benazepril

With concurrent therapy (e.g., furosemide, etc.) for the management of clinical signs of mild, moderate, or severe congestive heart failure in dogs due to atrioventricular valvular insufficiency (AVVI).

Cardalis™

CARDALIS is indicated with concurrent therapy (e.g. furosemide, etc.) for the management of clinical signs of mild, moderate, or severe congestive heart failure in dogs due to atrioventricular valvular insufficiency (AVVI).

FDA application 141-538

Mechanism of Action: The main pharmacological target of spironolactone and benazepril is the renin-angiotensin-aldosterone system (RAAS) at different levels in the cascade. Spironolactone and its active metabolites (including 7-α-thiomethyl-spironolactone and Canrenone) act as specific antagonists of aldosterone (regardless of the source) by binding competitively to mineralocorticoid receptors located in the kidneys, heart and blood vessels. Benazepril hydrochloride is a prodrug hydrolyzed in vivo into its active metabolite, benazeprilat. Benazeprilat is a highly potent and selective inhibitor of angiotensin-converting enzyme (ACE), thus preventing the conversion of inactive angiotensin I to active angiotensin II. This prevents deleterious effects of vasoconstriction and aldosterone release, including sodium and water retention, and vascular and myocardial remodeling. However, aldosterone release is not fully controlled by ACE inhibitors because angiotensin II is also produced by non-ACE pathways. Therefore, concomitant use of the aldosterone antagonist spironolactone and the ACE inhibitor benazepril hydrochloride inhibits both ACE and non-ACE pathways. Pharmacokinetics: Spironolactone is rapidly and extensively metabolized in humans and experimental animals, with species differences in the metabolism and disposition. Spironolactone is metabolized by microsomal cytochrome P450 enzymes to a primary metabolite, canrenone, and a secondary metabolite, 7α-thiomethyl-spironolactone (TMS), which are used as markers for spironolactone in dog plasma. Systemic exposure to both metabolites was comparable when spironolactone was administered alone or in association with benazepril in dogs. Spironolactone absorption is affected by food and the dose should be administered consistently in fed condition. Spironolactone is mainly excreted as metabolites. After oral administration of radiolabeled spironolactone to the dog, 70% of the dose is recovered in feces and 20% in the urine. After multiple oral doses of 20 mg of spironolactone in association with 2.5 mg of benazepril in dogs (n=18, 9 male and 9 female) for 10 consecutive days (steady state), no accumulation was observed. Benazepril hydrochloride is a prodrug which, after absorption from the gastrointestinal tract, is rapidly converted by nonspecific carboxyl esterases, mainly in the liver, into its active metabolite benazeprilat. Benazeprilat is itself poorly absorbed from the gastrointestinal tract and the overall bioavailability of benazeprilat after oral administration is estimated to be less than 7%. After multiple oral doses of 2.5 mg of benazepril in association with 20 mg of spironolactone in dogs (n=18, 9 male and 9 female) for 10 consecutive days (steady state), no accumulation was observed. In dogs, benazeprilat is excreted approximately equally by both renal (45%) and hepatic (55%) routes.

FDA application 141-538

Do not administer CARDALIS in conjunction with non-steroidal anti-inflammatory drugs (NSAIDs) in dogs with renal insufficiency. Do not administer CARDALIS to dogs with hypoadrenocorticism (Addison’s Disease), hyperkalemia, or hyponatremia. Do not administer CARDALIS to animals with known hypersensitivity to ACE inhibitors or spironolactone.

FDA application 141-538

Keep CARDALIS in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose. In case of accidental overdose, induce vomiting, lavage the stomach (depending on risk assessment), and monitor electrolytes. Symptomatic therapy (e.g. fluid therapy) should be provided as medically necessary. CARDALIS is only for use in dogs with clinical evidence of heart failure. Human Warnings: Not for use in humans. Keep this and all medications out of the reach of children. Consult a physician in case of ingestion by humans.

FDA application 141-538

A U.S. clinical field study comprised of a 360-day treatment period evaluated the safety and effectiveness of CARDALIS compared to benazepril hydrochloride in 569 client-owned dogs with left-sided AVVI. Table 1 summarizes the adverse reactions not directly related to the progression of disease that occurred in greater than 5% of the dogs treated with CARDALIS. The following adverse events were seen in fewer than 5% of the study animals, in decreasing order: urine abnormalities, fluid in abdomen, ataxia, weight loss, digestive tract disorder, hypertension, electrolyte disorder, bronchitis, and hyperactivity. Renal insufficiency was reported more frequently in dogs treated with CARDALIS. This finding may be also attributed to the concurrent administration of furosemide. The clinical pathology parameters associated with renal function were not statistically different between the treatment groups. The incidence of death, including euthanasia and sudden death, was similar in dogs treated with CARDALIS or benazepril hydrochloride. In most cases, death was attributable to the progression of heart disease or the clinical signs associated with congestive heart failure. Deaths of unknown cause were presumed to be cardiac in nature. Serum magnesium and potassium values were significantly higher in the CARDALIS group, although the mean values remained within the reference range and did not change significantly over time. These electrolyte changes are consistent with the potassium-sparing properties of spironolactone. One dog treated with CARDALIS was removed from the study at Day 7 because it developed hyperkalemia. Contact Information: To report suspected adverse events or to request a copy of the Safety Data Sheet (SDS), please call Ceva Animal Health at 1-800-999-0297. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at www.fda.gov/reportanimalae.

FDA application 141-538

Administer orally once daily, with food, at a dose of 0.9 mg per pound (/lb) (2 mg per kilogram (/kg)) spironolactone and 0.11 mg/lb (0.25 mg/kg) benazepril hydrochloride, according to dog body weight using a suitable combination of whole and/or half tablets.

Oral

Cardalis™

CARDALIS administration should begin after pulmonary edema is stabilized. CARDALIS should be administered orally once daily at a dose of 0.9 mg/lb (2 mg/kg) spironolactone and 0.11 mg/lb (0.25 mg/kg) benazepril hydrochloride, according to dog body weight using a suitable combination of whole and/or half tablets. All tablet strengths are scored and the calculated dosage according to dog’s weight should be to the nearest half-tablet increment. CARDALIS should be administered with food.

ORAL

FDA application 141-538