Galliprant (60 mg) (Canada)

(grapiprant tablets)

For Veterinary Use Only

For Dogs

DIN 02484250 (20 mg), 02484269 (60 mg), 02484277 (100 mg)

Description

GALLIPRANT (grapiprant tablets) is a prostaglandin E₂ (PGE₂) EP4 receptor antagonist; a non-cyclooxygenase (COX) inhibiting, non-steroidal, anti-inflammatory drug (NSAID) in the piprant class. Grapiprant is N-[[[2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4 methylbenzenesulfonamide.

INDICATION

GALLIPRANT is indicated for the treatment and control of pain and inflammation associated with osteoarthritis in dogs.

DOSAGE AND ADMINISTRATION

The dose of GALLIPRANT is 2 mg/kg once daily. Administer orally with or without food (see Pharmacokinetics). Dogs less than 3.6 kg cannot be accurately dosed.

Use the lowest effective dose for the shortest duration consistent with individual response. If no clinical improvement is apparent after 14 days, treatment with GALLIPRANT should be discontinued.

The following number of tablets can be given once daily to provide a dose of 2 mg per kg of bodyweight (equating to a dose of 1.5 - 2.9 mg/kg bodyweight).

Dosing Chart

The dosage should be calculated in half tablet increments when applicable. Only the 20 mg and 60 mg tablets of GALLIPRANT are scored. To break the 20 mg or 60 mg tablets in half, hold the tablet between the thumb and index finger of each hand on either side of the score line, with the score line facing downward. Separate into two halves by breaking the tablet down toward the score line.

The 100 mg tablet is not scored and should not be broken in half. Breaking the 100 mg tablet in half will not guarantee that half of the active ingredient is contained within each half of the tablet.

Owners should be informed of the potential for adverse reactions and clinical signs associated with possible NSAID intolerance. Always provide the “Information for Dog Owners” sheet with prescription (detach from the Package Insert).

Contraindications

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

CAUTIONS

The safe use of GALLIPRANT has not been evaluated in dogs younger than 9 months of age, less than 3.6 kg, or in dogs used for breeding, or dogs that are pregnant or lactating.

If GALLIPRANT is used long term, appropriate monitoring of clinical signs, hematology and serum chemistry is recommended. If vomiting, inappetence, lethargy, diarrhea, or other possible adverse reactions occur, the advice of a veterinarian should be sought as treatment may need to be discontinued (see Adverse Reactions).

Concurrent use with other anti-inflammatory drugs has not been studied. Concomitant use of GALLIPRANT with other anti-inflammatory drugs, such as COX-inhibiting NSAIDs or corticosteroids, should be avoided. If additional pain medication is needed after a daily dose of GALLIPRANT, a non-NSAID/non-corticosteroid class of analgesic should be chosen.

The use of GALLIPRANT in dogs with pre-existing liver, cardiovascular, renal, gastrointestinal disorders or that may become dehydrated should be closely monitored.

Drug compatibility should be monitored in patients requiring adjunctive therapy. Consider appropriate washout times when switching from one anti-inflammatory to another or when switching from corticosteroids or COX-inhibiting NSAIDs to GALLIPRANT use.

GALLIPRANT is highly bound to protein. The concomitant use of protein-bound drugs with GALLIPRANT has not been studied. Commonly used protein-bound drugs include cardiac, anticonvulsant and behavioural medications.

The use of GALLIPRANT in dogs with cardiac disease has not been studied.

It is not known whether dogs with a history of hypersensitivity to sulfonamide drugs will exhibit hypersensitivity to GALLIPRANT. GALLIPRANT is a methylbenzenesulfonamide.

WARNINGS

Keep out of reach of children. Consult a physician in case of accidental ingestion by humans.

ADVERSE REACTIONS

For Adverse Reactions reported in the pivotal field study see Safety Section, Table 2.

Post Market Reports

Although all adverse reactions are not reported, the following information is based on voluntary post-approval drug experience reporting. It is generally recognized that this results in significant under-reporting. The adverse events listed here reflect reporting and not necessarily causality.

The post-marketing adverse event experience for GALLIPRANT has shown the following signs to be reported rarely (less than 1 dog in 1,000): diarrhea, emesis, anorexia, lack of efficacy and lethargy. The following signs were reported very rarely (less than 1 dog in 10,000, including isolated reports): hemorrhagic diarrhea, elevated liver enzymes including elevated ALT, elevated BUN, and elevated creatinine.

To report suspected adverse drug events or for technical assistance, contact Elanco Canada Limited at 1-800-265-5475.

Information for Dog Owners

Owners should be advised of the potential for adverse reactions and be informed of the clinical signs associated with drug intolerance. Adverse reactions may include vomiting, diarrhea, decreased appetite, and decreasing albumin and total protein. If any of these signs of possible intolerance are observed, immediately contact your veterinarian.

Pharmacology

Mode of Action

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. E₂ 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 neurons and PGE₂-elicited inflammation. 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.

While the gastroprotective action of PGE₂ is mediated by EP1, the healing-promoting action of PGE₂ in the stomach is mediated by the EP4 receptor. In the kidney, the antinatiuretic effect of PGE₂ is mediated by the EP4 receptor.

EP4 receptors are abundantly expressed in the heart of dogs, 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).

Pharmacokinectics

The pharmacokinetic characterization of grapiprant following oral administration of GALLIPRANT tablets to healthy Beagles is provided in the table below.

Table 1: 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)

Grapiprant is absorbed rapidly following an oral dose of GALLIPRANT; with C_max values achieved within approximately 2 hr post-dose (T_max). Intake of the tablet with food reduces the oral bioavailability, with mean C_max 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 (T_1/2) 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%.

SAFETY

In a 9-month toxicity study, grapiprant in a methylcellulose suspension was administered by oral gavage once daily to healthy Beagles at doses of 1, 6, and 50 mg/kg/day.

Based on a relative bioavailability study comparing grapiprant in methylcellulose suspension to GALLIPRANT tablets, the corresponding equivalent doses were 0.75 mg/kg (0.12X - 0.25X), 4.44 mg/kg (0.72X - 1.48X) and 30.47 mg/kg (4.88X - 10.16X) of the GALLIPRANT tablets. Four animals/sex were used in each dose group and 2 additional animals/sex were used in the 50 mg/kg dose group to evaluate recovery after drug cessation.

Adverse gastrointestinal (GI) events of vomiting and soft-formed or mucus stool were observed in all groups, including controls, with higher incidence in grapiprant-treated dogs. The GI events decreased in the recovery group once grapiprant was discontinued. Decreases in serum albumin and total protein were seen with increasing doses of grapiprant but were not associated with any clinically significant observations or events and were reversible when treatment was discontinued. Three treated dogs and one control dog had elevated alkaline phosphatase values. One dog in the 50 mg/kg (equivalent to up to 30.47 mg/kg of the tablet formulation) had mild regeneration of the mucosal epithelium of the ileum.

In a controlled field study, 366 client-owned dogs were treated with GALLIPRANT at doses of 2 mg/kg once daily, 5 mg/kg once daily, 4 mg/kg twice daily, or placebo twice daily. The most common adverse reactions related to treatment were diarrhea, vomiting and inappetence with increasing incidence in the 5 mg/kg once daily and 4 mg/kg twice daily groups. Changes in clinical pathology included concurrent elevations of alkaline phosphatase and alanine aminotransferase values on Day 28, and dose-dependent decreases in total protein values. There was no clinical impact related to these clinical pathology changes.

In a confirmatory controlled field study, 285 dogs were evaluated for safety when given either GALLIPRANT at a dose of 2 mg/kg or a vehicle control (tablet minus grapiprant) once daily for 28 days. GALLIPRANT-treated dogs ranged in age from 2 to 16.75 years. The majority of cases of anorexia, inappetence, diarrhea, soft stool and vomiting resolved after a few days. The following adverse reactions were observed:

Table 2: Adverse Reactions Reported in the Confirmatory Field Study

*Dogs may have experienced more than one type or occurrence during the study.

GALLIPRANT was used during the field studies with other concurrent therapies, including antibiotics, parasiticides and vaccinations.

EFFICACY

Two hundred and eighty five (285) client-owned dogs were enrolled in a US multicentre field confirmatory safety and effectiveness study. GALLIPRANT-treated dogs ranging in age from 2 to 16.75 years and weighing between 4.1 and 59.6 kg with radiographic and clinical signs of osteoarthritis were enrolled in the placebo-controlled, masked study. Dogs had a 7-day washout period from NSAID or other current OA therapy. A total of 262 dogs (131 treated and 131 control cases) were included in the per protocol population for effectiveness evaluation. Dogs were assessed for improvements in pain and function by the owners using the Canine Brief Pain Inventory (CBPI) scoring system. A statistically significant difference in the proportion of treatment successes in the GALLIPRANT group (63/131 or 48.1%) was observed compared to the vehicle control group (41/131 or 31.3%). GALLIPRANT demonstrated statistically significant differences in owner assessed pain and function. The results of the field study demonstrate that GALLIPRANT, administered at 2 mg/kg once daily for 28 days, was effective for the treatment and control of pain and inflammation associated with osteoarthritis.

STORAGE CONDITIONS

Store at or below (30°C).

HOW SUPPLIED

GALLIPRANT is available in 20 mg, 60 mg and 100 mg flavoured tablets in 30 and 90 count bottles.

Each tablet is biconvex oval shaped and beige to brown speckled in colour. The 20 mg and 60 mg tablets are scored and can be divided into equal halves. Each tablet has “20”, “60” or “100” debossed on one half, with the letters “MG” on the other half of the face. The letter “G” is debossed on the opposite face.

MANUFACTURED FOR

Elanco Canada Limited, 1919 Minnesota Court, Suite 401, Mississauga, Ontario L5N 0C9

DATE: April 2023

Galliprant, Elanco and the diagonal bar logo are trademarks of Elanco or its affiliates.

© 2023 Elanco or its affiliates.

04Apr2023

CPN: 1231179.3