Onsior Solution for Injection for Dogs (Canada)

(robenacoxib)

Solution for Injection

(robenacoxib 20mg/mL sterile solution)

Non-Steroidal Anti-Inflammatory

For Veterinary Use Only

For Subcutaneous Use in Dogs

DIN 02374382

Description

ONSIOR contains robenacoxib which is a non-steroidal anti-inflammatory drug (NSAID) belonging to the coxib class. ONSIOR injection is a clear, colourless sterile solution containing the active ingredient, robenacoxib, 20 mg/mL.

Onsior Solution for Injection for Dogs Indications

ONSIOR (robenacoxib) injection is indicated:

1. for the control of pain and inflammation associated with orthopedic or soft tissue surgery.

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

Dosage and Administration

For subcutaneous use in dogs ≥ 4 months of age.

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

The recommended dose of ONSIOR (robenacoxib) injection is 2 mg/kg (1 mL per 10 kg of body weight) subcutaneously.

For the control of pain and inflammation associated with orthopedic or soft tissue surgery, administer subcutaneously once approximately 30 minutes before the start of surgery, around the time of induction of general anesthesia, at a dose of 2 mg/kg.

As an adjunctive medication in the control of postoperative pain and inflammation associated with soft tissue surgery, the recommended dosage of ONSIOR is 2 mg/kg body weight once daily, for a maximum of 3 days. Administer subcutaneously once approximately 30 - 45 minutes before the start of surgery as the pre-anesthetic agents are given.

After surgery, once daily treatment may be given via subcutaneous injection, or interchanged with the oral tablet in dogs ≥ 2.5 kg and ≥ 4 months of age, for up to a maximum of two additional days.

If subsequent doses are given by subcutaneous injection, different sites for each injection should be used (see ADVERSE REACTIONS).

The interchangeable use of ONSIOR 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, and be informed of the potential for adverse reactions and clinical signs associated with possible NSAID intolerance. Always provide the Client Information Sheet to the pet owner after administration (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 gastro-intestinal ulcers;

● dogs with impaired cardiac, renal or hepatic function or coagulation abnormalities;

● dogs that are dehydrated, hypovolemic, hypoproteinemic or hypotensive;

● dogs with a known hypersensitivity to robenacoxib or ONSIOR excipients or known intolerance to NSAIDs;

● concurrent use of other NSAIDs or corticosteroids;

● dogs used for breeding or that are pregnant or lactating, because the safety of robenacoxib has not been established in these animals.

CAUTIONS:

The safety of ONSIOR injection has not been established in dogs less than 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.

Monitor dogs post-injection for reactions. Injection site reactions and anaphylactic reactions have been associated with the use of ONSIOR injection (See ADVERSE REACTIONS).

Do not give additional ONSIOR injections if decreased appetite, vomiting, lethargy, diarrhea, or other suspected adverse reactions occur (see ADVERSE REACTIONS).

The adequacy of the analgesia should be assessed regularly following extubation. If additional analgesia is required choose a drug not of the anti-inflammatory class if it is to be administered within the 24 hours of treatment with ONSIOR.

As a class, cyclo-oxygenase inhibitory NSAIDs may be associated with gastrointestinal, renal, and hepatic toxicity. Sensitivity to drug-associated adverse events varies with the individual patient. Dogs that have experienced adverse reactions from one NSAID may experience adverse reactions from another NSAID. Patients at greatest risk for adverse events are those that are dehydrated, on concomitant diuretic therapy, or those with existing renal, cardiovascular, and/or hepatic dysfunction. Anesthetic drugs may affect renal perfusion; approach concomitant use of anesthetics and NSAIDs cautiously. Appropriate monitoring procedures (including ECG, blood pressure, and temperature regulation) should be employed during all surgical procedures. 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 may be necessary. Concurrent administration of potentially nephrotoxic drugs should be carefully approached and monitored. NSAIDs may inhibit prostaglandins which maintain normal homeostatic function. Such anti-prostaglandin effects may result in clinically significant disease in patients with underlying or pre-existing disease that has not been previously diagnosed. NSAIDs possess the potential to produce gastrointestinal ulcerations and/or gastrointestinal perforations.

Do not use ONSIOR concomitantly with other anti-inflammatory drugs, such as NSAIDs or corticosteroids. Consider appropriate washout times when switching from one NSAID to another or when switching from corticosteroid use to NSAID use.

The use of concomitantly protein-bound drugs with ONSIOR has not been studied in dogs. 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/injection, seek medical advice immediately and show the package insert or the label to the physician.

Adverse Reactions

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

The post-marketing adverse reaction reports for ONSIOR injectable have shown that very rarely (less than 1 animal in 10,000 animals, including isolated reports) reported adverse reactions in dogs included anorexia, emesis, lethargy, and diarrhea.

In the pivotal clinical trials, a total of 215 dogs received ONSIOR once prior to orthopedic or soft tissue surgery (Tables 1 and 2). The following adverse reactions were reported with ONSIOR with a frequency of more than 1% on the day of surgery or the following day:

Table 1: Adverse Reactions in Dogs Undergoing Orthopedic Surgery

Adverse reactions reported at a frequency of less than 1% in the ONSIOR group: vomiting and decreased appetite.

Table 2: Adverse Reactions in Dogs Undergoing Soft Tissue Surgery

In a controlled field study (See EFFICACY STUDIES), a total of 317 male and female dogs representing various breeds were included in the field safety analysis. ONSIOR-treated dogs ranged in age from 6 months to 15 years and weighed between 2.5 and 53.8 kg. The adverse reactions displayed in Table 3 were reported as being related to ONSIOR and occurred at a frequency of more than 1%. Those reported at a frequency of less than 1% in the ONSIOR group included facial edema, hypersensitivity and increased incisional bleeding.

Table 3: Adverse Reactions in Dogs in the Postoperative Soft Tissue Surgery Field Study

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

**Most often occurred as a single event.

Occurrences of hepatopathy, ataxia, skin lesions/urticaria, and anaphylaxis have been associated with the use of ONSIOR. In a month-long pilot study, 3 dogs that received ONSIOR developed hepatic toxicity. Two of these dogs were euthanized and a third dog recovered after prolonged hospitalization and supportive therapy. In foreign market experience, elevated liver enzymes, hepatic necrosis and death have been associated with the long term use of robenacoxib in dogs. Occurrences of liver failure, hepatitis, and cholangiohepatitis have been reported. In two other field studies, bradycardia, 2nd degree heart block in four dogs, and ventricular arrhythmia in one dog were noted in anesthetized dogs treated with ONSIOR injection.

Injection site reactions (edema, necrosis, and abscesses), and anaphylactic reactions (panting, drooling, shock, pallor, dyspnea, tachypnea, ataxia) have been associated with the use of ONSIOR injection.

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, like other drugs of its class, is not free from adverse reactions. Adverse reactions may include vomiting, diarrhea, decreased appetite, dark or tarry stools, increased water consumption, increased urination, anemia, yellowing of gums, skin or whites of the eye due to jaundice, lethargy, incoordination, seizure, or behavioural changes. Discontinue ONSIOR therapy and contact your veterinarian immediately if signs of possible intolerance are observed. The vast majority of patients with drug related adverse reactions have recovered when the signs are recognized, the drug is withdrawn, and veterinary care, if appropriate, is initiated.

Pharmacology

Mode of Action

Pharmacodynamics

Robenacoxib is a selective inhibitor of the cyclooxygenase 2 enzyme (COX-2), in vitro. The clinical relevance of this data has not been shown. 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: Peak blood concentrations of robenacoxib are attained rapidly after subcutaneous injection of ONSIOR in dogs. After a dosage of 2 mg/kg a T_max of 1 h, a C_max of 615 ng/mL and an AUC(0-_∞) of 2180 ng.h/mL is obtained. After a subcutaneous administration of 1 mg/kg the systemic bioavailability is 88%.

Distribution: Robenacoxib has a relatively small volume of distribution (Vss = 240 mL/kg in dogs) 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.

Elimination: After intravenous administration robenacoxib is rapidly cleared from blood (CL = 0.81 L/kg/h in dogs) with an elimination half-life (t1/2) of 0.8 h. After subcutaneous administration, the terminal half-life from blood is 1.2 h. Robenacoxib persists longer and in higher concentrations at sites of inflammation than in blood. Robenacoxib is excreted predominately via the biliary route in dogs (~65%) and the remainder via the kidneys. The pharmacokinetics of robenacoxib does not differ between male and female dogs.

Safety Studies

5-Week Safety Study:

Six month-old beagle dogs were administered ONSIOR by subcutaneous injection at dosages of 2 mg/kg (therapeutic dose), 6 mg/kg (3X overdose), and 20 mg/kg (10X overdose) once daily for 3 days every other week for 3 cycles. There was a higher incidence of pain on injection in the 10X males and 3X and 10X females. One 3X dog developed a heart murmur during the study. It is not known if the murmur was related to the treatment. Other observed changes included lower body weights in males in the 1X, 3X and 10X groups and females in the 1X and 10X groups compared to the control. There were no detectable pathological changes to the gastrointestinal tract, kidney or liver. There were no clinically significant changes to bleeding time. Reversible inflammation at the injection site was noted in all groups (including controls) and was more severe in the 6 and 20 mg/kg dose groups. As with any NSAID, overdose may cause gastrointestinal, kidney, or liver toxicity in sensitive or compromised animals.

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 orthopedic surgery or soft tissue surgery.

Efficacy was demonstrated using ONSIOR in two blinded positive controlled multi-centered field studies conducted in France and Germany involving client-owned dogs. In one study dogs requiring orthopaedic surgery such as repair of a ruptured anterior cruciate ligament, fracture, femoral neck excision, fragmented coronoid or osteochondrosis dissecans lesion surgery were randomly assigned to receive treatment with 2 mg/kg ONSIOR or the positive control article once. In the second study dogs undergoing soft tissue surgery, most commonly ovariectomy, ovariohysterectomy or mammary gland chain excision were randomly assigned to treatment with 2 mg/kg ONSIOR or the positive control once. There were 97 dogs enrolled in the ONSIOR group and 43 dogs in the positive control group in the orthopedic surgical study and 118 dogs in the ONSIOR group and 56 dogs in the positive control group for the soft tissue surgical study. The mean age of the dogs was 4 years in the orthopedic study and 5 years for the soft tissue study. In both studies the primary endpoint was the sum of the Glasgow Pain Scale scores conducted at 1, 2, 4, 8 and 24 h postoperatively. There were no dogs which required rescue therapy in either study. There were no differences in the number of dogs that were withdrawn for adverse events between the treatment groups. In both studies non-inferiority was demonstrated for the primary endpoint. The results of the studies demonstrated 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 (robencacoxib) injection in a blinded, controlled multi-site field study in which 317 client-owned dogs 6 months of age and older presenting for soft tissue surgery were randomized to receive ONSIOR injection or a placebo. Drug was administered approximately 45 minutes prior to surgery, along with pre-anesthestic medications including opioids, and continued once daily for two additional treatments. Efficacy was evaluated in 303 dogs and field safety was evaluated in 317 dogs. A statistically significant difference (p=value = 0.0055) was observed in the proportion of treatment success in the ONSIOR injection treatment group (108/151; 73.7%) compared to the placebo group (85/152; 58.1%). Forty three of the 151 dogs in the ONSIOR injection group and 67 of 152 dogs in the control group were treatment failures. Statistically significant differences in Response to Touch score (p=0.0013) and Posture/Activity (p=0.0466) were observed in the ONSIOR injection group relative to the control group. The results of the field study demonstrate that subcutaneous administration of ONSIOR (robenacoxib) injection, when administered for a maximum of 3 days is efficacious and well-tolerated for the control of postoperative pain associated with soft tissue surgery in dogs.

STORAGE CONDITIONS:

ONSIOR injection should be stored refrigerated at 2°C to 8°C. Avoid introduction of contamination. Keep the vial in the outer carton. After broaching of the vial, the product may be stored for 28 days at room temperature (15°C - 25°C).

PRESENTATION:

ONSIOR injection is available in a multi-dose amber glass vial.

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: 1231118.4