Spironolactone; Benazepril hydrochloride: what the FDA reviewed for dog products

Cardalis™ NADA 141-538, Original approval, July 27, 2020; sponsor Ceva Sante Animale; species: Dogs; foi_id 9488; FDA PDF

Indication

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

Dose regimen

2 mg/kg (0.9 mg/lb) spironolactone and 0.25 mg/kg (0.11 mg/lb) benazepril hydrochloride, Oral (chewable tablets), with food, Once daily, Begin after pulmonary edema is stabilized; dosed to nearest half-tablet; administer with food

CardalisTM 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 the dog's body weight, using a suitable combination of whole and/or half tablets.

Pharmacokinetics

Target-animal safety

dose multiples 0X, 1X (4 mg/kg spironolactone + 0.5 mg/kg benazepril HCl = 2x labeled dose, maximum exposure), 3X (12 + 1.5 mg/kg), 5X (20 + 2.5 mg/kg); duration 26 weeks (6 months), once daily orally with food; animals 32.

Objective: To assess the toxicity of CardalisTM in dogs when orally dosed daily at 1X, 3X, and 5X the maximum exposure dose (4 mg/kg spironolactone and 0.5 mg/kg benazepril hydrochloride) for a period of six months (26 weeks). Study Animals: 32 healthy Beagle dogs (16 male and 16 female), non-pregnant, non-lactating, approximately 1 year of age and weighing between 9.7 and 14.1 kg at the beginning of the treatment period, were randomly allocated to four treatment groups (0X, 1X, 3X, 5X).

Effectiveness

Well-controlled, multi-center (27 US sites), masked, randomized, active-controlled superiority field study of Cardalis vs benazepril HCl alone (same chewable formulation), once daily with food, all dogs on furosemide, 360 days; 569 dogs enrolled (284 Cardalis, 285 control); n = 414 (216 Cardalis, 198 benazepril); primary endpoint: Percent treatment failure on Day 360 (cardiac death/euthanasia, recurrence or worsening of pulmonary edema, new cardiogenic ascites, or furosemide > 8 mg/kg/day); result: Treatment failure on Day 360 (LS means) 80.59% Cardalis vs 88.09% benazepril, P = 0.0433; failure rate lower at every visit after Day 30

Of the 414 dogs included in the effectiveness evaluation, 48 of the 216 dogs treated with CardalisTM and 27 of the 198 dogs treated with benazepril hydrochloride alone successfully completed the study through Day 360. The rate of failure in the CardalisTM treatment group estimated from the model analysis was statistically different (P = 0.0433) and numerically lower than that of the benazepril control group. The primary effectiveness results are summarized in Table II.2. Table II.2: Treatment Failure Rates by Treatment Group (Least Square Means) on Day 360 Group N Percent of Treatment Failures a,b 95% Confidence Interval P-value c CardalisTM 216 80.59% 72.57, 86.69% 0.0433 Benazepril HCl 198 88.09% 81.40, 92.59% -

Adverse reactions

Extraction notes: No numeric PK parameters (half-life, Cmax, AUC) are given; PK entries are qualitative statements from the dose-selection and 6-month TAS sections. In the TAS study the '1X' dose (4 mg/kg spironolactone + 0.5 mg/kg benazepril) is twice the labeled dose (maximum exposure for a small dog by tablet size). Adverse reactions from Table II.4 (field safety population 284 vs 285).