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Previcox Test Studies

SCIENTIFIC DISCUSSION I. SUMMARY OF THE DOSSIER

Previcox tablets are uncoated, round chewable tablets manufactured in 57 mg and 227 mg strengths and half-scored to facilitate treatment of dogs of variable bodyweight. The tablets contain firocoxib as the active substance, which is a non-steroidal anti-inflammatory drug (NSAID) belonging to the Coxib group, which acts by selective inhibition of cyclooxygenase-2 (Cox-2)

Previcox is intended for the relief of pain and inflammation associated with osteoarthritis in dogs over 10 weeks of age or weighing more than 3 kg. The recommended dose is 5 mg per kg bodyweight once daily.

Side–effects such as emesis and diarrhoea have occasionally been reported. These reactions are generally of a transitory nature and are reversible when the treatment is stopped.

In January 2007, CVMP agreed to authorise an extension application to Previcox. The intended indication in horses is the alleviation of pain and inflammation in animals with ortheoarthritis and reduction of associated lameness.

The intended therapeutic dose in horses is 0.1 mg firocoxib/kg bw/day orally for up to 14 consecutive days. Previcox 0.82% oral paste for horses is presented in prefilled oral syringes containing 7.32 g of oral paste labelled in 100-kg dosing increments.

Each syringe contains sufficient product to treat a 600 kg horse. Data relating to maximum residue limits of firocoxib have been previously reviewed by the CVMP as part of an MRL application. Based on those data, firocoxib has been included in Annex III of Council Regulation 2377/90. The proposed withdrawal period for meat and offal (horse) is 26 days.

Tolerance in the target animal species - Dogs

The recommended daily dose of 5 mg firocoxib per kg bodyweight is usually well tolerated in dogs as demonstrated by various safety studies continuing for up to 6 months and field studies continuing for up to 3 months.

However, firocoxib has a relatively low safety margin and overdoses of 3-, 5- or 10-times the recommended therapeutic dose were associated with adverse side effects, some of them serious or fatal.

The organs most affected in the dog are the liver (lipid accumulation)the brain (vacuolisation) and the duodenum (ulceration). 17/26

At the recommended daily dose, effects on lipid metabolism were possibly present in pups aged 3-4 months and hepatic lipidosis was noted in some animals in higher dose groups.

The product literature (SPC section 5.9) therefore includes a relevant warning. Adverse effects on the gastrointestinal tract such as inappetence, bodyweight loss, vomiting and ulceration in the duodenum were observed in high dose groups and appropriate warnings have been included in the product literature.

Histological lesions (vacuolisation) in the brain were detected in some animals and it was considered possible that these lesions may arise as a chronic and cumulative effect of firocoxib, following long term administration of overdoses.

However, since no clinical signs of neurotoxicity were evident and lesions were not evident in certain recovery groups, the Committee also considered that vacuolation of white mater tracts might be a problem of tissue processing and not caused by the treatment.

In the absence of further data, the Committee agreed to retain the warning statement in the product literature (section 5.9 of the SPC) and to review future PSURs for any evidence of neurotoxicity at field level.

Mild glossal/pharyngeal lesions were noted in animals in a number of target animal safety studies. However, since no such clinical signs were observed in the field studies, the Committee concluded that the product literature would not need a special warning on this issue.

Based on the target animal safety studies presented, it appears that the safety margin is narrower in pups (2-3 months old) compared to animals aged 6-12 months old (adverse effects observed in overdose were more severe in the younger animals). Consequently, it is advised that special care must be taken when treating animals aged less than 6 months of age.

An appropriate warning has therefore been included in the product literature. Although geriatric dogs represent an important class of animals suffering from osteoarthritis processes, no specific target animal safety study in geriatric animals was provided.

However, it was accepted that the profile of the animals included in the field studies reflected the target population for this product (older animals) and that the product was well tolerated in those studies when administered at the recommended treatment dose for up to 3 months.

Dose determination

Two well designed in vivo studies were conducted using 0, 2.5, 5.0 (the proposed dose) or 7.5 mg fibrocoxib/kg bw, administered once orally. The model used was urate crystal synovitis, i.e. urate crystals were administered into predetermined stifle joints inducing moderate-severe lameness associated with joint inflammation/pain. The model was therefore considered relevant to the proposed indication.

Efficacy was measured both objectively, using force plate gait analysis, and subjectively, using scoring systems based on clinical parameters.

The first study demonstrated a significant treatment effect with beneficial effect of the test product for up to 18 hours post treatment. Given the small number of test animals included in the study, it was notable that a significant treatment effect was detected. However, no apparent dose-dependent response was noted.

In the second study, depending on the variable analysed, the dose response to firocoxib reached a plateau between 2.5 and 5.0 mg/kg at both 14 and 18 hours after treatment. For all force plate parameters, the data for animals treated at 5.0 mg/kg was quantitatively better that the 2.5 mg/kg data.

However, administration of 7.5 mg/kg was not any more effective than 5.0 mg/kg. It is notable that for lameness (mobility score), 2.5 mg/kg was as effective as 5.0 and 7.5 mg/kg.

When all variables are taken into account, optimal efficacy is achieved at 5.0 mg/kg. For each variable, the difference between the 5 mg/kg group and the placebo group was significant (p<0.05) at each time point.

At 10 hours after treatment administration, plasma firocoxib concentrations exhibit a dose-dependent relationship.

At 18 hours after administration of the test product, quantifiable residues of firocoxib were detected in plasma of most animals in the 2.5 mg/kg group, all animals in the 5.0 mg/kg group and most animals in the 7.5 mg/kg group.

No adverse effects to treatment were observed during both studies. These studies confirm that optimal efficacy is achieved at 5.0 mg/kg and that efficacy persists for up to 18 hours post treatment.

Dose confirmation

In addition to the two dose determination studies one well conducted double blind GCP-compliant dose confirmation study in dogs using the urate crystal synovitis model was conducted. The animals were treated orally either with a placebo, a single dose of the final product (5.0 mg firocoxib/kg bodyweight) or a reference product authorised in the EU for reduction of inflammation and relief of pain associated with musculo-skeletal disorders in the dog (vedaprofen or carprofen).

The model was considered appropriate since it gives rise to moderate-severe lameness due to joint pain/inflammation and is, therefore, relevant to the proposed indication.

Also, treatments were administered when synovitis was established, therefore the ability of the test product to alleviate established disease was evaluated.

Efficacy of firocoxib at the proposed treatment dose was demonstrated using both objective and subjective measures of efficacy. In this study, differences in efficacy parameters between the test product and placebo were significant and the test product was demonstrated to be at least as effective as the reference products.

Field Trials-Tablets for Dog

Five separate studies were conducted relating to the use of the final formulation in dogs for the control of pain and inflammation associated with osteoarthritis under field conditions. The studies were performed in Europe (2), United States, Canada and Australia.

European Study – using firocoxib and carprofen

A multicentre, controlled, blinded randomised field study involving dogs with a mean age of about 8 years was conducted in the EU. The dogs were treated for 30 days with either firocoxib (final formulation) or carprofen (positive control). Carprofen is authorised in the EU for reduction of inflammation and relief of pain associated with musculo-skeletal disorders in the dog.

Inclusion criteria were dogs scoring at least “one” for lameness with a combined score for lameness and pain on manipulation of at least “two” and radiographic evidence of degenerative articular changes or other bony change. All subjective clinical parameters evaluated were scored.

Exclusion criteria included prior treatment (within 7 days) with anti-inflammatory, anti-arthritic agents or corticosteroid treatment (within 30 days), systemic illness, pregnancy, fractures or surgery within the previous 14 days or planned elective surgery during the study period.

A marked improvement was noted in lameness and pain scores (relative to baseline) in both groups while animals were on treatment (improvement relative to baseline in 84.9% of dogs treated with firocoxib and 83.8 % of dogs treated with carprofen).

Improvements in swelling and range of motion were not as dramatic but this is to be expected given the chronic nature of the disease condition in the test population.

Twenty per cent of dogs treated with firocoxib experienced at least one abnormality during the course of the study. The majority of these events were considered as not being treatment related.

There was no significant difference between treatments with respect to incidence of abnormalities. NSAID typical adverse reactions in dogs receiving firocoxib or carprofen included diarrhoea, emesis and melena.

The test product was considered convenient to administer and palatable in most cases. Limited information is available in dogs less than one year old, however long-term use in young dogs is less commonly encountered under field conditions than in mature animals.

The SPC includes a contraindication for use in dogs less than 10 weeks of age and 3 kg bodyweight, and includes a statement that the recommended dose should not be exceeded.

Firocoxib was shown to be effective and well tolerated in adult dogs when administered in accordance with the recommended dosing schedule for 30 days.

United States Field Study – using firocoxib and etodolac

This field study was GCP compliant. This was conducted in the United States and involved dogs with a mean age of about 7 years. The dogs were treated for 30 days with either firocoxib (final formulation) or etodolac (positive control, which is not authorised in the EU).

The efficacy evaluation was based on clinical assessment (lameness, pain on manipulation/palpation, joint swelling, range of motion) and force plate gait analysis by a veterinarian and subjective assessment by the animal owners.

An improvement in clinical efficacy parameters in firocoxib treated animals was shown. While a certain percentage of firocoxib treated dogs were considered improved based on force plate analyses, improvement based on clinical assessment/owner perception was much more convincing. In a noninferiority comparison of treatments 87.3 % of all firocoxib treated dogs were considered “improved”.

The field safety data generated in this study showed that 9.4 % of dogs treated with firocoxib experienced at least one abnormality during the course of the study. The majority of these events were considered as not being treatment related.

NSAID typical adverse reactions in dogs receiving firocoxib included diarrhoea, emesis and melena. There was no significant difference between treatments with respect to incidence of these abnormalities.
No long-term field safety data (>30 days) were available for this trial.

Australian Field Study - using firocoxib and etodolac

This was a controlled, blinded, multicentre, randomised study conducted in Australia using dogs with a mean age of 9 years.
Dogs received either firocoxib at the proposed dosage or etodolac for 30 days. The inclusion/exclusion criteria and evaluation parameters for this study were the same as in the European study.

Since the reference product used in this study is not authorised in the EU, the relevance of the efficacy data in this study was considered limited. In addition, the numbers of dogs included were too small for the purposes of applying meaningful statistical analysis. However, it was noted that none of the firocoxib-treated dogs showed treatment related side effects.

Canadian Field Study - using firocoxib and carprofen

This was a controlled, blinded, multicentre, randomised study conducted in Canada using dogs with a mean age of about 6 years.
Dogs received either firocoxib at the proposed dosage or carprofen for 30 days. The inclusion/exclusion criteria and evaluation parameters for this study were the same as in the European study.

The numbers of dogs included in this study were too small to apply meaningful statistical analysis. Based on the data generated, the efficacy of firocoxib would appear to be as efficacious as the reference product.

European Field Study - firocoxib and meloxicam

The second European field study, conducted in three European countries used dogs with a mean age of about 8 years. Dogs received either firocoxib at the proposed dosage or meloxicam for up to 90 days.

Meloxicam is authorised in the EU. Inclusion/exclusion criteria were the same as those used in the other European study.

The primary efficacy variable was clinical improvement at study termination (Day 89+2). Secondary efficacy variables included clinical improvement at Day 14, 30 and 60 (non-inferiority of treatments performed) and individual parameters evaluated by the investigator (lameness, pain on manipulation, range of motion, joint swelling) and owners assessment of improvement.

The dependant variable for analysis was the difference between post treatment and baseline (pre-treatment) investigator evaluation scores.
In terms of efficacy, the results showed no significant differences between the two treatments groups. In terms of safety, no significant difference between treatments with respect to incidence of abnormalities was noted.

Some of the abnormalities observed were considered to be treatment related, however, most had an unknown relationship to the treatment or were considered not treatment related.

Gastro-intestinal side-effects were seen in some animals. Efficacy of the test product when administered at the recommended treatment dose for up to 90 days is comparable to the reference product and the efficacy data were considered acceptable.

The tolerance of the product, when administered at the recommended treatment dose for up to 90 days, is acceptable. Notwithstanding that fact and the fact that firocoxib has been shown to be well tolerated in target animal safety studies, when administered at the recommended treatment dose to healthy dogs for up to 6 months, the product literature includes a recommendation that long-term administration of the product should be reviewed regularly by the veterinary surgeon.

In addition, the Committee noted that no safety data relating to use in sick/debilitated animals were submitted. In the absence of such data, an appropriate warning statement has been included in the SPC.

Conclusion on the Clinical Part-Dogs

Tolerance studies in dogs indicated that firocoxib was generally well tolerated at the recommended therapeutic dose of 5 mg / kg bodyweight / day, although higher doses were associated with adverse effects on the liver, central nervous system and the gastrointestinal tract.

Although firocoxib displays preferential activity for COX-2, it is noted that severe adverse gastrointestinal effects may occur at higher repeated doses (five times the recommended dose in pups and ten times the recommended dose in mature dogs).

The presence of vacuoles in the brain, lesions (ulceration) in the duodenum and possible effects of lipid metabolism were detected in some studies.

Appropriate warnings have been included in the product literature. Firocoxib was not as well tolerated in pups as in older dogs; therefore, it is advised that use of the product in very young animals requires careful monitoring. An appropriate statement has been included in the product literature (section 5.5 of the SPC).

Based on the dose confirmation study, efficacy of the test product at the proposed dosage has been demonstrated in an appropriate model of canine lameness using both objective and subjective measures of efficacy.

It is noted that although the recommended dose is 5 mg/kg/day, the dosing recommendation will deliver dose rates in the range 5.0 to 10.3 mg/kg.

On the basis of two European field studies, it is accepted that administration of the product in accordance with the recommended dosing schedule for a period of up to 90 days resulted in an improvement in lameness score in dogs with established osteoarthritis.

The test product was shown to be comparable to the reference products (carprofen and meloxicam, respectively).

The relevance of the efficacy data in the US study is limited, as the reference product is not authorised in the EU. However, it is accepted that an improvement in clinical efficacy parameters, relative to baseline, was observed in firocoxib treated animals.

In addition, the value of the efficacy data in the Australian and Canadian studies is limited in that the reference product included in the Australian study is not authorised in the EU and both studies included relatively small numbers of test animals precluding meaningful evaluation of data.

Based on the data from all field studies conducted, firocoxib, when administered to otherwise healthy dogs for the management of osteoarthritis, appears to be well tolerated when used once daily in accordance with the recommended dosing schedule.

Given the safety profile of the product in field and target animal safety studies, the duration of therapy should be dependant on the clinical response observed under the condition that such long-term administration would be under regular veterinary supervision. In addition, the SPC includes a statement that only administration up to 90 consecutive days has been tested.

Benefit-Risk Assessment

Previcox is a veterinary medicinal product containing the active substance firocoxib. Firocoxib is a non-steroidal anti-inflammatory drug belonging to the Coxib group. In in vitro canine whole blood assays, firocoxib exhibits approximately 380-fold selectivity for COX-2 over COX-1.

The proposed indications for the product is for the relief of pain and inflammation associated with osteoarthritis in dogs and for the alleviation of pain and inflammation associated with osteoarthritis and reduction of associated lameness in horses.

The quality data provided are satisfactory and adhere to current guidelines. Details of the manufacturing processes for both the tablets and oral paste are provided which show that product of the desired quality is consistently produced.

The stability studies support a shelf-life of three years for the tablets and an in-use shelf-life of 7 days for the half tablets. A shelf life of 3 years for the oral paste with no special precautions for storage and in-use shelf life of 3 months is considered to be adequately supported by the data provided.

The finished product complies with the current TSE-Risk assessment according to Commission Directive 1999/104/EC and Note for Guidance EMEA/410/01-Rev. 2.

Firocoxib has a low acute toxicity potential. Repeat dose studies demonstrated that the target organs for toxicity were the liver, thyroid gland and kidney.

Several tolerance studies conducted in the target species indicated that firocoxib was generally well tolerated at the recommended dose, although multiples of the recommended dose were associated with adverse effects on the liver, central nervous system and gastro-intestinal tract.

The potential for adverse effects relating to these organs is appropriately and adequately addressed in the SPC. Firocoxib has a low safety margin in pups compared to older dogs; therefore, it is advised that use in very young animals requires careful monitoring.

Developmental toxicity studies revealed that firocoxib was embryotoxic/foetotoxic at sufficiently high dosage rates in both the rat and rabbit.

However, the rabbit was far more sensitive than the rat to these latter effects. Firocoxib induced a variety of external, visceral and skeletal malformations, anomalies and variations in the developmental toxicity studies performed.

A NOEL for teratogenicity could not be established in the rabbit. Consequently firocoxib is contraindicated for use during pregnancy and lactation.

Firocoxib is not considered to have any mutagenic or carcinogenic potential. Firocoxib is not irritant to skin or eyes, and does not appear to be a sensitising agent.

A User Safety assessment was provided and the user risk management procedures detailed in section 4.5 of the SPC are appropriate. A Phase I Environmental Impact Assessment for the oral paste for horses revealed that the levels of firocoxib residues likely to enter the environment (directly on pasture or as fertiliser) were below the trigger for a Phase II assessment in the VICH guideline.

A pharmacological ADI could not be established for firocoxib from the submitted data, however a temporary ADI of 0.215 μg/kg or 12.9 μg/person can be established. CVMP has recommended that firocoxib be placed in Annex III of Council Regulation 2377/90 with MRLs for muscle: 10 μg/kg; fat: 15 μg/kg; liver: 60 μg/kg; and kidney: 10 μg/kg.

In the pivotal residue study, horses were treated with firocoxib as the proposed commercial formulation. The CVMP accepted a withdrawal period of 26 days which is based on available residue data.

This duration is based on a statistically determined withdrawal period of 20 days plus a 30% safety factor to account for extrapolation in accordance with the note for guidance EMEA/CVMP/036/95.
Given the safety profile of the tablets for dogs in field and target animal safety studies, the Committee agreed that the duration of therapy should be dependant on the clinical response observed under the condition that such long-term administration would be under regular veterinary supervision.

The pharmacological activity of firocoxib has been studied in a number of in vitro and in vivo models. Firocoxib is a preferential COX-2 inhibitor with potent anti-inflammatory, antipyretic and analgesic properties in a number of animal species.

In horses, firocoxib is rapidly absorbed and achieves mean 26/26 peak plasma concentrations within 4 hours after administration.

Following multiple oral administrations, steady state is achieved approximately after 8 days of daily treatment. Firocoxib is strongly bound to plasma protein. Elimination is principally in the excreta (primarily the urine) with some biliary excretion also observed.

On the basis of two European field studies in dogs, it is accepted that administration of the chewable tablets in accordance with the recommended dosing schedule for a period of up to 90 days resulted in an improvement in lameness score in dogs with established osteoarthritis.

The test product was shown to be comparable to the reference products (carprofen and meloxicam, respectively). The safety of Previcox oral paste was studied in horses at doses up to 12.5 times the recommended dose for more than 6 times the recommended duration of use.

The recommended treatment dose (0.1mg/kg) was usually well tolerated when administered for a period of 14 days. Oral and/or skin lesions were noted in some animals in the dose determination and in the field studies when administered the recommended treatment dose.

While these lesions were typically mild at the recommended treatment dose, the incidence and severity of the lesions increased with increasing dose. An appropriate warning statement was therefore included in the SPC.

The most significant side effect associated with long term use of firocoxib at elevated dose levels is nephropathy, similar to the other NSAIDs used in horses.

This nephropathy was dose dependent, starting as a mild to moderate interstitial inflammation and minimal necrosis and edema of the interstitium in horses dosed at 2.5 times the recommended dose for more than 6 times the recommended duration of use.

It progressed to an infrequent renal fibrosis and papillary necrosis at 5X the recommended dose for three times the recommended duration of use.

Although the dosing range required to develop histologic signs of nephropathy is relatively narrow, the duration of use required for the signs to develop is considerably longer than the recommended treatment duration and occurs at an infrequent rate even then.

The potential for the development of renal pathology in horses when the product is administered in overdose and a warning to avoid concurrent administration of potentially nephrotoxic drugs, was therefore included in the SPC and product literature.

The dose for firocoxib paste was selected using horses with naturally occurring lameness of chronic nature due to osteoarthritis. A dose level of 0.1 mg/kg once daily, reduced clinical lameness similar to a higher dose level of 0.25 mg/kg.

Firocoxib was similar to phenylbutazone based on clinical lameness score although phenylbutazone was superior to firocoxib based on peak vertical force.

In clinical field studies, with horses diagnosed with osteoarthritis, performed in the USA, compared with phenylbutazone and in Europe compared with vedaprofen, firocoxib oral paste satisfied the defined non-inferiority criteria, demonstrating that it was comparable to the control products.

Based on the findings of both field studies, it is concluded that the test product is comparable to the reference products, phenylbutazone and vedaprofen. The CVMP therefore concluded that Previcox oral paste administered once daily for 14 days at a dose of 0.1 mg/kg was as effective as other authorised products in the alleviation of pain and inflammation associated with osteoarthritis and the reduction of associated lameness in horses.

Based on the data presented, the Committee for Veterinary Medicinal Products concluded that the quality, safety and efficacy of Previcox tablets for dogs were considered to be in accordance with the requirements of Council Directive 2001/82/EC and and that the subsequent extension application for the oral paste for horses was considered to be in accordance with the requirements of Council Directive 2004/28/EC, as amended. A favourable benefit-risk profile for this product was proven.  O