Description
Entyce (capromorelin oral solution) is indicated for appetite stimulation in dogs. See package insert for complete product details.
�
30 mg/mL
For oral use in dogs only
Appetite Stimulant
Caution:
Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.
Description:
ENTYCE� (capromorelin oral solution) is a selective ghrelin receptor agonist that binds to
receptors and affects signaling in the hypothalamus to cause appetite stimulation and binds
to the growth hormone secretagogue receptor in the pituitary gland to increase growth
hormone secretion. The empirical formula is C28H35N5
O4
�C4
H6
O6 and the molecular weight
655.70. The chemical name is 2-amino-N-[2-(3aR-benzyl-2-methyl-3-oxo-2,3,3a,
4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymethyl-2-oxo-ethyl]-isobutyramide
L-tartrate.
The chemical structure of capromorelin tartrate is:
Indication:
ENTYCE (capromorelin oral solution) is indicated for appetite stimulation in dogs.
Dosage and Administration:
Administer ENTYCE orally at a dose of 3 mg/kg (1.4 mg/lb) body weight once daily.
To administer ENTYCE, gently shake the bottle, and then withdraw the appropriate amount of
solution using the provided syringe. Rinse syringe between treatment doses.
The effectiveness of ENTYCE has not been evaluated beyond 4 days of treatment in the clinical
field study (See Effectiveness).
Contraindications:
ENTYCE should not be used in dogs that have a hypersensitivity to capromorelin.
Warnings:
Not for use in humans. Keep this and all medications out of reach of children and pets.
Consult a physician in case of accidental ingestion by humans. For use in dogs only
Precautions:
Use with caution in dogs with hepatic dysfunction. ENTYCE is metabolized by CYP3A4 and
CYP3A5 enzymes (See Clinical Pharmacology).
Use with caution in dogs with renal insufficiency. ENTYCE is excreted approximately 37% in
urine and 62% in feces (See Adverse Reactions and Clinical Pharmacology).
The safe use of ENTYCE has not been evaluated in dogs used for breeding or pregnant
or lactating bitches.
Adverse Reactions:
In a controlled field study, 244 dogs were evaluated for safety when administered either
ENTYCE or a vehicle control (solution minus capromorelin) at a dose of 3 mg/kg once daily
for 4 days. Enrolled dogs had a reduced or absent appetite for a minimum of 2 days prior to
day 0 and had various medical conditions: arthritis (40); gastrointestinal disease (24); allergy (22);
dental disease (22); cardiovascular disease (16); renal disease (13); and others. Some dogs
may have experienced more than one of the adverse reactions during the study. The following
adverse reactions were observed:
Table 1: Adverse Reactions reported in dogs administered ENTYCE oral solution
compared to vehicle control
Adverse Reactions ENTYCE (n = 171)
n (%)
Vehicle Control (n = 73)
n (%)
GASTROINTESTINAL
Diarrhea 12 (7.0 %) 5 (6.8 %)
Vomiting 11 (6.4 %) 4 (5.5 %)
Hypersalivation 4 (2.3 %) 0 (0.0 %)
Abdominal discomfort 2 (1.2 %) 0 (0.0 %)
Flatulence 2 (1.2 %) 0 (0.0 %)
Nausea 2 (1.2 %) 0 (0.0 %)
CLINICAL PATHOLOGY
Elevated blood urea nitrogen 7 (4.1 %) 2 (2.7 %)
Elevated phosphorus 4 (2.3 %) 1 (1.4 %)
Elevated creatinine 1 (0.6 %) 1 (1.4 %)
OTHER
Polydipsia 7 (4.1 %) 1 (1.4 %)
Lethargy/depression 2 (1.2 %) 0 (0.0 %)
The following adverse reactions were reported in < 1% of dogs administered ENTYCE:
hyperactivity, increase fecal volume, increase gut sounds, and polyuria.
To report suspected adverse drug events and/or to obtain a copy of the Safety Data Sheet (SDS)
or for technical assistance, call Aratana Therapeutics at 1-844-272-8262.
For additional information about adverse drug experience reporting for animal drugs, contact
FDA at 1-888-FDA-VETS or at https://www.fda.gov/AnimalVeterinary/SafetyHealth
Clinical Pharmacology:
Following oral administration of ENTYCE at a dose of 3 mg/kg to 12 Beagle dogs, absorption of
capromorelin was rapid with the maximum concentration (Cmax) reached within 0.83 hr (Tmax).
After Cmax, the plasma concentrations declined mono-exponentially with a short terminal
half-life (T�) of approximately 1.19 hrs. There were no gender differences in capromorelin
pharmacokinetics. The exposure (Cmax and AUC) of capromorelin increased with dose, but
the increases were not dose proportional following single and repeat once daily administrations
of capromorelin. There was no drug accumulation following repeat oral administration.
Table 2. Plasma PK parameters following oral administration of 3 mg/kg of ENTYCE
Parameter Mean SD
Tmax (hr) 0.83 0.58
Cmax (ng/mL) 330 143
AUCt
(ng*hr/mL) 655 276
AUCinf (ng*hr/mL) 695 262
T� (hr) 1.19 0.17
The mean absolute oral bioavailability of capromorelin was 44%. The mean total plasma
clearance and volume of distribution was 18.9 mL/min/kg and 2.0 L/kg, respectively.
Capromorelin was not highly bound (unbound fraction 51%) to plasma protein. The protein
binding was concentration-independent over the range of 10 to 1000 ng/mL. In vitro (human
liver microsomes) and in vivo (rats) metabolism studies suggest that capromorelin is metabolized
by hepatic enzymes, mainly CYP3A4 and CYP3A5. Therefore, drugs that inhibit CYP3A4 and
CYP3A5 activity may affect capromorelin metabolism. Following oral administration of
radio-labelled capromorelin to dogs, capromorelin was excreted in urine (37%) and in feces (62%)
within 72 hours.
Effectiveness:
Laboratory Effectiveness Study: Twenty four healthy Beagle dogs (6 dogs per sex in each
group) with normal appetite were randomized into two groups and dosed daily with ENTYCE
(capromorelin oral solution) at 3 mg/kg/day or vehicle control (solution minus capromorelin)
to compare food intake over a 4-day period. The dogs were 13 months of age and weighed
between 6.5 and 12.5 kg at the time of randomization. Six dogs administered ENTYCE repeatedly
exhibited salivation post dosing and two dogs administered vehicle control exhibited salivation
only one time on study day 0. Emesis was observed in one dog administered ENTYCE on study
day 1. Dogs administered ENTYCE at a dose of 3 mg/kg/day for 4 consecutive days had statistically
significantly increased food consumption compared to the vehicle control group (p < 0.001).
Clinical Field Study: Effectiveness was evaluated in 177 dogs (121 dogs in the ENTYCE group
and 56 dogs in the vehicle control group) in a double-masked, vehicle controlled field study.
Dogs with a reduced appetite or no appetite, with various medical conditions, for a minimum
of 2 days prior to day 0 were enrolled in the study. The dogs ranged in age from 4 months to
18 years. Dogs were randomized to treatment group and dosed once daily for 4 days with
ENTYCE at 3 mg/kg or vehicle control. Dogs were assessed for appetite by owners on day 0
and day 3 � 1 using an "increased", "no change" or "decreased" scoring system. Dogs were
classified as a treatment success if the owner scored their dog's appetite as "increased" on
day 3 � 1. The success rates of the two groups were significantly different (p = 0.0078);
68.6% (n = 83) of dogs administered ENTYCE were successes, compared to 44.6% (n = 25)
of the dogs in the vehicle control group.
Animal Safety:
In a 12-month laboratory safety study, 32 healthy Beagle dogs (4 dogs per sex per group)
approximately 11-12 months of age and weighing 9-13.6 kg were dosed orally with capromorelin
in deionized water daily at 0X (placebo), 0.3 (0.13X), 7 (3.07X), and 40 (17.5X) mg/kg/day.
Administration of capromorelin was associated with increased salivation and reddening/
swollen paws, increased liver weights and hepatocellular cytoplasmic vacuolation. Treatment
related decreases were seen in red blood cell count, hemoglobin and hematocrit in the 40 mg/kg
group. Pale skin, pale gums, and decreased red blood cell count, hemoglobin and hematocrit
were observed in one dog administered 40 mg/kg/day. Increases were seen in cholesterol,
high density lipoproteins, and the liver specific isozyme of serum alkaline phosphatase in
the 40 mg/kg group. Growth hormone and insulin-like growth factor 1 plasma levels were
increased in all groups administered capromorelin. There were no effects noted on gross
necropsy. Capromorelin levels were similar in plasma collected on days 90, 181, and 349
indicating no accumulation of drug.
Storage Conditions:
Store at or below 86� F (30� C)
How Supplied:
30 mg/mL flavored solution in 10 mL, 15 mL and 30 mL bottles with measuring syringe
NADA 141-457, Approved by FDA
US Patent: 6,107,306
US Patent: 6,673,929
Made in Canada
Manufactured for:
Aratana Therapeutics, Inc.
Leawood, KS 66211
ENTYCE is a trademark of Aratana Therapeutics, Inc.
� Aratana Therapeutics, Inc.
C-A213
June 2016
