capromorelin

For appetite stimulation in dogs.

The safe use of ENTYCE has not been evaluated in dogs used for breeding or pregnant or lactating bitches.

ENTYCE™

For management of weight loss in cats with chronic kidney disease.

Elura™

ENTYCE (capromorelin oral solution) is indicated for appetite stimulation in dogs.

FDA application 141-457

For management of weight loss in cats with chronic kidney disease.

Elura™

Mechanism of Action ELURA is a selective ghrelin receptor agonist. The ghrelin receptor is found in many tissues in various species and may have effects in the central nervous system, gastrointestinal tract, cardiovascular system and energy homeostasis. ELURA binds to receptors in the hypothalamus to stimulate appetite and in the pituitary to stimulate secretion of growth hormone (GH). Increased GH stimulates release of insulin like growth factor 1 (IGF-1) from the liver, which in turn can stimulate weight gain. IGF-1 remains elevated during administration of the drug. In humans, IGF-1 elevation may act as a negative feedback regulator of GH, but this is unknown in cats. The clinical effects of ELURA in cats are thought to be due to a combination of increased food intake and metabolic changes resulting in weight gain. Pharmacokinetics The pharmacokinetic parameters of capromorelin were evaluated in a cross-over study in 4 male and 8 female laboratory cats receiving a single oral dose of ELURA at 2 mg/kg in the fed or fasted state. Following 8 hours of fasting, half the cats were fed a meal of canned food 30 minutes before dosing and the others continued to be fasted until 4 hours post ELURA administration. Blood samples were collected prior to dosing (pre-feeding) and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dosing for determination of serum capromorelin concentrations. Serum concentrations of capromorelin were measured using a liquid chromatography with mass spectrometry detection method. Blood samples were collected prior to dosing (pre-feeding) and at 8, 12, and 24 h post-dosing for determination of serum IGF-1. Table 2. Mean (Standard Deviation) Pharmacokinetic Parameters for Serum Capromorelin Data were analyzed for only 10 and 6 cats in the fasted and fed groups respectively, because there was an insufficient number of quantifiable serum concentrations for analysis. aMedian and Range bInsufficient data to calculate mean and standard deviation for T½ Tmax = time to maximum serum concentration Cmax =maximum serum concentration AUClast = area under the curve from the time of dosing to the last quantifiable serum concentration T½= half-life Capromorelin was rapidly absorbed following oral administration of ELURA to fasted cats. The Cmax and AUClast for capromorelin were 55% and 43% lower, respectively, in the fed state, as compared to the fasted state. Serum IGF-1 values did not appear to be affected by the feeding state. Parameter Fasted Fed Tmax a (hr) 0.25 (0.25-1) (n=10) 0.75 (0.5-4) (n=6) Cmax (ng/mL) 59 ± 42 (n=10) 28 ± 20 (n=6) AUClast (ng*hr/mL) 83 ± 42 (n=10) 51 ± 21 (n=6) T½ (hr) 1.12 ± 0.16 (n=8) NAb

Elura™

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 (T½) 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 T½ (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.

FDA application 141-457

ENTYCE should not be used in dogs that have a hypersensitivity to capromorelin.

FDA application 141-457

User Safety Warnings Not for use in humans. Keep this drug, including used syringes, out of reach of children. Wash hands immediately after use as this product may be dermally absorbed. Consult a physician in case of accidental ingestion by humans. To obtain a Safety Data Sheet(s), contact Elanco US Inc. at 1-888-545-5973. For oral use in cats only. Animal Safety Warnings Do not use in cats with hypersomatotropism (acromegaly). ELURA may increase serum glucose for several hours after dosing (see Animal Safety and Clinical Pharmacology). Use in cats with current or historical diabetes mellitus has not been evaluated and use may not be appropriate. Keep ELURA in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

Elura™

User Safety Warnings: Not for use in humans. Keep this drug, including used syringes, out of reach of children. Wash hands immediately after use as this product may be dermally absorbed. Consult a physician in case of accidental ingestion by humans. To obtain a Safety Data Sheet(s), contact Elanco US Inc. at 1-888-545-5973. For use in dogs only. Animal Safety Warnings: Keep ENTYCE in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

FDA application 141-457

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 oral use in cats only. Do not use in cats with hypersomatotropism (acromegaly). ELURA may increase serum glucose for several hours after dosing (see Animal Safety and Clinical Pharmacology). Use in cats with current or historical diabetes mellitus has not been evaluated and use may not be appropriate.

Elura™

Safety was evaluated in a 56-day field effectiveness study in 176 client-owned cats (118 administered ELURA, 58 administered vehicle control) that received at least one dose. Cats enrolled had ≥5% unintended weight loss and a history of chronic kidney disease (CKD). Cats had a mean age of 15 years and at enrollment 11.4% of the cats were in Stage 1 CKD, 66.5% were in Stage 2, 21.0% were in Stage 3, and 1.1% were in Stage 4. Cats enrolled in the study had a variety of comorbid conditions: dental disease (88.1%), moderate or severe muscle loss (43.2%), heart murmur (28.4%), history of vomiting or underlying gastrointestinal disease (28.4%), hyperthyroidism (13.6%) and hypertension (9.7%). Table 1: Adverse Reactions in the Field Effectiveness Study Note: If an animal experienced the same event more than once, only the first occurrence was tabulated. a Behavior change included hiding from the owner (8 ELURA, 1 vehicle control); owner reported difficulty administering medication (7 ELURA, 1 vehicle control); and redirected aggression to another household cat (2 ELURA, 1 vehicle control). b Two ELURA and 1 vehicle control cat increased by two CKD stages; 8 ELURA and 2 vehicle control cats increased one CKD stage. It could not be determined if the progressive renal disease was the natural course of the pre-existing disease or treatment related. Adverse Reaction ELURA (n=118) Vehicle Control (n=58) Vomiting 35 (29.6%) 13 (22.4%) Hypersalivation 25 (21.2%) 0 (0.0%) Inappetence 22 (18.6%) 7 (12.0%) Behavior Change a 17 (14.4%) 3 (5.2%) Lethargy 16 (13.6%) 6 (10.3%) Anemia 11 (9.3%) 1 (1.7%) Dehydration 11 (9.3%) 2 (3.4%) Stage of CKD Increased b 10 (8.5%) 3 (5.2%) Diarrhea 9 (7.6%) 2 (3.4%) Urinary Tract Infection 8 (6.8%) 2 (3.4%) Hyperglycemia 8 (6.8%) 2 (3.4%) Upper Respiratory Infection 7 (5.9%) 1 (1.7%) Hypercalcemia 7 (5.9%) 0 (0.0%) Facial Skin Lesion 6 (5.1%) 3 (5.2%) Hyperkalemia 5 (4.2%) 0 (0.0%) Ataxia 4 (3.4%) 0 (0.0%) Diabetes Mellitus 1 (0.8%) 0 (0.0%) Congestive Heart Failure 1 (0.8%) 0 (0.0%) Hypersalivation was generally associated with dosing and resolved within a few minutes. Nine cats (8 ELURA and 1 vehicle control) either died or were euthanized during or shortly after the study. Six ELURA cats were euthanized or died from decompensated CKD. One ELURA cat was euthanized after study withdrawal on Day 33 for declining quality of life and recent identification of a new mass. One ELURA cat acutely declined and was euthanized for findings of nodules in both kidneys and diagnosis of sarcoma. The vehicle control cat was euthanized for acute onset of right hindlimb paresis and suspected embolic event. Two additional cats were diagnosed with neoplasia during the study (one ELURA cat with unspecified soft tissue sarcoma and one control cat with mammary adenocarcinoma) but completed the study. Post-Approval Experience (2025) The following adverse events are based on post-approval adverse drug experience reporting for ELURA. Not all adverse events are reported to FDA/CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data. The following adverse events in cats are categorized in order of decreasing reporting frequency by body system and in decreasing order of reporting frequency within each body system: Gastrointestinal: hypersalivation, vomiting General: lethargy, anorexia, recumbency, weakness Behavioral: unusual behaviors, hiding, vocalization, hyperactivity Cardiovascular: bradycardia, hypotension Neurological: loss of consciousness, sedation Respiratory: dyspnea

Elura™

Safety was evaluated in a 56-day field effectiveness study in 176 client-owned cats (118 administered ELURA, 58 administered vehicle control) that received at least one dose. Cats enrolled had ≥5% unintended weight loss and a history of chronic kidney disease (CKD). Cats had a mean age of 15 years and at enrollment 11.4% of the cats were in Stage 1 CKD, 66.5% were in Stage 2, 21.0% were in Stage 3, and 1.1% were in Stage 4. Cats enrolled in the study had a variety of comorbid conditions: dental disease (88.1%), moderate or severe muscle loss (43.2%), heart murmur (28.4%), history of vomiting or underlying gastrointestinal disease (28.4%), hyperthyroidism (13.6%) and hypertension (9.7%). Table 1: Adverse Reactions in the Field Effectiveness Study Note: If an animal experienced the same event more than once, only the first occurrence was tabulated. a Behavior change included hiding from the owner (8 ELURA, 1 vehicle control); owner reported difficulty administering medication (7 ELURA, 1 vehicle control); and redirected aggression to another household cat (2 ELURA, 1 vehicle control). b Two ELURA and 1 vehicle control cat increased by two CKD stages; 8 ELURA and 2 vehicle control cats increased one CKD stage. It could not be determined if the progressive renal disease was the natural course of the pre-existing disease or treatment related. Adverse Reaction ELURA (n=118) Vehicle Control (n=58) Vomiting 35 (29.6%) 13 (22.4%) Hypersalivation 25 (21.2%) 0 (0.0%) Inappetence 22 (18.6%) 7 (12.0%) Behavior Change a 17 (14.4%) 3 (5.2%) Lethargy 16 (13.6%) 6 (10.3%) Anemia 11 (9.3%) 1 (1.7%) Dehydration 11 (9.3%) 2 (3.4%) Stage of CKD Increased b 10 (8.5%) 3 (5.2%) Diarrhea 9 (7.6%) 2 (3.4%) Urinary Tract Infection 8 (6.8%) 2 (3.4%) Hyperglycemia 8 (6.8%) 2 (3.4%) Upper Respiratory Infection 7 (5.9%) 1 (1.7%) Hypercalcemia 7 (5.9%) 0 (0.0%) Facial Skin Lesion 6 (5.1%) 3 (5.2%) Hyperkalemia 5 (4.2%) 0 (0.0%) Ataxia 4 (3.4%) 0 (0.0%) Diabetes Mellitus 1 (0.8%) 0 (0.0%) Congestive Heart Failure 1 (0.8%) 0 (0.0%) Hypersalivation was generally associated with dosing and resolved within a few minutes. Nine cats (8 ELURA and 1 vehicle control) either died or were euthanized during or shortly after the study. Six ELURA cats were euthanized or died from decompensated CKD. One ELURA cat was euthanized after study withdrawal on Day 33 for declining quality of life and recent identification of a new mass. One ELURA cat acutely declined and was euthanized for findings of nodules in both kidneys and diagnosis of sarcoma. The vehicle control cat was euthanized for acute onset of right hindlimb paresis and suspected embolic event. Two additional cats were diagnosed with neoplasia during the study (one ELURA cat with unspecified soft tissue sarcoma and one control cat with mammary adenocarcinoma) but completed the study. In voluntary post-approval reporting for extra-label use of a capromorelin product for dogs, the following adverse events have been reported in cats (listed in decreasing order of reporting frequency): bradycardia, lethargy, hypersalivation, hypotension, behavior change, and vomiting. To report suspected adverse events, for technical assistance or to obtain a copy of the Safety Data Sheet (SDS), contact Elanco US, Inc. at 1-888-545-5973. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/reportanimalae.

Elura™

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. Post-Approval Experience (2025): The following adverse events are based on post-approval adverse drug experience reporting for ENTYCE. Not all adverse events are reported to FDA/CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data. The following adverse events in dogs are categorized in order of decreasing reporting frequency by body system and in decreasing order of reporting frequency within each body system: Gastrointestinal: vomiting, hypersalivation, diarrhea General: lethargy, polydipsia, weakness, hyperglycemia, recumbency Behavioral: Unusual behaviors (some of these behaviors were related to avoidance of medication), vocalization, hyperactivity Neurological: ataxia, loss of consciousness, disorientation, sedation Respiratory: panting, dyspnea Cardiovascular: bradycardia, hypotension

FDA application 141-457

Administer 3 mg/kg once daily by mouth.

Oral

The safe use of ENTYCE has not been evaluated in dogs used for breeding or pregnant or lactating bitches.

ENTYCE™

2 mg/kg once daily

Oral

Elura™

Administer ENTYCE orally at a dose of 3 mg/kg (1.4 mg/lb) body weight once daily. To administer ENTYCE follow the written instructions below and see illustrations 1 through 4 for administration steps. 1.Gently shake the bottle. 2.Remove the bottle cap and insert the provided dosing syringe firmly into the opening of the bottle. 3.Turn the bottle upside down and withdraw the appropriate volume of solution. Return the bottle to the upright position before removing the syringe, and replace the cap. 4.Administer the solution with the syringe into the dog's mouth. Rinse the syringe and plunger with water between treatment doses. Leave the syringe and plunger apart to dry. Wash hands immediately after use. The effectiveness of ENTYCE has not been evaluated beyond 4 days of treatment in the clinical field study (See Effectiveness).

ORAL

FDA application 141-457

Administer ELURA orally at a dose of 2 mg/kg (0.9 mg/lb) or 0.1 mL/kg (0.045 mL/lb) body weight once daily. To administer ELURA: •Remove the cap, insert the dosing syringe, invert the bottle, withdraw the appropriate amount of solution. •Return the bottle to the upright position, remove syringe, replace the cap. •Administer the solution into the cat's mouth. •Rinse the syringe and plunger with water and leave apart to dry. If the cat is routinely fed meals, offer food 30 minutes after administering the dose. If the cat vomits within 15 minutes or only receives a partial dose, then the dose may be re-administered.

ORAL

Elura™