Summary of medicine characteristics - Onsior
SUMMARY OF PRODUCT CHARACTERISTICS
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1. NAME OF THE VETERINARY MEDICINAL PRODUCT
Onsior 6 mg tablets for cats
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains:
Active substance:
Robenacoxib 6 mg.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet.
Round, beige to brown tablets with imprints “NA” on one side and “AK” on the other side.
4. CLINICAL PARTICULARS4.1 Target species
Cats.
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4.2 Indications for use, specifying the target species
For the treatment of pain and inflammation associated with acute or chronic musculoskeletal disorders in cats.
For the reduction of moderate pain and inflammation associated with orthopaedic surgery in cats.
4.3 Contraindications
Do not use in cats suffering from gastrointestinal ulceration.
Do not use concomitantly with corticosteroids or other non-steroidal anti-inflammatory drugs (NSAIDs).
Do not use in case of hypersensitivity to the active substance or to any of the excipients.
Do not use in pregnant and lactating animals (see section 4.7).
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4.4 Special warnings for each target species
None.
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4.5 Special precautions for use
Special precautions for use in animals
The safety of the veterinary medicinal product has not been established in cats weighing less than 2.5 kg or under 4 months of age.
Use in cats with impaired cardiac, renal or hepatic function or in cats that are dehydrated, hypovolaemic or hypotensive may involve additional risks. If use cannot be avoided, these cats require careful monitoring.
Response to treatment should be monitored at regular intervals by a veterinary surgeon. Clinical field studies showed that robenacoxib was well-tolerated by most cats for up to 12 weeks.
Use this veterinary medicinal product under strict veterinary monitoring in cats with a risk of gastrointestinal ulcers, or if the cat previously displayed intolerance to other NSAIDs.
Special precautions to be taken by the person administering the veterinary medicinal product to animals
Wash hands after use of the veterinary medicinal product.
In small children, accidental ingestion increases the risk for NSAID adverse effects. In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.
In pregnant women, particularly near term pregnant women, prolonged dermal exposure increases the risk for premature closure of the ductus arteriosus in the foetus.
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4.6 Adverse reactions (frequency and seriousness)
Mild and transient diarrhoea, soft faeces or vomiting were commonly reported in clinical trials with treatment up to 6 days. Lethargy may be observed in very rare cases. In addition, elevated renal parameters (creatinine, BUN and SDMA), and renal insufficiency have been reported very rarely in post marketing safety experience, more commonly in older cats and with concomitant use of anaesthetic or sedative agents (see also Sections 4.5 Special precautions for use, 4.8 Interaction with other medicinal products and forms of interaction, and 4.9 Amounts to be administered and administration route).
The frequency of adverse reactions is defined using the following convention: – very common (more than 1 in 10 animals treated displaying adverse reaction(s)) – common (more than 1 but less than 10 animals in 100 animals treated) – uncommon (more than 1 but less than 10 animals in 1,000 animals treated) – rare (more than 1 but less than 10 animals in 10,000 animals treated) – very rare (less than 1 animal in 10,000 animals treated, including isolated reports).
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4.7 Use during pregnancy, lactation or lay
Do not use in pregnant and lactating animals because the safety of robenacoxib has not been established during pregnancy and lactation or in cats used for breeding.
4.8 Interaction with other medicinal products and other forms of interaction
Onsior must not be administered in conjunction with other NSAIDs or glucocorticosteroids. Pre-treatment with other anti-inflammatory medicines may result in additional or increased adverse effects and, accordingly, a treatment-free period with such substances should be observed for at least 24 hours before the commencement of treatment with Onsior. The treatment-free period, however, should take into account the pharmacokinetic properties of the products used previously.
Concomitant treatment with medicines displaying action on renal flow, e.g. diuretics or angiotensinconverting enzyme (ACE) inhibitors, should be subject to clinical monitoring. In healthy cats treated with or without the diuretic furosemide, concomitant administration of Onsior with the ACE inhibitor benazepril for 7 days was not associated with any negative effects on plasma aldosterone concentrations, plasma renin activity or glomerular filtration rate. No safety data in the target population and no efficacy data in general exist for the combined treatment of robenacoxib and benazepril.
As anaesthetics may affect renal perfusion, the use of parenteral fluid therapy during surgery should be considered to decrease potential renal complications when using NSAIDs peri-operatively.
Concurrent administration of potentially nephrotoxic medicines should be avoided as there might be an increased risk of renal toxicity.
Concurrent use of other active substances that have a high degree of protein binding may compete with robenacoxib for binding and thus lead to toxic effects.
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4.9 Amounts to be administered and administration route
For oral use.
Give either without food or with a small amount of food. Onsior tablets are easy to administer and well accepted by most cats. The tablets should not be divided or broken.
The recommended dose of robenacoxib is 1 mg/kg body weight with a range 1–2.4 mg/kg. The following number of tablets should be given once daily at the same time every day:
| Body weight (kg) | Number of tablets |
| 2.5 to < 6 | 1 tablet |
| 6 to 12 | 2 tablets |
Acute musculoskeletal disorders: treat for up to 6 days.
Chronic musculoskeletal disorders: Duration of treatment should be decided on an individual basis. Please refer to section 4.5.
A clinical response is normally seen within 3–6 weeks. Treatment should be discontinued after 6 weeks if no clinical improvement is apparent.
Orthopaedic surgery: Give as a single oral treatment prior to orthopaedic surgery.
Premedication should only be carried out in combination with butorphanol-analgesia. The tablet(s) should be administered without food at least 30 minutes prior to surgery.
After surgery, once daily treatment may be continued for up to two further days. If necessary, additional analgesic treatment with opioids is recommended.
The interchangeable use of Onsior tablets and Onsior solution for injection has been tested in a target animal safety study and was shown to be well tolerated by cats.
For cats, Onsior solution for injection or tablets may be used interchangeably in accordance with the indications and directions of use approved for each pharmaceutical form. Treatment should not exceed one dose (either tablet or injection) per day. Please note that the recommended doses for the two formulations are different.
4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary
In healthy young cats aged 7–8 months, oral robenacoxib administered at high overdoses (4, 12 or 20 mg/kg/day for 6 weeks) did not produce any signs of toxicity, including no evidence of any gastrointestinal, kidney or liver toxicity and no effect on bleeding time.
In healthy young cats aged 7– 8 months, oral robenacoxib (Onsior tablets) administered at overdoses of up to 5 times the maximum recommended dose (2.4 mg, 7.2 mg, 12 mg robenacoxib/kg bodyweight) for 6 months was well tolerated. A reduction in body weight gain was observed in treated animals. In the high dose group kidney weights were decreased and sporadically associated with renal tubular degeneration/regeneration but not correlated with evidence of renal dysfunction on clinical pathology parameters.
The interchangeable use of Onsior tablets and Onsior solution for injection in 4-month old cats at overdoses of up to 3 times the maximum recommended dose (2.4 mg, 4.8 mg, 7.2 mg robenacoxib/kg orally and 2.0 mg, 4.0 mg and 6.0 mg robenacoxib/kg subcutaneously) resulted in a dose-dependent increase of sporadic oedema at the injection site and minimal to mild subacute/chronic inflammation of the subcutaneous tissue. A dose-dependent increase in the QT interval, a decreased heart rate and corresponding increased respiratory rate were observed in laboratory studies. No relevant effects on body weight, bleeding time or evidence of any gastrointestinal, kidney or liver toxicity were observed.
In overdose studies conducted in cats, there was a dose-dependent increase in the QT interval. The biological relevance of increased QT intervals outside of normal variations observed following overdose of robenacoxib is unknown. No changes in the QT interval were observed after single intravenous administration of 2 or 4 mg/kg robenacoxib to anaesthetised healthy cats.
As with any NSAID, overdose may cause gastrointestinal, kidney, or liver toxicity in sensitive or compromised cats. There is no specific antidote. Symptomatic supportive therapy is recommended and should consist of administration of gastrointestinal protective agents and infusion of isotonic saline.
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4.11 Withdrawal period(s)
Not applicable.
5. PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group: Anti-inflammatory and anti-rheumatic products, non-steroids, coxibs. ATCvet code: QM01AH91.
5.1 Pharmacodynamic properties
Robenacoxib is a non-steroidal anti-inflammatory drug (NSAID) of the coxib class. It is a 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, e.g. in the gastrointestinal tract and kidneys. COX-2 is the inducible form of the enzyme which is responsible for the production of mediators including PGE2 which induce pain, inflammation or fever.
In the in vitro whole blood assay in cats, the selectivity of robenacoxib was approximately 500 fold higher for COX-2 (IC50 0.058 p.M) as compared to COX-1 (IC50 28.9 |iM). At a dose of 1–2 mg/kg body weight, robenacoxib tablets produced a marked inhibition of COX-2 activity in cats and had no effect on COX-1 activity. In an inflammation model in cats, robenacoxib injection had analgesic, anti-inflammatory and anti-pyretic effects and a rapid onset of action (0.5 h). In clinical trials in cats, robenacoxib tablets reduced pain and inflammation associated with acute musculoskeletal disorders and reduced the need for rescue treatment when given as premedication in case of orthopaedic surgery, in combination with opioids. In two clinical trials in (mainly indoor) cats with chronic musculoskeletal disorder (CMSD), robenacoxib increased the activity and improved subjective scores of activity, behaviour, quality of life, temperament and happiness of the cats. Differences between robenacoxib and placebo were significant (P<0.05) for the client specific outcome measures, but did not reach significance (P=0.07) for the feline musculoskeletal pain index.
In a clinical study, 10 of 35 CMSD cats were assessed to be significantly more active when treated with robenacoxib for three weeks compared to these same cats when they received a placebo treatment. Two cats were more active when given placebo and for the remaining 23 cats no significant difference in activity could be detected between robenacoxib and placebo treatment.
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5.2 Pharmacokinetic particulars
Absorption
After oral administration of robenacoxib tablets at approximately 2 mg/kg without food, peak blood concentrations are attained rapidly with a Tmax of 0.5 h, a Cmax of 1,159 ng/ml and an AUC of 1,337 ngJVml. Co-administration of robenacoxib tablets with one third of the daily food ration produced no change in Tmax (0.5 h), Cmax (1,201 ng/ml) or AUC (1383 ngJVml). Co-administration of robenacoxib tablets with the entire daily food ration produced no delay in Tmax (0.5 h), but a lower Cmax (691 ng/ml) and a slightly lower AUC (1,069 ngJVml). The systemic bioavailability of robenacoxib tablets was 49% without food.
Distribution
Robenacoxib has a relatively small volume of distribution (Vss 190 ml/kg) and is highly bound to plasma proteins (>99%).
Biotransformation
In cats robenacoxib is extensively metabolised by the liver. Apart from one lactam metabolite, the identity of other metabolites is not known in cats.
Elimination
Robenacoxib is rapidly cleared from blood (CL 0.44 L/kg/h) with an elimination t1/2 of 1.1 h after intravenous administration. After oral administration of tablets, the terminal half-life from blood was 1.7 h. Robenacoxib persists longer and at higher concentrations at sites of inflammation than in blood. Robenacoxib is excreted predominantly via the biliary route (-70%) rather than via the kidneys (-30%). The pharmacokinetics of robenacoxib do not differ between male and female cats.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Yeast powder
Cellulose, microcrystalline
Povidone (K-30)
Crospovidone
Silica, colloidal anhydrous
Magnesium stearate
6.2 Major incompatibilities
Not applicable.
6.3 Shelf life
Shelf life of the veterinary medicinal product as packaged for sale: 4 years.
6.4. Special precautions for storage
Store below 25 °C.
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6.5 Nature and composition of immediate packaging
Cardboard box containing 6 × 1, 12 × 1, 30 × 1 or 60 × 1 tablets in Alu/Alu perforated unit dose blisters. Not all pack sizes may be marketed.
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6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products
Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Elanco GmbH
Heinz-Lohmann-Str. 4
27472 Cuxhaven
Germany
8. MARKETING AUTHORISATION NUMBERS
EU/2/08/089/001–003
EU/2/08/089/021
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 16/12/2008.
Date of last renewal: 08/11/2013.
10 DATE OF REVISION OF THE TEXT
Detailed information on this veterinary medicinal product is available on the website of the European
Medicines Agency.
PROHIBITION OF SALE, SUPPLY AND/OR USE
Not applicable.
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1. NAME OF THE VETERINARY MEDICINAL PRODUCT
Onsior 10 mg tablets for dogs
Onsior 20 mg tablets for dogs
Onsior 40 mg tablets for dogs
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains:
Active substance:
5 mg tablets: Robenacoxib 5 mg
10 mg tablets: Robenacoxib 10 mg
20 mg tablets: Robenacoxib 20 mg
40 mg tablets: Robenacoxib 40 mg
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet
Round, beige to brown tablets with the imprint “NA” on one side and the following imprint on the other side:
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5 mg tablet: AK
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10 mg tablet: BE
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20 mg tablet: CD
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40 mg tablet: BCK
4. CLINICAL PARTICULARS4.1 Target species
Dogs.
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4.2 Indications for use, specifying the target species
For the treatment of pain and inflammation associated with chronic osteoarthritis in dogs.
For the treatment of pain and inflammation associated with soft tissue surgery in dogs.
4.3 Contraindications
Do not use in dogs suffering from gastrointestinal ulceration or with hepatic disease.
Do not use concomitantly with corticosteroids or other non-steroidal anti-inflammatory drugs (NSAIDs).
Do not use in case of hypersensitivity to the active substance or to any of the excipients.
Do not use in pregnant and lactating animals (see section 4.7).
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4.4 Special warnings for each target species
In clinical studies in dogs with osteoarthritis, inadequate response to treatment was seen in 10–15% of the dogs.
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4.5 Special precautions for use
Special precautions for use in animals
The safety of the veterinary medicinal product has not been established in dogs weighing less than 2.5 kg or under 3 months of age.
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.
Use in dogs with impaired cardiac or renal function or dogs that are dehydrated, hypovolaemic or hypotensive may involve additional risks. If use cannot be avoided, these dogs require careful monitoring.
Use this product under strict veterinary monitoring in dogs with a risk of gastrointestinal ulcers, or if the dog previously displayed intolerance to other NSAIDs.
Special precautions to be taken by the person administering the veterinary medicinal product to animals
Wash hands after use of the veterinary medicinal product.
In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician. In small children, accidental ingestion increases the risk for NSAID adverse effects.
For pregnant women, particularly near term pregnant women, prolonged dermal exposure increases the risk of premature closure of the ductus arteriosus in the foetus.
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4.6 Adverse reactions (frequency and seriousness)
Gastrointestinal adverse events were reported very commonly, but most cases were mild and recovered without treatment. Vomiting and soft faeces were very common, decreased appetite and diarrhoea were common, and blood in the faeces was uncommon.
In dogs treated up to 2 weeks no increases in liver enzyme activities were observed. However, with long-term treatment, increases in liver enzyme activities were common. In most cases there were no clinical signs and the liver enzyme activities either stabilised or decreased with continued treatment. Increases in liver enzyme activities associated with clinical signs of anorexia, apathy or vomiting were uncommon. In very rare cases, lethargy may be observed.
The frequency of adverse reactions is defined using the following convention:
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– very common (more than 1 in 10 animals treated displaying adverse reaction(s))
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– common (more than 1 but less than 10 animals in 100 animals treated)
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– uncommon (more than 1 but less than 10 animals in 1,000 animals treated)
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– rare (more than 1 but less than 10 animals in 10,000 animals treated)
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– very rare (less than 1 animal in 10,000 animals treated, including isolated reports).
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4.7 Use during pregnancy, lactation or lay
Do not use in pregnant or lactating dogs because the safety of robenacoxib has not been established during pregnancy and lactation or in dogs used for breeding.
4.8 Interaction with other medicinal products and other forms of interaction
Onsior must not be administered in conjunction with other NSAIDs or glucocorticoids. Pre-treatment with other anti-inflammatory medicines may result in additional or increased adverse effects and accordingly a treatment-free period with such substances should be observed for at least 24 hours before the commencement of treatment with Onsior. The treatment-free period, however, should take into account the pharmacokinetic properties of the products used previously.
Concomitant treatment with medicines displaying action on renal flow, e.g. diuretics or angiotensin-converting enzyme (ACE) inhibitors, should be subject to clinical monitoring. In healthy dogs treated with and without the diuretic furosemide, concomitant administration of Onsior with the ACE inhibitor benazepril for 7 days was not associated with any negative effects on urine aldosterone concentrations, plasma renin activity or glomerular filtration rate. No safety data in the target population and no efficacy data in general exist for the combined treatment of robenacoxib and benazepril.
Concurrent administration of potentially nephrotoxic medicines should be avoided as there might be an increased risk of renal toxicity.
Concurrent use of other active substances that have a high degree of protein binding may compete with robenacoxib for binding and thus lead to toxic effects.
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4.9 Amounts to be administered and administration route
For oral use.
Do not administer with food since clinical trials demonstrated better efficacy of robenacoxib for osteoarthritis when administered without food or at least 30 minutes before or after a meal.
Onsior tablets are flavoured and are taken voluntarily by most dogs. The tablets should not be divided or broken.
Osteoarthritis: The recommended dose of robenacoxib is 1 mg/kg body weight with a range 1–2 mg/kg. Administer once daily at the same time every day according to the table below.
Number of Tablets by Strength and Body Weight for Osteoarthritis
| Body Weight (kg) | Number of Tablets by Strength | |||
| 5 mg | 10 mg | 20 mg | 40 mg | |
| 2.5 to < 5 | 1 tablet | |||
| 5 to < 10 | 1 tablet | |||
| 10 to <20 | 1 tablet | |||
| 20 to < 40 | 1 tablet | |||
| 40 to 80 | 2 tablets | |||
A clinical response is normally seen within a week. Treatment should be discontinued after 10 days if no clinical improvement is apparent.
For long-term treatment, once a clinical response has been observed, the dose of Onsior can be adjusted to the lowest effective individual dose reflecting that the degree of pain and inflammation associated with chronic osteoarthritis may vary over time. Regular monitoring should be undertaken by the veterinarian.
Soft tissue surgery: The recommended dose of robenacoxib is 2 mg/kg body weight with a range of 2–4 mg/kg. Give as a single oral treatment prior to soft tissue surgery.
The tablet(s) should be administered without food at least 30 minutes prior to surgery.
After surgery, once daily treatment may be continued for up to two further days.
Number of Tablets by Strength and Body Weight for Soft Tissue Surgery
| Body Weight (kg) | Number of Tablets by Strength | |||
| 5 mg | 10 mg | 20 mg | 40 mg | |
| 2.5 | 1 tablet | |||
| > 2.5 to < 5 | 1 tablet | |||
| 5 to < 10 | 1 tablet | |||
| 10 to<20 | 1 tablet | |||
| 20 to < 40 | 2 tablets | |||
| 40 to < 60 | 3 tablets | |||
| 60 to 80 | 4 tablets | |||
The interchangeable use of Onsior tablets and Onsior solution for injection has been tested in a target animal safety study and was shown to be well tolerated by dogs.
For dogs, Onsior solution for injection or tablets may be used interchangeably in accordance with the indications and directions of use approved for each pharmaceutical form. Treatment should not exceed one dose (either tablet or injection) per day. Please note that the recommended doses for the two formulations may be different.
4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary
In healthy young dogs aged 5–6 months, oral robenacoxib administered at high overdoses (4, 6 or 10 mg/kg/day for 6 months) did not produce any signs of toxicity, including no evidence of any gastrointestinal, kidney or liver toxicity and no effect on bleeding time. Robenacoxib also had no detrimental effects on cartilages or joints.
As with any NSAID, overdose may cause gastrointestinal, kidney, or liver toxicity in sensitive or compromised dogs. There is no specific antidote. Symptomatic, supportive therapy is recommended consisting of administration of gastrointestinal protective agents and infusion of isotonic saline.
The interchangeable use of Onsior tablets and Onsior solution for injection in mongrel dogs at overdoses of up to 3 times the maximum recommended dose (2.0, 4.0 and 6.0 plus 4.0, 8.0 and 12.0 mg robenacoxib/kg orally and 2.0 mg, 4.0 mg and 6.0 mg robenacoxib/kg subcutaneously) resulted in dose-related oedema, erythema, thickening of the skin and skin ulceration at the subcutaneous injection site and inflammation, congestion or haemorrhage in the duodenum, jejunum and caecum. No relevant effects on body weight, bleeding time or evidence of any kidney or liver toxicity were observed.
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4.11 Withdrawal period(s)
Not applicable.
5. PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group: Anti-inflammatory and anti-rheumatic products, non-steroids, coxibs. ATCvet code: QM01AH91.
5.1 Pharmacodynamic properties
Robenacoxib is a non-steroidal anti-inflammatory drug (NSAID) of the coxib class. It is a 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, e.g. in the gastrointestinal tract and kidneys. 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.
In an in vitro whole blood assay in dogs, robenacoxib was approximately 140 fold selective for COX-2 (IC50 0.04 |iM) as compared to COX-1 (IC50 7.9 p.M). Robenacoxib produced marked inhibition of COX-2 activity and had no effect on COX-1 activity in dogs at oral doses ranging from 0.5 to 4 mg/kg. Robenacoxib tablets are therefore COX-1 sparing at recommended doses in dogs. Robenacoxib had analgesic and anti-inflammatory actions in an inflammation model in dogs with single oral doses ranging from 0.5 to 8 mg/kg, with an ID50 of 0.8 mg/kg and a rapid onset of action (0.5 h). In clinical trials in dogs, robenacoxib reduced the lameness and inflammation associated with chronic osteoarthritis, and pain, inflammation and the need for rescue treatment in dogs undergoing soft tissue surgery.
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5.2 Pharmacokinetic particulars
Absorption
After oral administration of robenacoxib flavoured tablets at 1 mg/kg without food, peak blood concentrations are attained rapidly with a Tmax of 0.5 h, a Cmax of 1,124 ng/ml and an AUC of 1,249 ngJVml. Co-administration of robenacoxib non-flavoured tablets with food produced no delay in Tmax, but slightly lower values for Cmax (832 ng/ml) and AUC (782 ngJVml). The systemic bioavailability of robenacoxib tablets in dogs was 62% with food and 84% without food.
Distribution
Robenacoxib has a relatively small volume of distribution (Vss 240 ml/kg) and is highly bound to plasma proteins (>99%).
Biotransformation
Robenacoxib is extensively metabolised by the liver in dogs. Apart from one lactam metabolite, the identity of other metabolites is not known in dogs.
Elimination
Robenacoxib is cleared rapidly from blood (CL 0.81 L/kg/h) with an elimination t1/2 of 0.7 h after intravenous administration. After oral administration of the 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 predominantly via the biliary route (-65%) and the remainder via the kidneys. Repeated oral administration of robenacoxib to dogs at dosages of 2–10 mg/kg for 6 months produced no change in the blood profile, with neither accumulation of robenacoxib nor enzyme induction. Accumulation of metabolites has not been tested. The pharmacokinetics of robenacoxib do not differ between male and female dogs, and are linear over the range 0.5–8 mg/kg.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Yeast powder
Cellulose, microcrystalline
Flavour, artificial beef
Cellulose, powdered
Povidone (K-30)
Crospovidone
Silica, colloidal anhydrous Magnesium stearate
6.2 Major incompatibilities
Not applicable.
6.3 Shelf life
Shelf life of the veterinary medicinal product as packaged for sale: 4 years.
6.4. Special precautions for storage
Do not store above 25 °C.
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6.5 Nature and composition of immediate packaging
Cardboard box containing 7, 14, 28 or 70 tablets in Alu/Alu blisters, 30 × 1 tablets in Alu/Alu perforated unit dose blisters or 60 × 1 tablets in Alu/Alu perforated unit dose blisters.
Not all pack sizes may be marketed.
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6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products
Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Elanco GmbH
Heinz-Lohmann-Str. 4
27472 Cuxhaven
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/2/08/089/004–019
EU/2/08/089/022–029
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 16/12/2008.
Date of last renewal: 08/11/2013.
10 DATE OF REVISION OF THE TEXT
Detailed information on this veterinary medicinal product is available on the website of the European
Medicines Agency.
PROHIBITION OF SALE, SUPPLY AND/OR USE
Not applicable.
-
1. NAME OF THE VETERINARY MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains:
Active substance:
Robenacoxib 20 mg
Excipient:
Sodium metabisulphite (E 223)
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection.
Clear, colourless to slightly coloured (pink) liquid.
4. CLINICAL PARTICULARS4.1 Target species
Cats and dogs.
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4.2 Indications for use, specifying the target species
For the treatment of pain and inflammation associated with orthopaedic or soft tissue surgery in dogs. For the treatment of pain and inflammation associated with orthopaedic or soft tissue surgery in cats.
4.3 Contraindications
Do not use in animals suffering from gastrointestinal ulceration.
Do not use concomitantly with corticosteroids or other non-steroidal anti-inflammatory drugs (NSAIDs).
Do not use in case of hypersensitivity to the active substance or to any of the excipients.
Do not use in pregnant and lactating animals (see section 4.7).
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4.4 Special warnings for each target species
None.
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4.5 Special precautions for use
Special precautions for use in animals
The safety of the veterinary medicinal product has not been established in cats less than 4 months of age and in dogs less than 2 months of age, or in cats or dogs less than 2.5 kg body weight.
Use in animals with impaired cardiac, renal or hepatic function or those are dehydrated, hypovolaemic or hypotensive may involve additional risks. If use cannot be avoided, these animals require careful monitoring and fluid therapy.
Use this veterinary medicinal product under strict veterinary monitoring in cases at risk of gastrointestinal ulceration, or if the animal previously displayed intolerance to other NSAIDs.
Special precautions to be taken by the person administering the veterinary medicinal product to animals
Wash hands and exposed skin immediately after use of the product.
In case of accidental ingestion or self-injection, seek medical advice immediately and show the package leaflet or the label to the physician.
For pregnant women, particularly near term pregnant women, accidental injection and prolonged dermal exposure increases the risk for premature closure of the ductus arteriosus in the foetus.
-
4.6 Adverse reactions (frequency and seriousness)
Cats:
Gastrointestinal adverse events (vomiting, soft faeces or diarrhoea) were commonly reported, but most cases were mild and recovered without treatment. Diarrhoea or vomiting with blood were uncommon. Pain at injection site was commonly reported.
Dogs:
Gastrointestinal adverse events (diarrhoea and vomiting) were commonly reported but most cases were mild and recovered without treatment. Soft and dark faeces or reduced appetite were uncommon. Slight pain at injection site was commonly reported. Moderate or severe pain at injection site was uncommon.
The frequency of adverse reactions is defined using the following convention: – very common (more than 1 in 10 animals treated displaying adverse reaction(s)) – common (more than 1 but less than 10 animals in 100 animals treated) – uncommon (more than 1 but less than 10 animals in 1,000 animals treated) – rare (more than 1 but less than 10 animals in 10,000 animals treated) – very rare (less than 1 animal in 10,000 animals treated, including isolated reports).
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4.7 Use during pregnancy, lactation or lay
Do not use in pregnant and lactating animals because the safety of robenacoxib has not been established during pregnancy and lactation or in cats and dogs used for breeding.
4.8 Interaction with other medicinal products and other forms of interaction
Onsior must not be administered in conjunction with other NSAIDs or glucocorticosteroids. Pre-treatment with other anti-inflammatory medicines may result in additional or increased adverse effects and accordingly a treatment-free period with such substances should be observed for at least 24 hours before the commencement of treatment with Onsior. The treatment-free period, however, should take into account the pharmacokinetic properties of the products used previously.
Concomitant treatment with medicines displaying action on renal flow, e.g. diuretics or angiotensin-converting enzyme (ACE) inhibitors, should be subject to clinical monitoring. In healthy cats or dogs treated with or without the diuretic furosemide, concomitant administration of Onsior with the ACE inhibitor benazepril for 7 days was not associated with any negative effects on plasma (cats) or urine (dogs) aldosterone concentrations, plasma renin activity or glomerular filtration rate. No safety data in the target population and no efficacy data in general exist for the combined treatment of robenacoxib and benazepril.
As anaesthetics may affect renal perfusion, the use of parenteral fluid therapy during surgery should be considered to decrease potential renal complications when using NSAIDs peri-operatively.
Concurrent administration of potentially nephrotoxic medicines should be avoided as there might be an increased risk of renal toxicity.
Concurrent use of other active substances that have a high degree of protein binding may compete with robenacoxib for binding and thus lead to toxic effects.
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4.9 Amounts to be administered and administration route
Subcutaneous use.
Administer subcutaneously to cats or dogs approximately 30 minutes before the start of surgery, for example around the time of induction of general anaesthesia, at a dose of 1 ml per 10 kg of body weight (2 mg/kg). After surgery in cats, once daily treatment may be continued at the same dosage and at the same time every day for up to 2 days. After soft tissue surgery in dogs, once daily treatment may be continued at the same dosage and at the same time every day for up to 2 days.
The interchangeable use of Onsior tablets and Onsior solution for injection has been tested in target animal safety studies and was shown to be well tolerated by cats and dogs.
Onsior solution for injection or tablets may be used interchangeably in accordance with the indications and directions of use approved for each pharmaceutical form. Treatment should not exceed one dose (either tablet or injection) per day. Please note that the recommended doses for the two formulations may be different.
4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary
In healthy young dogs aged 6 months, once daily subcutaneous administration of robenacoxib at doses of 2 (recommended therapeutic dose; RTD), 6 (3 times RTD), and 20 mg/kg (10 times RTD) for 9 administrations over a 5 week period (3 cycles of 3 consecutive once daily injections) did not produce any signs of toxicity, including gastrointestinal, kidney or liver toxicity and had no effect on 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.
In healthy young cats aged 10 months, once daily subcutaneous administration of robenacoxib at doses of 4 mg/kg (twice RTD) for 2 consecutive days and 10 mg/kg (5 times RTD) for 3 consecutive days did not produce any signs of toxicity, including signs of gastrointestinal, kidney or liver toxicity and had no effect on bleeding time. Reversible, minimal injection site reactions were noted in both dose groups.
The interchangeable use of Onsior tablets and Onsior solution for injection in 4-month old cats at overdoses of up to 3 times the maximum recommended dose (2.4 mg, 4.8 mg, 7.2 mg robenacoxib/kg orally and 2.0 mg, 4.0 mg and 6.0 mg robenacoxib/kg subcutaneously) resulted in a dose-dependent increase of sporadic oedema at the injection site and minimal to mild subacute/chronic inflammation of the subcutaneous tissue. A dose-dependent increase in the QT interval, a decreased heart rate and corresponding increased respiratory rate were observed in laboratory studies. No relevant effects on body weight, bleeding time or evidence of any gastrointestinal, kidney or liver toxicity were observed.
In overdose studies conducted in cats, there was a dose-dependent increase in the QT interval. The biological relevance of increased QT intervals outside of normal variations observed following overdose of robenacoxib is unknown. No changes in the QT interval were observed after single intravenous administration of 2 or 4 mg /kg robenacoxib to anaesthetised healthy cats.
The interchangeable use of Onsior tablets and Onsior solution for injection in mongrel dogs at overdoses of up to 3 times the maximum recommended dose (2.0, 4.0 and 6.0 plus 4.0, 8.0 and 12.0 mg robenacoxib/kg orally and 2.0 mg, 4.0 mg and 6.0 mg robenacoxib/kg subcutaneously) resulted in dose-related oedema, erythema, thickening of the skin and skin ulceration at the subcutaneous injection site and inflammation, congestion, or haemorrhage in the duodenum, jejunum, and caecum. No relevant effects on body weight, bleeding time or evidence of any kidney or liver toxicity were observed.
No changes to blood pressure or the electrocardiogram were observed after single administration to healthy dogs of 2 mg/kg robenacoxib subcutaneously or 2 or 4 mg/kg intravenously. Vomiting occurred 6 or 8 hours post-dosing in 2 of 8 dogs administered the solution for injection at a dosage of 4 mg/kg intravenously.
As with any NSAID, overdose may cause gastrointestinal, kidney, or liver toxicity in sensitive or compromised animals. There is no specific antidote. Symptomatic, supportive therapy is recommended consisting of administration of gastrointestinal protective agents and infusion of isotonic saline.
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4.11 Withdrawal period(s)
Not applicable.
5. PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids, coxibs. ATCvet code: QM01AH91.
5.1 Pharmacodynamic properties
Robenacoxib is a non-steroidal anti-inflammatory drug (NSAID) of the coxib class. It is a 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, e.g. in the gastrointestinal tract and kidneys. 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.
In cats , using an in vitro whole blood assay, robenacoxib was approximately 500 fold selective for COX-2 (IC50 0.058 p.M) as compared to COX-1 (IC50 28.9 |1M). In vivo, robenacoxib solution for injection produced marked inhibition of COX-2 activity and had no effect on COX-1 activity. At the recommended dosage (2 mg/kg), analgesic, anti-inflammatory and anti-pyretic effects were demonstrated in an inflammation model, and in clinical trials, robenacoxib reduced pain and inflammation in cats undergoing orthopaedic or soft tissue surgery.
In dogs , robenacoxib was in vitro approximately 140 fold selective for COX-2 (IC50 0.04 p.M) as compared to COX-1 (IC50 7.9 p.M). In vivo , robenacoxib solution for injection produced marked inhibition of COX-2 activity and had no effect on COX-1 activity. At dosages ranging from 0.25 to 4 mg/kg, robenacoxib had analgesic, anti-inflammatory and anti-pyretic effects in an inflammation model with a rapid onset of action (1 h). In clinical trials at the recommended dose (2 mg/kg), robenacoxib reduced pain and inflammation in dogs undergoing orthopaedic or soft tissue surgery, and reduced the need for rescue treatment in dogs undergoing soft tissue surgery.
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5.2 Pharmacokinetic particulars
Absorption
Peak blood concentrations of robenacoxib are attained rapidly after subcutaneous injection in cats and dogs. After a dosage of 2 mg/kg a Tmax of 1 h (cats and dogs), a Cmax of 1,464 ng/ml (cats) and 615 ng/ml (dogs), and an AUC of 3,128 ng^h/ml (cats) and 2,180 ng^h/ml (dogs) is obtained. After a subcutaneous administration of 1 mg/kg the systemic bioavailability is 69% in cats and 88% in dogs.
Distribution
Robenacoxib has a relatively small volume of distribution (Vss of 190 ml/kg in cats and 240 ml/kg in dogs) and is highly bound to plasma proteins (>99%).
Biotransformation
Robenacoxib is extensively metabolised by the liver in cats and dogs. Apart from one lactam metabolite, the identity of other metabolites is not known in cats or dogs.
Elimination
After intravenous administration robenacoxib was rapidly cleared from blood (CL of 0.44 L/kg/h in cats and 0.81 L/kg/h in dogs) with an elimination t1/2 of 1.1 h in cats and 0.8 h in dogs. After subcutaneous administration, the terminal half-life from blood was 1.1 h in cats and 1.2 h in dogs.
Robenacoxib persists longer and in higher concentrations at sites of inflammation than in blood. Robenacoxib is excreted predominantly via the biliary route in cats (-70%) and dogs (-65%) and the remainder via the kidneys. Repeated subcutaneous administration at dosages of 2–20 mg/kg produced no change in the blood profile, with neither bioaccumulation of robenacoxib nor enzyme induction. Bioaccumulation of metabolites has not been tested. The pharmacokinetics of robenacoxib injection do not differ between male and female cats and dogs, and are linear over the range of 0.25–4 mg/kg in dogs.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Macrogol 400
Ethanol, anhydrous
Poloxamer 188
Citric acid monohydrate
Sodium metabisulphite (E 223)
Sodium hydroxide
Water for injections
6.2 Major incompatibilities
In the absence of compatibility studies, this veterinary medicinal product must not be mixed with other veterinary medicinal products.
6.3 Shelf life
Shelf life of the veterinary medicinal product as packaged for sale: 3 years.
Shelf life after first broaching of the vial: 28 days.
6.4. Special precautions for storage
Store in a refrigerator (2 °C – 8 °C). Refrigeration is not required during the 4-week in-use period after first broaching of the vial. Avoid introduction of contamination. Keep the vial in the outer carton.
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6.5 Nature and composition of immediate packaging
Multi-dose amber glass vial containing 20 ml solution for injection, closed with a rubber stopper and sealed with an aluminium cap. One vial packed in a cardboard box.
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6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products
7. MARKETING AUTHORISATION HOLDER
Elanco GmbH
Heinz-Lohmann-Str. 4
27472 Cuxhaven
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/2/08/089/020
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 16/12/2008.
Date of last renewal: 08/11/2013.