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|Drug Name and Strength||Benazepril 5mg/ Spironolactone 40mg|
|Indication||Treatment of heart failure and reduction in mortality caused by chronic degenerative valvular disease in dogs. Treatment of left-sided heart failure resulting from mitral regurgitation in dogs.|
|Contraindications||Do not use in dogs with hypoadrenocorticism, hyperkalaemia or hyponatraemia. Do not use in dogs known to be hypersensitive to benazepril.|
|Actions||Clinical studies investigating survival time showed that the fixed combination of benazepril hydrochloride and spironolactone increased the life expectancy in dogs with congestive heart failure. There was an 89% reduction in the relative risk of cardiac mortality assessed in dogs treated with spironolactone in combination with benazepril compared to dogs treated with benazepril alone (mortality was classified as death or euthanasia due to heart failure). Combination treatment also allowed a quicker improvement of cough and activity and a slower degradation of cough, heart sounds and appetite. 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. Spironolactone. Spironolactone is a natriuretic, historically described as a soft diuretic. Spironolactone and its active metabolites (including 7a-thiomethyl-spironolactone and canrenone) act as specific antagonists of aldosterone. Spironolactone and its active metabolites exert their effects by binding competitively to the mineralocorticoid receptors located in the kidneys, heart and blood vessels. In the kidney, spironolactone inhibits aldosterone-induced sodium retention leading to an increase in sodium and subsequently water excretion, and potassium retention. The reduction in extracellular volume decreases the cardiac preload and left atrial pressure, resulting in an improvement in heart function. In the cardiovascular system, spironolactone prevents the detrimental effects of aldosterone, i.e. myocardial fibrosis, myocardial and vascular remodelling and endothelial dysfunction. 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 defined, aldosterone promotes myocardial fibrosis, myocardial and vascular remodelling and endothelial cell dysfunction. In experimental models in dogs, it was shown that long term therapy with an aldosterone antagonist prevents progressive left ventricular dysfunction and attenuates left ventricular remodelling in dogs with chronic heart failure. Combined effect. The association of spironolactone and benazepril is beneficial because it acts on the RAAS at two different levels along the signal transduction cascade. Benazepril, by preventing the formation of angiotensin II inhibits the detrimental effects of vasoconstriction and stimulation of aldosterone release. However, aldosterone release is not fully controlled by ACE inhibitors because angiotensin II is also produced by non-ACE pathways such as chymase. Secretion of aldosterone can also be stimulated by factors other than angiotensin II, notably K+ increase or ACTH. Therefore, to achieve a more complete inhibition of the deleterious effects of RAAS overactivity which occurs with heart failure, it is recommended to concomitantly use aldosterone antagonists, such as spironolactone, concomitantly with ACE inhibitors to block specifically the activity of aldosterone (regardless of the source), through competitive antagonism on mineralocorticoid receptors.The end result is an improvement in the clinical status of the dog. The combination of spironolactone and benazepril leads to an extension of the life span of dogs with heart failure and also improves clinical signs, notably a reduction in coughing and improvement in the quality of life. Cardalis may be used in combination therapy with diuretics (e.g. furosemide), digoxin and antiarrhythmic drugs as necessary.After oral administration of benazepril hydrochloride, peak levels of benazepril are attained rapidly and decline quickly as the drug is partially metabolised by liver enzymes to benazeprilat. After multiple oral doses of benazepril hydrochloride 0.25 mg/kg bodyweight for 10 consecutive days, peak benazeprilat concentrations (Cmax of 35.9 nanogram/mL) are achieved with a Tmax of 1.5 hours. The systemic bioavailability is incomplete (approximately 13% in dogs) due to incomplete absorption (38% in dogs) and first-pass metabolism. There is no significant difference in the pharmacokinetics of benazeprilat when benazepril hydrochloride is administered to fed or fasted dogs. The mean residence time of benazeprilat ranges from 15 to 17 hours. Spironolactone. The pharmacokinetic properties of spironolactone are based on its metabolites, as the parent compound is unstable at assay. After oral administration of spironolactone to dogs, it was shown that the three metabolites achieved levels of 32% to 49% of the administered dose. Food increases the bioavailability to 80% to 90%. After oral administration of spironolactone 2 to 4 mg/kg, absorption increases linearly over the range. After multiple oral doses of spironolactone 2 mg/kg bodyweight for 10 consecutive days, no accumulation was observed. Mean Cmax of 324 microgram/L and 66 microgram/L are achieved for the primary metabolites 7a-thiomethyl-spironolactone and canrenone after two and four hours, respectively. Steady-state conditions are reached by day 2. The mean volumes of distribution of 7a-thiomethyl-spironolactone and canrenone are approximately 153 L and 177 L, respectively. The mean residence times of the metabolites range from 9 to 14 hours, and they are preferentially distributed to the gastrointestinal tract, kidney, liver and adrenal glands.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. When used in combination with ACE-inhibitors, spironolactone may counteract the effects of ‘aldosterone escape’.Pharmacology Benazepril. Benazepril hydrochloride, by inhibiting the renin-angiotensin-aldosterone system (RAAS), minimises the undesirable effects of vasoconstriction and sodium retention mediated by this system. Benazepril is a prodrug hydrolysed in vivo to benazeprilat, which inhibits the angiotensin converting enzyme (ACE), thus preventing the conversion of inactive angiotensin I into active angiotensin II. Cardalis reduces all effects mediated by angiotensin II, including vasoconstriction of both arteries and veins and retention of sodium and water by the kidney. Cardalis causes long-lasting inhibition of plasma ACE in dogs, with significant inhibition persisting for 24 hours after a single dose.Pharmacokinetics Benazepril. Benazepril is rapidly but incompletely absorbed from the gastrointestinal tract following oral administration. Absorbed benazepril is partially hydrolysed by hepatic enzymes to the active substance, benazeprilat; unchanged benazepril and hydrophilic metabolites account for the remainder. Peak plasma benazeprilat concentrations are attained within about two hours both in fasting and fed situations. Benazepril and benazeprilat are bound to plasma proteins, and in tissues are found mainly in the liver and kidney. Most benazeprilat is rapidly eliminated, although there is in addition a slow terminal elimination phase. Benazeprilat is excreted approximately equally via both biliary and urinary routes in dogs. Repeated administration of Cardalis leads to a slight accumulation of benazeprilat in plasma; steady state is attained within four days.|
|Precautions||This product should not be used in dogs and bitches intended for breeding purposes; in pregnant and lactating bitches; or in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs) in dogs with renal insufficiency. Kidney function and serum potassium levels should be evaluated before initiating combined treatment with spironolactone and 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 appropriately hydrated. Monitoring of their renal function and plasma potassium levels is recommended before initiation and during treatment with combined therapy. As spironolactone undergoes extensive hepatic biotransformation, care should be taken when using the product to treat dogs with hepatic dysfunction. As spironolactone has an antiandrogenic effect, it is not recommended to administer the product to growing dogs.Harmful if swallowed. Will irritate the eyes and skin. Repeated exposure may cause allergic disorders. Avoid contact with eyes and skin. Wash hands after use.First Aid If poisoning occurs, contact a doctor or Poisons Information Centre. Phone Australia 131 126.Disposal Dispose of empty container by wrapping with paper and putting in garbage.|
|Dosage and Administration||For oral administration only. Give spironolactone 2 mg/kg bodyweight and benazepril hydrochloride 0.25 mg/kg bodyweight once daily. The dose of benazepril may be doubled, still administered once daily, if judged clinically necessary and advised by a veterinarian. In these cases, benazepril tablets could be added to the product. The product should be administered with food. The tablet can either be mixed with a small amount of food offered before the main meal or with the meal.|
|Storage||Store below 25°C (air conditioning). Store in the original container only. Once opened, use within 6 months.|
|MSDS (external link)||Not specified|
|Label (external link)||Not specified|
|Manufacturer||Ceva Animal Health Pty Limited|