Onsior (tablets for dogs) (10 mg) (Canada)

(robenacoxib)

5 mg, 10 mg, 20 mg and 40 mg tablets for dogs

Non-Steroidal Anti-Inflammatory

For Veterinary Use Only

For Use in Dogs Only

DIN 02374692 (5 mg), 02374706 (10 mg), 02374714 (20 mg), 02374722 (40 mg)

Description

ONSIOR contains robenacoxib, which is a non-steroidal anti-inflammatory drug (NSAID) belonging to the coxib class. The flavoured tablets are round, beige to brown in colour and are not scored.

Onsior (tablets for dogs) (10 mg) Indications

ONSIOR tablets are indicated:

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

2. as an adjunctive medication in the control of postoperative pain and inflammation associated with soft tissue surgery.

Dosage and Administration

Carefully consider the potential benefits and risks of ONSIOR and other treatment options before deciding to use ONSIOR (robenacoxib). Use the lowest effective dose for the shortest duration consistent with individual response.

Give orally without food or with a small quantity of food (see PHARMACOLOGY).

For the control of pain and inflammation associated with osteoarthritis in dogs ≥ 2.5 kg AND ≥ 6 months of age, the recommended dosage of ONSIOR is 1 mg/kg body weight with a range 1 to 2 mg/kg. Administer orally once per day according to the dosing chart below. There is no maximal limit to duration of treatment.

Dosing Chart of ONSIOR (robenacoxib) Tablets for Dogs for Osteoarthritis

As an adjunctive medication in the control of postoperative pain and inflammation associated with soft tissue surgery in dogs ≥ 2.5 kg AND ≥ 4 months of age, the dosage of ONSIOR is 2 mg/kg body weight with a range of 2 to 4 mg/kg. Administer orally once per day for up to a maximum of 3 days according to the dosing chart below. The first dose should be administered approximately 30 - 45 minutes (without food) before the start of surgery, at the same time as the pre-anesthetic agents are given.

After surgery, once daily treatment may be continued for up to two days with either ONSIOR tablets or ONSIOR injection. If subsequent doses are given by subcutaneous injection, different sites for each injection should be used.

Dosing Chart of ONSIOR (robenacoxib) Tablets for Dogs for Postoperative Pain and Soft Tissue Surgery

Tablets are not scored and should not be broken.

Do not use in dogs weighing less than 2.5 kg as these animals cannot be accurately dosed.

The interchangeable use of ONISOR injection and ONSIOR tablets has been tested in a target animal safety study and was shown to be well tolerated by dogs. ONSIOR injection or tablets may be used interchangeably in accordance with the indications and duration of use approved for each pharmaceutical form. Treatment should not exceed one dose (either tablet or injection) per day. Please note that the recommended dose for individual indications may differ.

Owners should be advised when their pet has received a robenacoxib injection prior to initiating the use of ONSIOR tablets, and be informed of the potential for adverse reactions and clinical signs associated with possible NSAID intolerance. Always provide the Client Information Sheet with prescription (detach from Package Insert).

Contraindications

As with all non-steroidal anti-inflammatory drugs (NSAIDs), administration of this drug is contraindicated in the following circumstances:

● dogs with gastrointestinal ulcers, renal disease, hepatic disorders, hypoproteinemia, dehydration, cardiac disease or coagulation disorders;

● a known hypersensitivity to robenacoxib or its excipients;

● concurrent use of other NSAIDs or corticosteroids;

● do not use in breeding, pregnant or lactating animals because the safety of robenacoxib has not been established.

CAUTIONS:

The safety of ONSIOR tablets when administered without limit to duration of treatment has not been established in dogs weighing less than 2.5 kg or under 6 months of age.

The safety of ONSIOR tablets when administered for up to a maximum three consecutive days has not been established in dogs weighing less than 2.5 kg or under 4 months of age.

All dogs should undergo a thorough history and physical exam before the initiation of NSAID therapy. Appropriate laboratory tests should be conducted to establish hematological and biochemical baseline data before the administration of an NSAID. If gastrointestinal (vomiting, diarrhea) or other side effects (anorexia, lethargy) occur, treatment should be discontinued.

Stop administration of ONSIOR immediately if decreased appetite, vomiting, lethargy, diarrhea or other suspected adverse reactions occur, and seek the advice of a veterinarian (see ADVERSE REACTIONS).

When administering NSAIDs for long-term therapy, liver enzymes should be monitored at the start of therapy, e.g. after 2, 4 and 8 weeks. Thereafter it is recommended to continue regular monitoring, e.g. every 3-6 months. Therapy should be discontinued if liver enzyme activities increase markedly or the dog shows clinical signs such as anorexia, apathy or vomiting in combination with elevated liver enzymes.

ONSIOR should be used with caution in dogs with a known hypersensitivity to other NSAIDs.

Pre-treatment other anti-inflammatory medicines may result in additional or increased adverse effects and accordingly a treatment-free period with such substances should be observed. The treatment-free period should take into account the pharmacokinetic properties of the products used previously. Concomitant treatment with drugs which affect renal flow, e.g. anesthetics, should be subject to clinical monitoring including blood pressure, ECG and body temperature. The use of parenteral fluids during surgery is recommended to decrease potential renal complications when using NSAIDs perioperatively.

If additional pain medication is needed after a daily dose of ONSIOR, a non-NSAID/non-corticosteroid class of analgesic should be administered.

Concurrent administration of potentially nephrotoxic drugs should be avoided as there might be an increase of renal toxicity.

Studies to determine the activity of robenacoxib when administered concomitantly with other protein-bound or similarly metabolized drugs have not been conducted. Commonly used protein-bound drugs include cardiac, anticonvulsant, and behavioral medications. The influence of concomitant drugs that may inhibit metabolism of ONSIOR has not been evaluated. Drug compatibility should be monitored in patients requiring adjunctive therapy.

It is unknown whether dogs with a history of hypersensitivity to β lactam drugs will exhibit hypersensitivity to ONSIOR. Robenacoxib is poorly soluble in water and in acid solutions readily degrades to form γ-lactam. In dogs, lactam is a minor metabolite of robenacoxib. Additionally, lactam is a degradation product that increases over the shelf life of the solution. Neurologic signs have been associated with the use of β lactam drugs; it is unknown if the lactam produced by robenacoxib may cause similar neurologic signs.

Warnings

KEEP OUT OF REACH OF CHILDREN. In case of accidental ingestion, seek medical advice immediately and show the package insert or the label to the physician.

Adverse Reactions

Although all adverse events are not reported, the following information is based on post-approval drug experience reporting. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using this data.

The post-marketing adverse event reports for ONSIOR tablets have shown the following signs to be reported very rarely (less than 1 animal in 10,000 animals, including isolated reports): vomiting, anorexia, diarrhea, lethargy, and elevated liver enzymes.

In the pivotal clinical trial, a total of 125 dogs with chronic osteoarthritis were treated with ONSIOR at a robenacoxib dosage of 1 to 2 mg/kg once daily for 3 months. Adverse reactions reported at a frequency of more than 1% in the ONSIOR group are listed in the table below (by frequency):

* including one case of hemorrhagic diarrhea

** hemorrhagic gastroenteritis

Adverse reactions reported at a frequency of less than 1% in the ONSIOR group: anxiety, gastric torsion, hyperactivity, polyuria, pruritus, somnolence, tenesmus and urinary incontinence.

Three dogs treated with ONSIOR and two treated with the positive control article had liver associated adverse reactions during the study. One ONSIOR treated dog was a 14 year old Collie with signs of polydipsia, vomiting and anorexia after 36 days of treatment. Liver values were normal at the start of treatment, and on day 42 ALT, ALP and AST values were all increased. Treatment was stopped and 1 month later the dog had recovered. In the second case, a 10 year old dog treated with ONSIOR started vomiting, was polyuric and polydipsic, and was lethargic on the 33rd day of treatment. The dog entered the study with an increased ALT and on day 27 of the study there were marked increases in ALT, ALP and AST. Treatment was stopped and the dog recovered 6 weeks later. In the third ONSIOR case, a 12 year old German Shepherd had severe vomiting, diarrhea, abdominal pain and was lethargic and anorexic after 26 days of treatment. At the start of the study ALT and ALP were increased, however by day 28 of treatment there was a large increase in ALT, ALP and AST values. A liver biopsy showed severe active hepatitis. The dog died the day following the liver biopsy. In the positive control group, one dog, an 11 year old Great Pyrenees Mountain, developed a fatty liver one week after starting treatment. This dog had mild increases in liver enzymes at the start of treatment and the values increased slightly with treatment. The second positive control dog, a 13 year old Labrador retriever, was polydipsic and lethargic 5 days after starting treatment. By day 56 the dog had lost more than 10% of its body weight and treatment was stopped. The dog had increased liver enzymes at inclusion and the values increased with treatment. These cases show the importance of ensuring no liver abnormalities are present before starting treatment.

One ONSIOR treated dog, an 11 year old Labrador Retriever, had vomiting, hematochezia and anorexia after 56 days treatment. Values of ALT, ALP and AST were increased in the dog. However no link between the gastrointestinal signs and hepatic disease was made by the treating veterinarian. The treatment was stopped and 1.5 months later the dog had recovered.

Of the 17 dogs treated with ONSIOR that had normal ALT values at the start of the study that increased to 3x normal during the study, 10 dogs had no clinical signs, 4 dogs had mild signs of soft feces or vomiting and three dogs had severe clinical signs of vomiting, lethargy and anorexia. None of the 4 dogs treated with the positive control article that had ALT values 3x normal had clinical signs.

In the pivotal clinical trial, a total of 119 dogs were treated with ONSIOR as an adjunctive medication in the control of postoperative pain and inflammation associated with soft tissue surgery at a robenacoxib dosage of 2 mg/kg once daily for maximum of 3 days. Adverse reactions reported at a frequency of more than 1% in the ONSIOR group are listed in the table below (by frequency):

Adverse Reactions Reported in the Soft Tissue Surgery Field Study

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

Adverse Reactions reported at a frequency of less than 1% in the ONSIOR tablets group included hypotension and body weight loss.

For technical support or to report a suspected adverse drug reaction, contact Elanco Canada Limited at 1-800-265-5475.

Information for Dog Owners:

ONSIOR is the product your veterinarian has chosen to treat your dog’s pain. It belongs to a class of drugs called “non-steroidal anti-inflammatory” or NSAIDs. These drugs must be used according to your veterinarian’s directions. Occasionally, NSAIDs can cause side effects. If your dog stops eating, is depressed, vomits or has diarrhea stop the drug immediately and contact your veterinarian. In most cases the side effects will disappear when the drug is stopped but in rare cases it may be serious. For this reason, it is important to consult with your veterinarian. If you notice any serious side effects or others not mentioned in the insert, please inform your veterinarian.

Pharmacology

Mode of Action

Pharmacodynamics

Robenacoxib is an NSAID of the coxib class. It is a highly potent and selective inhibitor of the cyclooxygenase 2 enzyme (COX-2). The cyclooxygenase enzyme (COX) is present in two forms. COX-1 is the “constitutive” form of the enzyme and has protective functions including in the gastrointestinal tract and kidney. COX-2 is the “inducible” form of the enzyme and is responsible for the production of mediators including PGE₂ which induce pain, inflammation or fever.

Pharmacokinetics

Absorption: After oral administration of robenacoxib flavoured tablets at 1 mg/kg without food, peak blood concentrations are attained rapidly with a T_max of 0.5 h, a C_max of 1124 ng/mL and an AUC of 1249 ng.h/mL. In a canine pharmacokinetic study, co-administration of tablets with the entire daily ration of food reduced the AUC by 22% (bioavailability was 62% with food versus 84% when fasted) and the C_max by 15% (C_max was 917 ng/mL with food versus 1076 ng/mL when fasted). However, T_max was not delayed with food (0.3 h) as compared to when fasted (0.5 h). The terminal half-life was 1.15 h with food as compared to fasted (0.86 h); this difference is very small but may indicate a slower absorption of part of the ingested robenacoxib with food. In an efficacy study with osteoarthritic dogs using ONSIOR, the efficacy was slightly but significantly better when robenacoxib tablets were administered without food.

Distribution: Robenacoxib has a relatively small volume of distribution (Vss 240 mL/kg) and is highly bound to plasma proteins (>98%).

Biotransformation: Robenacoxib is extensively metabolized by the liver in dogs. Apart from one gamma-lactam metabolite, the identity and activity of other metabolites is not known in dogs.

Elimination: Robenacoxib is cleared rapidly from blood (CL 0.81 L/kg/h) with an elimination half-life of 0.7 h after intravenous administration.

After oral administration of flavoured tablets, the terminal half-life in blood was 1.2 h. Robenacoxib persists longer and at higher concentrations at sites of inflammation than in blood. Robenacoxib is excreted predominately via the biliary route (65%) and the remainder via the kidneys. The pharmacokinetics of robenacoxib do not differ between male and female dogs.

SAFETY STUDIES:

6 Month Target Animal Safety Study:

In a 6 month study, 6-7 month old healthy Beagle dogs (4/sex/group) were administered ONSIOR at doses of 0, 1X (2 mg/kg), 3X (6 mg/kg) or 5X (10 mg/kg) once daily as oral tablets. All dogs survived to their scheduled termination at the end of the six-month study. No effect of treatment was observed on clinical findings, food consumption, water consumption, buccal mucosal bleeding time, ophthalmoscopic, electrocardiographic, physical and neurological examinations, hematology, coagulation, urinalysis, fecal findings and microscopic examinations.

Vomiting, soft feces, injected sclera and salivation were commonly observed in the treated and control groups. Pooled body weights of animals at the 1X dose were slightly higher, but statistically significant, compared to controls during weeks 8 through 14. Albumin was slightly lower compared to the controls in the 3X group on day 91 and in the 1X and 5X groups on day 181. Mean ovarian weights were significantly decreased in the females of the 3X and 5X groups when compared to the controls. These changes appeared to be test article related but there were no histopathological changes. There was a red locus on the cecum of a 3X male and on the duodenum of a 5X female. These lesions were not associated with intestinal erosions on histopathology.

Individual blood profiles of all animals from all treatment groups showed large inter-animal variation on study Days 1, 30, and 150. The C_max and AUC data determined for Days 1, 30, and 150, considering the large inter-animal variation, reached comparable levels with no accumulation except for the 1X dose. In the 1X dose, data from Day 30 to Day 150 showed a strong increase in the mean C_max and AUC; no similar trend was seen in the data from study Day 1 to Day 30. Blood concentrations were below the limit of detection within 24 h postdose in the 1X and 3X groups for all animals at all time points. For the 5X group, a few animals on Day 30 and Day 50 had low but detectable blood levels at 24 h postdose, with a majority of the animals exhibiting blood concentrations below the limit of quantification. In general, the C_max and AUC data showed a dose-related increase between the three dose groups.

The daily oral administration of ONSIOR at 1X, 3X, and 5X the maximum target exposure in adult Beagle dogs was well tolerated in this 6-month study. Nevertheless it is strongly recommended that the dose of ONSIOR be tapered to the lowest effective dose and that liver enzymes be monitored regularly.

88-Day Interchangeable Use Study:

In an 88-day laboratory interchangeable use study, 4-month old healthy mongrel dogs (4 sex/dose) were administered three 20 day cycles (separated by a 14-day washout) of alternating regimens of ONSIOR tablets and ONSIOR injection. Each cycle included a schedule of 7 days of once daily oral tablet administration (0, 2, 4 or 6 mg/kg/day; groups 1, 2, 3 and 4, respectively), subcutaneous injection (0, 4, 8 or 12 mg/kg/day; groups 1, 2, 3 and 4, respectively), and then 7 days once daily oral administration (0, 2, 4 or 6 mg/kg/day; groups 1, 2, 3, and 4 respectively). The groups correspond to 0, 1x, 2x and 3x the labelled dose. The negative control group (group 1) received empty gelatin capsules or saline injections.

All dogs were in good health through study termination. Injection site reactions, including skin thickening, ulceration, or granulation, occurred in dogs in all groups in a dose-dependent manner, including one control dog. Histologically, there was minimal to severe subcutaneous necrosis, degeneration, and/or fibrosis with occasional myonecrosis of the underlying panniculus muscle. On gross pathology, one dog in the group 2, the 1x labelled dose, had discolouration throughout the entire duodenal, jejunal, and ileal mucosa as well as multiple mucosal discolorations in the stomach with a jejunal ulcer with minimal inflammation but no other corresponding histopathological findings. Another dog in group 2 had stomach, duodenal and jejunal mucosal discoloration with no corresponding histopathology findings. One group 3 (2x labelled dose) dog had multiple mucosal discoloration in the stomach and duodenum with no histopathology findings; and microscopic minimal cecal hemorrhage with microscopic cecal inflammation. This dog also vomited on 2 days. Another dog in group 3 had discoloration grossly along with the entire duodenal and jejunal mucosa with no correlating histopathology findings; a single mucosal discoloration in the stomach with no histopathology findings, and slight duodenal congestion microscopically. The dog vomited on 3 study days. Microscopic cecal inflammation was noted in one group 4 dog (3x labelled dose). There were no gastrointestinal findings noted in the control group. More treated male dogs had increased severity of thymus lymphocyte depletion compared to the control dogs.

EFFICACY STUDIES:

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

Efficacy was demonstrated using ONSIOR in a blinded, positive-controlled, multi-centered field study conducted in France involving client-owned dogs. In this study dogs with clinical signs of osteoarthritis of at least 3 weeks duration confirmed by radiographic changes and lameness were randomly assigned to receive treatment with 1 to 2 mg/kg ONSIOR or the positive control article for up to 12 weeks. There were 125 dogs in the ONSIOR group and 63 dogs in the positive control group. The primary endpoint was a global investigator score, a composite score for posture, lameness at walk and trot, willingness to raise the contralateral limb and pain on palpation/mobilization. One dog in each group was withdrawn because of lack of efficacy. Eleven dogs (9%) in the ONSIOR group and 5 dogs (8%) in the positive control group were withdrawn because of adverse reactions which may or may not have been related to the treatment. The efficacy of robenacoxib was demonstrated to be non-inferior to the positive control for the primary endpoint. The results of the study demonstrated that the efficacy of ONSIOR was non-inferior to the positive control treatment.

2. As an adjunctive medication in the control of postoperative pain and inflammation associated with soft tissue surgery.

Efficacy was demonstrated using ONSIOR tablets in a blinded, controlled, multi-site field study involving client owned dogs. In this study, 239 dogs presenting for soft tissue surgery were randomly administered ONSIOR tablets or the control article. Drug was administered approximately 45 minutes before surgery along with pre-anesthetic medications including opioids and continued once daily for two additional treatments. All dogs received fluids perioperatively. Efficacy was evaluated in 231 dogs and field safety was evaluated in 239 dogs. A statistically significant difference in the proportion of treatment successes in the ONSIOR tablet treatment group (89/116; 76.92%) compared to the control group (74/115; 64.35%) was observed. Twenty seven of the 116 dogs in the robenacoxib group and 41 of the 115 control dogs were treatment failures. On the day of surgery, significant improvement in the total pain scores at various post-surgical time points up to 8 hours, and overall significant improvement in response to touch and posture/activity were observed. The results of the field study demonstrate that ONSIOR tablets, when administered for a maximum of 3 days, are effective and well-tolerated for the control of postoperative pain associated with soft tissue surgery in dogs.

STORAGE CONDITIONS:

ONSIOR tablets should be stored between 5°C and 25°C.

PRESENTATION:

ONSIOR tablets are available in 5, 10, 20 and 40 mg tablet strengths in colour-coded packaging for oral administration.

Date: April 2023

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

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

© 2023 Elanco or its affiliates.

04Apr2023

CPN: 1231110.6