غرابيبرانت

For the control of pain and inflammation associated with osteoarthritis in dogs.

For oral use in dogs only.

Galliprant™

GALLIPRANT (grapiprant tablets) is indicated for the control of pain and inflammation associated with osteoarthritis in dogs.

GalliprantTM

Grapiprant is a prostaglandin E2 (PGE2) EP4 receptor antagonist; a non- cyclooxygenase inhibiting, non-steroidal, anti-inflammatory drug. Grapiprant has a canine EP4 receptor binding affinity (Ki) of 24 nM. Prostaglandins have a wide variety of physiologic effects. Prostaglandin E2 (PGE2) is a prostanoid that exerts its effects via four receptors, EP1, EP2, EP3, and EP4. PGE2 is involved in mediating inflammatory pain, vasodilation, increasing vascular permeability; as well as gastrointestinal homeostasis, renal function and reproductive functions. The EP4 receptor is important in mediating pain and inflammation as it is the primary mediator of the PGE2-elicited sensitization of sensory neurons1 and PGE2-elicited inflammation.2 Grapiprant blocks PGE2-elicited pain and inflammation by antagonizing the EP4 receptor. The EP4 receptor, along with the EP1, EP2 and EP3 receptors, is involved in PGE2 mediated effects on gastrointestinal homeostasis and renal function. PGE2 effects mediated solely by the EP4 receptor are stimulation of mucus secretion in the stomach and large intestine, stimulation of acid secretion in the stomach, inhibition of small intestine motility and inhibition of cytokine expression in the large intestine.3 While PGE2 gastroprotective action is mediated by EP1, the healing- promoting action of PGE2 in the stomach is mediated by the EP4 receptor.4 In the kidney, the PGE2 antinatiuretic effect is mediated by the EP4 receptor.5 EP4 receptors are abundantly expressed in the heart of dogs,6 the clinical relevance of which is unknown. The EP4 receptor is not involved in generation of pyrexia. Grapiprant is not a potential inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 mediated metabolism pathways. Grapiprant is a substrate of P-glycoprotein transport. In vitro metabolism with dog liver microsomes identified two oxidative metabolites, M3 (hydroxyl) and M5 (N-dealkylation). The pharmacokinetic characterization of grapiprant following oral administration of GALLIPRANT tablets to healthy Beagles is provided in the table below. Table 2. Mean (±SD) Plasma Pharmacokinetic Parameters for Grapiprant in Beagles after single oral dose of GALLIPRANT tablet formulation 1Study 1 was a food effect determination study. 2Study 2 was a PK bridging study conducted using 60 mg GALLIPRANT tablets at 6 mg/kg dose and 5 X 100 mg GALLIPRANT tablets at 50 mg/kg dose. 3Median (Range) Study Study 11 Study 11 Study 22 Study 22 PK Parameter 2 mg/kg (n = 10) (Fasted) 2 mg/kg (n = 10) (Fed) 6 mg/kg (n = 8) (Fasted) 50 mg/kg (n = 8) (Fasted) Tmax3 (hr) 1.0 (0.5 – 1.03) 1.0 (0.5 – 8.07) 1.0 (1.0 – 2.0) 2.0 (1.0 – 4.0) Cmax (ng/mL) 1210 (341) 278 (179) 5720 (3220) 98500 (13100) AUC(0-inf) (ng*hr/mL) 2790 (982) 1200 (523) 17800 (5520) 414000 (73700) T1/2 (hr) 4.60 (4.19) 5.67 (3.27) 5.01 (1.95) 5.21 (1.66) Fed/Fasted Relative Bioavailability Geometric Mean Ratio of AUC (90% Confidence Limits) 0.37 (0.28 – 0.46) NA Grapiprant is absorbed rapidly following an oral dose of the GALLIPRANT; with Cmax values achieved within approximately 2 hr post-dose (Tmax). Intake of the tablet with food significantly reduces the oral bioavailability, with mean Cmax and AUC grapiprant values reduced 4-fold and 2-fold, respectively. The systemic grapiprant exposure increases in a greater than dose proportional manner. The mean terminal elimination half-life (T1/2) ranges between 4.60 to 5.67 hr. Following once daily dosing, negligible drug accumulation in the blood is anticipated. Following an oral dose of radiolabeled grapiprant to dogs, the majority of the dose was excreted within the first 72 hr (84%) and approximately 88.7% of the dose was excreted in 192 hr. In a bile duct cannulated dog study, approximately 55.6%, 15.1% and 19.1% of the dose was excreted in bile, urine and feces, respectively, suggesting the high oral bioavailability of grapiprant in dogs (> 70%). Four metabolites were identified; two hydroxylated metabolites, one N-deamination metabolite (major metabolite urine (3.4%) and feces (7.2%)) and one N-oxidation metabolite. Metabolite activity is not known. Plasma protein binding of grapiprant was ~95%.

GalliprantTM

GALLIPRANT should not be used in dogs that have a hypersensitivity to grapiprant.

GalliprantTM

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. All dogs should undergo a thorough history and physical examination before the initiation of NSAID therapy. Appropriate laboratory tests to establish hematological and serum biochemical baseline data prior to and periodically during administration of any NSAID is recommended. Owners should be advised to observe for signs of potential drug toxicity (see Adverse Reactions , Post-Approval Experience , and Animal Safety ) and be given an “Information for Dog Owners” Sheet about GALLIPRANT. Do not administer GALLIPRANT in conjunction with any other oral or injectable NSAID or corticosteroid. Keep GALLIPRANT in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

GalliprantTM

In a controlled field study, 285 dogs were evaluated for safety when given either GALLIPRANT or a vehicle control (tablet minus grapiprant) at a dose of 2 mg/kg (0.9 mg/lb) once daily for 28 days. GALLIPRANT-treated dogs ranged in age from 2 to 16.75 years. The following adverse reactions were observed: Table 1. Adverse reactions reported in the field study. *Dogs may have experienced more than one type or occurrence during the study. Adverse reaction* GALLIPRANT (grapiprant tablets) N = 141 Vehicle control (tablets minus grapiprant) N = 144 Vomiting 24 9 Diarrhea, soft stool 17 13 Anorexia, inappetence 9 7 Lethargy 6 2 Buccal ulcer 1 0 Immune mediated hemolytic anemia 1 0 GALLIPRANT was used safely during the field studies with other concurrent therapies, including antibiotics, parasiticides and vaccinations.

GalliprantTM

0.9 mg/lb (2 mg/kg) once daily.

Oral

For oral use in dogs only.

Galliprant™

Always provide “Information for Dog Owners” Sheet with prescription. Carefully consider the potential benefits and risks of GALLIPRANT and other treatment options before deciding to use GALLIPRANT. Use the lowest effective dose for the shortest duration consistent with individual response. The dose of GALLIPRANT (grapiprant tablets) is 0.9 mg/lb (2 mg/kg) once daily. Only the 20 mg and 60 mg tablets of GALLIPRANT are scored. The dosage should be calculated in half tablet increments. Dogs less than 8 lbs. (3.6 kgs) cannot be accurately dosed.

ORAL

GalliprantTM