA01.

5.1 Pharmacodynamic properties

Spironolactone and its active metabolites (including 7a-thiomethyl-spironolactone and canrenone) act as specific antagonists of aldosterone, and exert their effects by binding competitively to the mineralocorticoid receptor located in the kidneys, heart and blood vessels.

Spironolactone is a natriuretic drug (historically described as a soft diuretic). In the kidney, spironolactone inhibits the aldosterone-induced sodium retention leading to increase in sodium and subsequently water excretion, and potassium retention.

The renal effects of spironolactone and its metabolites lead to a decrease in extracellular volume and consequently in a decrease of cardiac preload and left atrial pressure. The result is an improvement in heart function.

In the cardiovascular system, spironolactone prevents the detrimental effects of aldosterone. Although the precise mechanism of action is not yet clearly defined, aldosterone promotes myocardial fibrosis, myocardial and vascular remodelling and endothelial dysfunction.

In experimental models in dogs, it was shown that long term therapy with an aldosterone antagonist prevents progressive left ventricle dysfunction and attenuates left ventricle remodelling in dogs with chronic heart failure.

In a clinical study investigating the survival time in dogs with congestive heart failure, there was a 65% reduction in the relative risk of mortality at 15 months in dogs treated with spironolactone in combination with standard therapy compared to dogs treated with standard therapy alone. (Mortality was classified as death or euthanasia due to heart failure).

When used in combination with ACE-inhibitors, spironolactone may counteract the effects of “aldosterone escape”.

A slight increase in aldosterone blood levels may be observed in animals on treatment. This is thought to be due to activation of feedback mechanisms without adverse clinical consequence. There may be a dose related hypertrophy of the adrenal zona glomerulosa at high dose rates.

• 5.2 Pharmacokinetic particulars

The pharmacokinetics of spironolactone are based on its metabolites, as the parent compound is unstable at assay.

Absorption

After oral administration of spironolactone to dogs, it was demonstrated that the three metabolites achieved levels from 32 % to 49 % of the administered dose. Food increases the bioavailability from 80 % to 90 %. Following oral administration of 2 to 4 mg/kg, absorption increases linearly over the range. After multiple oral doses of 2 mg spironolactone/ kg for 10 consecutive days, no accumulation is observed. Mean Cmax of 382 jxg/l and 94 pg/l are achieved for the primary metabolites, 7a-thiomethyl-spironolactone and canrenone, after 2 and 4 hours, respectively. Steady-state conditions are reached by day 2.

Distribution

The mean volumes of distribution (Vss) of 7a-thiomethyl-spironolactone and canrenone are approximately 153 litres and 177 litres, respectively.

The mean residence time of the metabolites ranges from 9 to 14 hours and they are preferentially distributed to the gastro-intestinal tract, kidney, liver and adrenal glands.

Metabolism

Spironolactone is rapidly and completely metabolised by the liver into its active metabolites, 7a-thiomethyl-spironolactone and canrenone, which are the primary metabolites in the dog.

Elimination

Spironolactone is mainly excreted via its metabolites. Plasma clearance of canrenone is 1.45±0.39 l/h/kg and 7a-thiomethyl-spironolactone is 0.89±0.44 l/h/kg. After oral administration of radiolabelled spironolactone to the dog, 70 % of the dose is recovered in faeces and 20 % in the urine.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Lactose monohydrate

Cellulose, microcrystalline

Crospovidone

Povidone K30

Artificial beef flavour

Compressible sugar

Magnesium stearate

6.2 Incompati­bilities

Not applicable.

6.3 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 3 years

2 months after first opening the bottle.

X?

6.4. Special precautions for storage

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

Partially used tablets should be stored in the original bottle.

• 6.5 Nature and composition of immediate packaging

White HDPE bottle containing 30 tablets with a white polypropylene child-resistant tamper-evident screw cap fitted with a desiccant insert, packaged in a cardboard box.

Not all pack sizes may be marketed.

• 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

Ceva Santé Animale

10, av. de La Ballastière

33500 Libourne

France

8. MARKETING AUTHORISATION NUMBER(S)

EU/2/07/074/007–009

9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

Date of first authorisation: 20 June 2007

Date of last renewal: 22 May 2012

10 DATE OF REVISION OF THE TEXT

Detailed information on this veterinary medicinal product is available on the website of the European

Medicines Agency.

PROHIBITION OF SALE, SUPPLY AND/OR USE

Not applicable.

4.3 Contraindications

Kidney function and serum potassium levels should be evaluated before initiating combined treatment with spironolactone and Angiotensin Converting Enzyme (ACE) inhibitors. Unlike in humans, an increased incidence of hyperkalaemia was not observed in clinical trials performed in dogs with this combination. However, in dogs with renal impairment regular monitoring of renal function and serum potassium levels is recommended as there may be an increased risk of hyperkalaemia.

Dogs treated concomitantly with spironolactone and NSAIDs should be correctly hydrated.

Monitoring of their renal function and plasma potassium levels is recommended before initiation and during treatment with combined therapy (see section 4.3).

As spironolactone has an antiandrogenic effect, it is not recommended to administer the veterinary medicinal product to growing dogs.

As spironolactone undergoes extensive hepatic biotransformation, care should be taken when using veterinary medicinal product to treat dogs with hepatic dysfunction.

May cause skin sensitisation: people with known hypersensitivity to spironolacto contact with the veterinary medicinal product. Wash hands after use.

In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.

4.6 Adverse reactions (frequency and seriousness)

A reversible prostatic atrophy is often observed in entire ma

4.7 Use during pregnancy, lactation or lay

Do not use during pregnancy and lactation, laboratory studies in species (rat, mouse, rabbit and monkey) have shown evidence of developmental toxic

4.8 Interaction with other medicinal products other forms of interaction

Furosemide and pimobendan have been used together with Spironolactone Ceva in dogs with heart failure without any clinical evidence of adverse reactions.

Spironolactone decreases digoxin elimination and hence raises digoxin plasma concentration. As the therapeutic index for digoxin is very narrow, it is advisable to monitor closely dogs receiving both digoxin and spironolactone.

The administration of either deoxycorticosterone or NSAIDs with spironolactone may lead to a moderate reduction of the natriuretic effects (reduction of urinary sodium excretion) of spironolactone. Concomitant administration of spironolactone with ACE-inhibitors and other potassium-sparing drugs (as angiotensin receptor blockers, ß-blockers, calcium channels blockers…etc) may potentially lead to hyperkalaemia (see section 4.5).

Spironolactone may cause both induction and inhibition of cytochrome P450 enzymes and could therefore affect the metabolism of other drugs utilizing these metabolic pathways.

4.9 Amounts to be administered and administration route

/kg of body weight of spironolactone once daily. The veterinary medicinal product should be administered with food. The tablet can either be mixed with a small amount of food offered prior to the main meal, or administered directly into the mouth after feeding.

lets contain beef flavouring to improve palatability, and a study conducted in healthy dogs that they were voluntarily and fully consumed 75% of the time.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessaryto healthy dogs, dose-

After administration of up to 10 times the recommended dose dependent adverse effects were noted (see section 4.6).

In case of an accidental massive ingestion by a dog, there is n therefore recommended to induce vomiting, gastric lavage (depending on risk assessment) and monitor electrolytes. Symptomatic treatment, e.g., fluid therapy, should be provided.

4.11 Withdrawal period

Not applicable.

Pharmacotherapeutic group: Aldosterone antagonist. ATCvet code: QC03DA01.

5.1 Pharmacodynamic properties

Spironolactone and its active metabolites (including 7a-thiomethyl-spironolactone and canrenone) act as specific antagonists of aldosterone, and exert their effects by binding competitively to the mineralocorticoid receptor located in the kidneys, heart and blood vessels.

Spironolactone is a natriuretic drug (historically described as a soft diuretic). In the kidney, spironolactone inhibits the aldosterone-induced sodium retention leading to increase in sodium and subsequently water excretion, and potassium retention.

The renal effects of spironolactone and its metabolites lead to a decrease in extracellular volume and consequently in a decrease of cardiac preload and left atrial pressure. The result is an improvement in heart function.

In the cardiovascular system, spironolactone prevents the detrimental effects of aldosterone. Although the precise mechanism of action is not yet clearly defined, aldosterone promotes myocardial fibrosis, myocardial and vascular remodelling and endothelial dysfunction.

In experimental models in dogs, it was shown that long term therapy with an aldosterone antagonist prevents progressive left ventricle dysfunction and attenuates left ventricle remodelling in dogs with chronic heart failure.

In a clinical study investigating the survival time in dogs with congestive heart failure, there was a 65% reduction in the relative risk of mortality at 15 months in dogs treated with spironolactone in combination with standard therapy compared to dogs treated with standard therapy alone. (Mortality was classified as death or euthanasia due to heart failure).

When used in combination with ACE-inhibitors, spironolactone may counteract the effects of “aldosterone escape”.

A slight increase in aldosterone blood levels may be observed in animals on treatment. This is thought to be due to activation of feedback mechanisms without adverse clinical consequence. There may be a dose related hypertrophy of the adrenal zona glomerulosa at high dose rates.

5.2 Pharmacokinetic particulars

The pharmacokinetics of spironolactone are based on its metabolites, as the parent compound is unstable at assay.

Absorption

After oral administration of spironolactone to dogs, it was demonstrated that the three metabolites achieved levels from 32 % to 49 % of the administered dose. Food increases the bioavailability from 80 % to 90 %. Following oral administration of 2 to 4 mg/kg, absorption increases linearly over the range. After multiple oral doses of 2 mg spironolactone/ kg for 10 consecutive days, no accumulation is observed. Mean Cmax of 382 jxg/l and 94 pg/l are achieved for the primary metabolites, 7a-thiomethyl-spironolactone and canrenone, after 2 and 4 hours, respectively. Steady-state conditions are reached by day 2.

Distribution

The mean volumes of distribution (Vss) of 7a-thiomethyl-spironolactone and canrenone are approximately 153 litres and 177 litres, respectively.

The mean residence time of the metabolites ranges from 9 to 14 hours and they are preferentially distributed to the gastro-intestinal tract, kidney, liver and adrenal glands.

Metabolism

Spironolactone is rapidly and completely metabolised by the liver into its active metabolites, 7a-thiomethyl-spironolactone and canrenone, which are the primary metabolites in the dog.

Elimination

Spironolactone is mainly excreted via its metabolites. Plasma clearance of canrenone is 1.45±0.39 l/h/kg and 7a-thiomethyl-spironolactone is 0.89±0.44 l/h/kg. After oral administration of radiolabelled spironolactone to the dog, 70 % of the dose is recovered in faeces and 20 % in the urine.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Lactose monohydrate

Cellulose, microcrystalline

Crospovidone

Povidone K30

Artificial beef flavour

Compressible sugar

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 3 years

2 months after first opening the bottle.

6.4. Special precautions for storage

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

Partially used tablets should be stored in the original bottle.

6.5 Nature and composition of immediate packaging

White HDPE bottle containing 30 tablets with a white polypropylene child-resistant tamper-evident screw cap fitted with a desiccant insert, packaged in a cardboard box.

Not all pack sizes may be marketed.

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

Ceva Santé Animale

10, av. de La Ballastière

33500 Libourne

France

8. MARKETING AUTHORISATION NUMBER(S)

EU/2/07/074/007–009

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 June 2007

Date of last renewal: 22 May 2012

10 DATE OF REVISION OF THE TEXT

Detailed information on this veterinary medicinal product is available on the website of the European

Medicines Agency.

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS

4.1 Target species

4.2 Indications for use, specifyi

4.3 Contraindications

4.5 Special precautions for use

Kidney function and serum potassium levels should be evaluated before initiating combined treatment with spironolactone and Angiotensin Converting Enzyme (ACE) inhibitors. Unlike in humans, an increased incidence of hyperkalaemia was not observed in clinical trials performed in dogs with thi combination. However, in dogs with renal impairment regular monitoring of renal function and potassium levels is recommended as there may be an increased risk of hyperkalaemia.

Dogs treated concomitantly with spironolactone and NSAIDs should be correctly hydrated.

Monitoring of their renal function and plasma potassium levels is recommended before initi and during treatment with combined therapy (see section 4.3).

As spironolactone has an antiandrogenic effect, it is not recommended to administer the veterinary

medicinal product to growing dogs.

As spironolactone undergoes extensive hepatic biotransformation, care should b veterinary medicinal product to treat dogs with hepatic dysfunction.

May cause skin sensitisation: people with known hypersensitivity to contact with the veterinary medicinal product. Wash hands after use. In case of accidental ingestion, seek medical advice immediately and label to the physician.

4.6 Adverse reactions (frequency and seriousnes

A reversible prostatic atrophy is often observed in entire male dogs.

4.7 Use during pregnancy, lactation or lay

Do not use during pregnancy and lactation, laboratory studies in species (rat, mouse, rabbit and monkey) have shown evidence of developmental toxicity.

4.8 Interaction with other medicinal products and other forms of interaction

Furosemide and pimobendan have been used together with Spironolactone Ceva in dogs with heart failure without any clinical evidence of adverse reactions.

Spironolactone decreases digoxin elimination and hence raises digoxin plasma concentration. As the therapeutic index for digoxin is very narrow, it is advisable to monitor closely dogs receiving both digoxin and spironolactone.

The administration of either deoxycorticosterone or NSAIDs with spironolactone may lead to a moderate reduction of the natriuretic effects (reduction of urinary sodium excretion) of spironolactone. Concomitant administration of spironolactone with ACE-inhibitors and other potassium-sparing drugs (as angiotensin receptor blockers, ß-blockers, calcium channels blockers…etc) may potentially lead to hyperkalaemia (see section 4.5).

Spironolactone may cause both induction and inhibition of cytochrome P450 enzymes and could therefore affect the metabolism of other drugs utilizing these metabolic pathways.

Administer 2 mg/kg of body weight of spironolactone once daily. The veterinary medicinal product should be administered with food. The tablet can either be mixed with a small amount of food offered prior to the main meal, or administered directly into the mouth after feeding.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessaryto healthy dogs, dose-

After administration of up to 10 times the recommended dose dependent adverse effects were noted (see section 4.6).

In case of an accidental massive ingestion by a dog, there is n therefore recommended to induce vomiting, gastric lavage (depending on risk assessment) and monitor electrolytes. Symptomatic treatment, e.g., fluid therapy, should be provided.

• 4.11 Withdrawal period

  
  

Not applicable.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Aldosterone antagonist.

ATCvet code: QC03DA01.

5.1 Pharmacodynamic properties

Spironolactone and its active metabolites (including 7a-thiomethyl-spironolactone and canrenone) act as specific antagonists of aldosterone, and exert their effects by binding competitively to the mineralocorticoid receptor located in the kidneys, heart and blood vessels.

Spironolactone is a natriuretic drug (historically described as a soft diuretic). In the kidney, spironolactone inhibits the aldosterone-induced sodium retention leading to increase in sodium and subsequently water excretion, and potassium retention.

The renal effects of spironolactone and its metabolites lead to a decrease in extracellular volume and consequently in a decrease of cardiac preload and left atrial pressure. The result is an improvement in heart function.

In the cardiovascular system, spironolactone prevents the detrimental effects of aldosterone. Although the precise mechanism of action is not yet clearly defined, aldosterone promotes myocardial fibrosis, myocardial and vascular remodelling and endothelial dysfunction.

In experimental models in dogs, it was shown that long term therapy with an aldosterone antagonist prevents progressive left ventricle dysfunction and attenuates left ventricle remodelling in dogs with chronic heart failure.

In a clinical study investigating the survival time in dogs with congestive heart failure, there was a 65% reduction in the relative risk of mortality at 15 months in dogs treated with spironolactone in combination with standard therapy compared to dogs treated with standard therapy alone. (Mortality was classified as death or euthanasia due to heart failure).

When used in combination with ACE-inhibitors, spironolactone may counteract the effects of “aldosterone escape”.

A slight increase in aldosterone blood levels may be observed in animals on treatment. This is thought to be due to activation of feedback mechanisms without adverse clinical consequence. There may be a dose related hypertrophy of the adrenal zona glomerulosa at high dose rates.

5.2 Pharmacokinetic particulars

The pharmacokinetics of spironolactone are based on its metabolites, as the parent compound is unstable at assay.

Absorption

After oral administration of spironolactone to dogs, it was demonstrated that the three metabolites achieved levels from 32 % to 49 % of the administered dose. Food increases the bioavailability from 80 % to 90 %. Following oral administration of 2 to 4 mg/kg, absorption increases linearly over the range. After multiple oral doses of 2 mg spironolactone/ kg for 10 consecutive days, no accumulation is observed. Mean Cmax of 382 jxg/l and 94 pg/l are achieved for the primary metabolites, 7a-thiomethyl-spironolactone and canrenone, after 2 and 4 hours, respectively. Steady-state conditions are reached by day 2.

Distribution

The mean volumes of distribution (Vss) of 7a-thiomethyl-spironolactone and canrenone are approximately 153 litres and 177 litres, respectively.

The mean residence time of the metabolites ranges from 9 to 14 hours and they are preferentially distributed to the gastro-intestinal tract, kidney, liver and adrenal glands.

Metabolism

Spironolactone is rapidly and completely metabolised by the liver into its active metabolites, 7a-thiomethyl-spironolactone and canrenone, which are the primary metabolites in the dog.

Elimination

Spironolactone is mainly excreted via its metabolites. Plasma clearance of canrenone is 1.45±0.39 l/h/kg and 7a-thiomethyl-spironolactone is 0.89±0.44 l/h/kg. After oral administration of radiolabelled spironolactone to the dog, 70 % of the dose is recovered in faeces and 20 % in the urine.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Beef flavouring

Mannitol

Sodium laurilsulfate

Microcrystalline cellulose

Povidone

Sorbitol

Talc

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 3 years Partially used tablets to be used within 7 days.

6.4. Special precautions for storage

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

Partially used tablets should be stored in the original blister.

6.5 Nature and composition of immediate packaging

Polyamide/alu­minium/polyvi­nyl chloride//aluminium blisters containing 10 tablets.

Pack sizes

Cardboard box containing 3 or 18 blisters of 10 tablets.

Not all pack sizes may be marketed.

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

Ceva Santé Animale 10, av. de La Ballastière 33500 Libourne

France

8. MARKETING AUTHORISATION NUMBER(S)EU/2/07/074/001-0069. DATE OF FIRSHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisati June 2007

Date of last renewal: 22 May 2012

10 DATE OF REVISION OF THE TEXT

Detailed information on this veterinary medicinal product is available on the website of the European Medicines Agency.