Onsior [Robenacoxib] for Dogs and Cats

By | 2012-01-29

Active substance / Generic: Robenacoxib

Scientific discussion

This medicine is approved for use in the European Union

The active substance of Onsior is robenacoxib, a non-steroidal anti-inflammatory drug (NSAID) of the coxib class which selectively inhibits the cyclooxygenase 2 enzyme (COX-2). The active substance, robenacoxib is a structural analogue to diclofenac.

Onsior is available as tablets in five different strengths (6 mg for cats, and 5 mg, 10 mg, 20 mg and 40 mg for dogs) and as a solution for injection (20 mg/ml for dogs and cats).

The benefits of Onsior are its efficacy in the treatment of pain and inflammation in dogs and cats.

The most common side effects are gastrointestinal adverse events (vomiting, soft faeces) in cats and dogs; in dogs following long-term oral treatment, an increase in liver enzyme activities was noted. The solution for injection might cause pain on injection.

The approved indications are:

Onsior Tablets

Cats: Treatment of acute pain and inflammation associated with musculo-skeletal disorders at a once daily dose of 1 mg/kg body weight up up to six days.

Dogs: Treatment of pain and inflammation associated with chronic osteoarthritis at a once daily dose of 1 mg/kg body weight as long as required (as directed by the veterinarian).

Onsior Solution for injection

Cats: Treatment of pain and inflammation associated with soft tissue surgery.

Dogs: Treatment of pain and inflammation associated with orthopaedic or soft tissue surgery in dogs.

Onsior: Quality Assessment

Composition

The tablets are biconvex, round, beige to brown, imprinted on one side with the company logo ” NA” and on the other side referring to the dosage strength (AK, BE, CD, BCK for dogs and AK for cats). Tablets of 6 mg robenacoxib are presented for cats, and tablets with a strength of 5, 10, 20, 40 mg robenacoxib for dogs. Conventional pharmaceutical excipients for tablets are used and full details are included in the SPC. In order to facilitate palatability, tablets for cats contain yeast powder and tablets for dogs contain yeast powder and artificial beef flavour.

The solution for injection for cats and dogs is a clear, colourless to slightly coloured (pink) liquid containing 20 mg/ml robenacoxib as active substance. Other substances are Macrogol 400, ethanol, anhydrous Poloxamer 188, citric acid monohydrate, sodium metabisulphite, sodium hydroxide and water for injections.

Container

The tablets are packaged into aluminium / aluminium foil blisters, each containing 7 tablets. One cardboard box contains one, two, four (dogs only) or ten blisters.

The solution for injection is presented in a 20 ml multidose amber glass vial, closed with a gray rubber stopper, sealed by an aluminium cap.

Development Pharmaceutics

Robenacoxib is a free acid. It is freely soluble in aqueous solution at alkaline pH values above 8, and in most organic solvents tested. At acidic pH values robenacoxib is practically insoluble in aqueous solution; solubility in pure water is poor. In acid solutions the active substance readily degrades to form a lactam. Robenacoxib exists in different polymorphic forms. The more stable form at room temperature was chosen and was shown to be chemically and physically stable under registration stability conditions.

The excipients used for the tablets are standard substances in tablet formulations for use in dogs and cats. In both, tablets for dogs and cats, yeast, microcrystalline cellulose, crospovidone, povidone, anhydrous colloidal silica and magnesium stearate are used. The tablets for dogs also contain powdered cellulose and artificial beef flavour as a flavour.

The excipients selected for the solution for injection are well accepted for use in injection formulations and are standard ingredients and their choice was based on the properties of the active substance. In the solution for injection, water for injection is used as solvent, macrogol 400 and ethanol as cosolvent, poloxamer 188 as solubiliser, citric acid monohydrate and sodium hydroxide for pH control, and sodium metabisulphite as antioxidant. Compatability of the various excipients was established.

Container

Because of absorptive properties of the yeast and in order to avoid water uptake, a non moisture-permeable (Al/Al) blister was selected. The suitability of the primary packaging was shown in the stability studies. No incompatibility of the formulation with the primary packaging material in contact with the product was noticed.

The solution for injection is presented in a 20 ml amber Type I glass vial, with a closure comprising a chlorobutyl stopper with aluminium crimp seal. The use of amber coloured vials to prevent photo-instability of the finished product is justified, since solutions of robenacoxib in various solvents proved to be very sensitive to light resulting in an increase of degradation products.

Conclusions On Quality

Onsior is presented as tablets for dogs and cats and as a solution for injection for both dog and cat containing the active substance robenacoxib. The tablets are immediate release tablets presented in aluminium/aluminium blisters packs. The tablets for dogs are available in four dosage strengths containing 5, 10, 20 or 40 mg of active substance while the tablet for cats contains 6 mg of active substance. The different strengths have been developed in order to permit an oral administration of 1 or 2 tablets per dose. The tablets for dogs and cats differ slightly with regard to different flavour agents included which is intended to improve the palatability specifically for the target species. The solution for injection contains 20 mg of robenacoxib per ml which can be administrated to both target species (dog and cat). It is packed in an amber multidose glass vial closed with a rubber stopper.

Robenacoxib is not described in any Pharmacopoeia. Full information is provided in the dossier to justify the quality of batches. Excipients used in the manufacture of the product are considered quite common for use in tablets or injection preparations. The dossier provides a suitable description of the active substance and the chosen formulations, and confirms production of the active substance and the products to a consistent quality. Analytical methods are well described, and data of their validation confirm their suitability.

Manufacturing processes are sufficiently detailed for all preparations and demonstrate that production of the final product leads to a consistent quality. The specifications for the final products contain sufficient acceptance criteria and corresponding tests. Stability studies have been performed according to VICH guidelines. The stability studies on the active substance and the finished products allow a re-test period of 48 months for robenacoxib and justify a shelf-life of 2 years for the tablets for dogs and cats and 3 years for the solution for injection, with a 28 day in-use shelf-life.

Robenacoxib: Safety Assessment

Although the information is limited, the data submitted indicate the toxicity of robenacoxib to be low. The oral LD50 for the rat was between 500 and 200 mg/kg bw and signs of intoxication did not indicate a specific toxic effect. When administered to rats for 13 weeks at a dose of 60 mg/kg bw/day, a decrease in creatinine levels in female rats was observed.

Reproduction toxicity was not studied. However, it was noted that cyclooxygenase inhibitors may produce adverse effects on the foetus or neonate if administered during gestation.

Robenacoxib is not considered to be mutagenic or carcinogenic.

Robenacoxib does not cause dermal irritation or hypersensitivity.

The applicant provided a user safety assessment taking account of different product formulations (tablets and solution for injection) and scenarios. CVMP identified potential risk for users of the tablets as accidential ingestion by children and prolonged dermal contact by pregnant woman and for the solution for injection, accidential self-injection by the veterinarian or accidential dermal exposure by pregnant women. Relevant user warnings were included in the SPC and product literature.

The use of Onsior (tablets or solution for injection) does not pose a risk to the environment.

Robenacoxib: Efficacy Assessment

Robenacoxib is a selective inhibitor of COX-2. In vitro data in cats indicate an approximately 500-fold COX selectivity for COX-2 as compared to COX-1. In dogs, robenacoxib was approximately 140 fold selective for COX-2. Analgesic and anti-inflammatory effects were confirmed in different animal models. In dogs, a maximum inhibition in COX-2 activity was achieved following a single intramuscular dose of 2 mg/kg bw. In the models used, a dose-response relationship in dogs was noted.

Following oral or subcutaneous administration, absorption is rapid with a Tmax of less than 2 hours. Presence of food reduced bioavailibity for robenacoxib and it is recommended to administer the product without food or with small amounts only. Robenacoxib has a relatively small volume of distribution and is highly bound to plasma proteins (>99%). Since robenacoxib showed some tissue selectivity at sites of inflammation, efficacy duration might be longer than predicted from plasma level profiles. Apart from one lactam metabolite, the identity of other metabolites is not known in cats or dogs, but no pharmacological action was demonstrated for any known metabolite. Robenacoxib is rapidly metabolised by the liver. Following subcutaneous or oral administration, the terminal half-life from blood was less than 2 hours in both, cats and dogs. Robenacoxib is excreted predominately via the biliary route in cats (-70 %) and dogs (-65 %) and the remainder via the kidneys. Clearance is age- and condition dependent (higher in healthy young animals), which might have clinical impact. Accumulation was not observed.

In general, tolerance in dogs and cats was considered good. Target animals safety studies with the oral formulation showed good tolerance for both, dogs and cats receiving daily doses of up to 5 x the recommended daily dose over 1 month (cats) or 6 months (dogs). Since robenacoxib is a selective COX-2 inhibitor, effects on the gastrointestinal tract are expected to be less severe than generally for NSAIDs.. This was also confirmed in laboratory studies where robenacoxib was well-tolerated gastro-intestinally in rats.

The subcutaneous injection can cause local reactions, being somewhat more severe in the cat than in the dog. Pain at injection can be observed; injection site reactions disappear within a few days. Pain at injection site has been addressed in the SPC. Increased creatinine blood levels were considered as a result of muscle necrosis following subcutaneous injection. However, it should be noted that tolerance studies were carried out in young healthy dogs. Since clearance is much higher in young animals, the validity of the result from the tolerance studies is limited with respect to the safety of robenacoxib in animal patients. Complications concerning cardiovascular disorders (as found in humans for COX-2 inhibitors), have not been observed in animals.

In cats, no dose titration study was performed but PK/PD modelling was conducted from results with 2 mg/kg by subcutaneous injection in the kaolin model and since PK and PD parameters were approximately similar in cats and dogs, a species-extrapolation was undertaken and an oral dose of 1-2 mg robenacoxib/kg bodyweight was chosen. For the subcutaneous solution, a single laboratory study was provided using an injectable dose of 2 mg/kg in a kaolin-induced paw inflammation model. The study was followed by a PK/PD analysis. Overall, sufficient efficacy was shown for the tested dose of 2 mg/kg although a considerable degree of variability in pain scores was present. A new pilot study in cats was submitted as a response to questions, supporting the clinical efficacy in cats and the once-daily dosing regime.

Dose determination in the dog was mainly based on the urate synovitis model. No marked gain in efficacy was seen when the dose was raised above 2 mg/kg although considerable variability in efficacy responses was seen. The applicant’s intention was to select the lowest effective dose, to maximise the safety index. Therefore, the applicant selected a minimal oral dose of 1 mg/kg and an injectable dose of 2 mg/kg for the clinical trials. Non-responders were seen in the urate arthritis model but the extent was not directly assessable and therefore the field trials are pivotal in the assessment of effect. Considering the model used, it is concluded that the 2 mg/kg dose did produce a maximum inhibition of COX-2 activity.

Conclusion

Onsior is available in different tablet strengths and as solution for injection for different indications in the two target species, cats and dogs. In support of the individual indications, the applicant provided GCP compliant clinical studies for each indication and target species.

For cats, the CVMP accepted the following indication and dose: Treatment of acute pain and inflammation associated with musculo-skeletal disorders at a once daily dose of 1 mg/kg body weight up to six days. For dogs, the CVMP accepted the following indication and dose: Treatment of pain and inflammation associated with chronic osteoarthritis at a once daily dose of 1 mg/kg body weight as long as required (as directed by the veterinarian).

The solution for injection is intended for use in dogs and cats for a single subcutaneous dose of 1 ml per 10 kg of body weight (2 mg/kg). For cats, the CVMP accepted the following indication: Treatment of pain and inflammation associated with soft tissue surgery. For dogs, the CVMP accepted the following indication: Treatment of pain and inflammation associated with orthopaedic or soft tissue surgery in dogs.

In the field studies the level of poor responders was equal to that of other NSAIDs when used for the same indications, being within the range of 10-15% among the osteoarthritis canine patients and few in the other patients groups for both dogs and cats. This has been reflected in the SPC.

Both tablets and solution for injection were in general well tolerated. Most common adverse effects were non-serious gastrointestinal reactions (vomiting, diarrhoe, soft faeces), which did not require further treatment.

Cases of serious liver function impairment were observed in the clinical trials in a few dogs with preexisting liver pathology. In some dogs with long-term oral treatment, increased liver enzymes (ALT) were seen. Although these increases remained in the normal range and did not result in clinical signs, the SPC includes appropriate warnings and recommendations for long term oral treatment. Pain at injection was only reported in individual animals.

Tablets were in general well accepted by both cats and dogs.

Onsior: Benefit – Risk Balance

Benefit assessment

Direct benefits

Onsior Tablets

In cats sufficient reduction of acute pain and inflammation associated with musculo-skeletal disorders has been demonstrated to accept as an indication.

In dogs sufficient pain reduction has also been presented to accept as an indication for the treatment of chronic osteoarthritis. The indications for relief of pain and inflammation after surgery for the tablets were insufficiently substantiated for both dogs and cats and, therefore, these indications do not contribute to the benefits of the product.

Onsior Solution for injection

Sufficient clinical efficacy has been presented for the peri-operative use in both cats and dogs treated with the injectable formulation at the recommended dose. For cats this concerned the use after soft tissue surgery only, where as in dogs, this concerned the use after orthopaedic as well as soft tissue surgery.

Additional benefits

The risk for gastro-intestinal bleeding after robenacoxib treatment is considered lower as compared to non-selective COX-inhibitors.

Risk assessment

At the recommended dose range, the level of adverse effects after administration of robenacoxib is low. Clinical signs are similar to those of other NSAIDs and within acceptable limits. Robenacoxib may have an effect on liver enzymes in dogs. However, liver toxicity was reversible after stopping the treatment. It appears mainly to pose a risk in dogs with evidence of pre-existing liver pathology and sufficient SPC warnings have been included.

Evaluation of the benefit risk balance

Discussion

Efficacy has been demonstrated for peri-operative use in cats and dogs for the injection formulation. In addition, efficacy of tablets has also been demonstrated for reduction of pain associated with osteoarthritis in dogs, and reduction of acute pain and inflammation associated with musculo-skeletal disorders in cats. The benefits of these effective treatments outweigh the risks which were low at the recommended dose. Risks for cats and dogs suffering from gastro-intestinal bleeding, and risks for dogs with a hepatic disease could be mitigated by contra-indicating the use of the product in these animals.

For the use of the tablets in dogs and cats for relief of pain and inflammation following surgery, no direct benefits were identified, and consequently the benefit-risk balance is not favourable for this proposed indication.

Conclusions

Based on the original and complementary data presented, the Committee for Medicinal Products for Veterinary Use (CVMP) concluded that the quality, safety and efficacy of Onsior were considered to be in accordance with the requirements of Council Directive 2001/82/EC, as amended, and that the benefit-risk balance was favourable for the following indications and posology:

Onsior Tablets

Cats: Treatment of acute pain and inflammation associated with musculo-skeletal disorders at a once daily dose of 1 mg/kg body weight up to six days.

Dogs: Treatment of pain and inflammation associated with chronic osteoarthritis at a once daily dose of 1 mg/kg body weight as long as required (as directed by the veterinarian).

Onsior Solution for injection:

Cats: Treatment of pain and inflammation associated with soft tissue surgery at a single dose of 2 mg/kg body weight given by subcutaneous injection before the start of surgery.

Dogs: Treatment of pain and inflammation associated with orthopaedic or soft tissue surgery in dogs at a single dose of 2 mg/kg body weight given by subcutaneous injection before the start of surgery.