Capromorelin: what the FDA reviewed for dog products

1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Capromorelin, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.

Products

ENTYCE™ (NADA/ANADA 141-457)

ENTYCE™ NADA 141-457, Original approval, May 16, 2016; sponsor Elanco US Inc.; species: Dogs; foi_id 943; FDA PDF

Indication

Appetite stimulation in dogs

Dose regimen

3 mg/kg (1.4 mg/lb), oral (flavored solution), once daily, Field study dosed for 4±1 days

A dose of 3 mg/kg (1.4 mg/lb; capromorelin as the tartrate salt) of ENTYCE administered orally as a flavored solution once daily for appetite stimulation in dogs was selected based on the following two studies.

Pharmacokinetics

Parameter	Value	Conditions	Quote
tmax	0.5 hr (median)	3 mg/kg single oral dose, fasted Beagles (n=12), ENTYCE and deionized-water formulations	At the 3 mg/kg dose, the median Tmax and mean terminal half-life following both the formulations was similar (0.5 hr and ~1 hr respectively).
half-life	~1 hr (mean terminal)	3 mg/kg single oral dose, fasted Beagles (n=12)	At the 3 mg/kg dose, the median Tmax and mean terminal half-life following both the formulations was similar (0.5 hr and ~1 hr respectively).
bioavailability	74.4% (relative, ENTYCE vs API in deionized water, geometric mean AUC(0-t) ratio; 90% CI 61.12-90.57)	3 mg/kg single oral dose, fasted Beagles, crossover (n=12)	Dogs administered 3 mg/kg of ENTYCE had a lower capromorelin exposure than the dogs administered 3 mg/kg of the API in deionized water (relative bioavailability based on geometric mean AUC(0-t) ratio of 74.4% with 90% CI: 61.12 to 90.57).
auc	590.68 hr*ng/mL (geometric mean AUC(0-t), ENTYCE)	3 mg/kg single oral dose, fasted; deionized-water formulation 793.88; Table 12 row order: deionized, ENTYCE, ratio %, 90% CI, p	AUC(0-t) (hr*ng/mL) 793.88 590.68 74.40 (61.12, 90.57) 0.0214
cmax	299.84 ng/mL (geometric mean, ENTYCE)	3 mg/kg single oral dose, fasted; deionized-water formulation 360.96	Cmax (ng/mL) 360.96 299.84 83.07 (64.20, 107.5) 0.2212

Target-animal safety

dose multiples 0.13X (0.3 mg/kg/day), 3.07X (7 mg/kg/day), 17.5X (40 mg/kg/day); duration 12 consecutive months, once daily oral gavage (API in deionized water, not final formulation); animals Thirty-two.

Objective: To investigate the potential toxicity of CP-424,391-18 (also known as capromorelin) in Beagle dogs following oral administration, once daily, for 12-months at 0 (placebo), 0.3, 7, and 40 mg/kg/day. b. Study Animals: Thirty-two healthy Beagle dogs, approximately 11-12 months old at first dose administration, weighing 9-13.6 kg.

Finding	Quote
Increased salivation and reddening/swollen paws	Administration of capromorelin was associated with increased salivation and reddening/swollen paws.
Increased PRQ interval 1-2 h post-dose at 7 and 40 mg/kg/day; no cardiac histologic lesions	Electrocardiograms noted an increase in the PRQ interval at 1 to 2 hours post-dose in the 7 mg/kg/day and 40 mg/kg/day groups.
Decreased RBC count, hemoglobin and hematocrit at 40 mg/kg	There were treatment related decreases in red blood cell count, hemoglobin, and hematocrit in the 40 mg/kg group.
Increased liver weights at 7 and 40 mg/kg/day; hepatocellular cytoplasmic vacuolation in all groups	Liver weights were increased in the 7 mg/kg/day and 40 mg/kg/day groups. An increase in hepatocellular cytoplasmic vacuolation was observed in all groups.
GH and IGF-1 increased in all capromorelin groups	Growth hormone and insulin like growth factor-1 (IGF-1) plasma levels were increased in all groups administered capromorelin.
No drug accumulation over 12 months	Capromorelin levels were similar in plasma collected on days 90, 181, and 349 indicating no accumulation of the drug.

Effectiveness

Pivotal multi-site, masked, vehicle-controlled GCP field study (Study AT002-CCL-13-003): 2:1 randomization to ENTYCE 3 mg/kg or vehicle once daily for 4±1 days in dogs with reduced/no appetite for at least 2 days (244 enrolled: 171 ENTYCE, 73 vehicle); per-protocol effectiveness population; n = 177 (121 ENTYCE, 56 vehicle control); primary endpoint: Owner appetite assessment at day 3±1: 'increased' = treatment success; result: Observed success 83/121 (68.6%) ENTYCE vs 25/56 (44.6%) vehicle; model-estimated 67.9% vs 42.6%, P=0.0078; secondary questionnaire success 56.2% vs 26.8%; body weight gain >0% in 76.0% vs 44.6%

Effectiveness was evaluated by owner appetite assessment in 177 dogs; 121 dogs in the ENTYCE oral solution group and 56 dogs in the vehicle control group. Table 6: Owner Appetite Assessment: Observed success rate on day 3±1 compared to Day 0 Success/Failure ENTYCE oral solution (N=121) Vehicle Control (N=56) Success 83 (68.6%) 25 (44.6%) Failure 38 (31.4%) 31 (55.4%) Based on the statistical model, the estimated success rates are 67.9% and 42.6% for the ENTYCE group and the vehicle control groups, respectively. The difference in success rates is significant at P=0.0078.

Adverse reactions

Term	Treated	Control	Quote
Diarrhea	12 (7.0%)	5 (6.8%)	Diarrhea 12 (7.0 %) 5 (6.8 %)
Vomiting	11 (6.4%)	4 (5.5%)	Vomiting 11 (6.4 %) 4 (5.5 %)
Hypersalivation	4 (2.3%)	0 (0.0%)	Hypersalivation 4 (2.3 %) 0 (0.0 %)
Elevated blood urea nitrogen	7 (4.1%)	2 (2.7%)	Elevated blood urea nitrogen 7 (4.1 %) 2 (2.7 %)
Polydipsia	7 (4.1%)	1 (1.4%)	Other Polydipsia 7 (4.1 %) 1 (1.4 %)
Elevated phosphorus	4 (2.3%)	1 (1.4%)	Elevated phosphorus 4 (2.3 %) 1 (1.4 %)

Extraction notes: Adverse reaction denominators (Table 9): ENTYCE N=171, vehicle N=73. TAS n_animals is spelled out in the text ('Thirty-two'; 4/sex/group). The 12-month TAS used API in deionized water; the PK bridging study showed ENTYCE gives lower exposure (74.4% relative bioavailability), so TAS exposure is considered representative.

Reproduce: foi_structured_search(query="Capromorelin") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).