Advice summary application for registration of a chemical product

Data relied on to provide the advice

Data No	Data Source*	Author(s)	Title	Date	Data Type	Data Sub-type	Authorising Party	Inherited Application No.
35130	S	Anon	Stability data tables for Mavacoxib Tablets	2009	Chemistry and Manufacture	Product, Stability	Applicant
35131	S	Anon	Results of stability studies for Mavacoxib Tablets 6mg	2009	Chemistry and Manufacture	Product, Stability	Applicant
35132	S	Anon	MavacoxibTablet for Dogs. Marketing Authorisation Application. Part 2 - Chemical, Pharmaceutical and Biological Documentation.	April 2007	Chemistry and Manufacture	Product, Manufacturing/Quality Control
35168	S	BD Hummel.	Distribution and Excretion of 14C-PHA-739521 [Mavacoxib] in Dogs after a Single 4 mg/kg Oral or IV Dose.	7 November 2005	Metabolism and Kinetics	Target Animals	Applicant
35170	S	J Hill, A Fielder.	In Vitro Assessment of Protein Binding for PHA-739521 in Canine Plasma.	28 September 2006	Metabolism and Kinetics	Target Animals	Applicant
35160	S	JA Robinson.	Fed/Fasted Pharmacokinetic Study of PHA-739521 in Dogs Following a Single Oral Administration of Prototype Tablets at a Dose of 4 mg/kg BW.	15 December 2004	Metabolism and Kinetics	Target Animals	Applicant
35159	S	MC Savides.	Study of the Absolute Bioavailability of Mavacoxib (PHA-739521) and the Effect of Feeding on the Bioavailability of Orally Administered Mavacoxib in Beagle Dogs.	15 November 2006	Metabolism and Kinetics	Target Animals	Applicant
35169	S	BD Hummel.	Profiling of 14C-PHA-739521 [Mavacoxib] Related Residues in Dog Urine, Faeces and Bile.	9 January 2007	Metabolism and Kinetics	Target Animals	Applicant
35161	S	BD Hummel.	Comparative Pharmacokinetics of Orally Administered PHA-739521 Flavoured Tablets in Dogs.	3 May 2004	Metabolism and Kinetics	Target Animals	Applicant
35163	S	MC Savides.	Multiple-Dose Study in Beagles to Evaluate the Pharmacokinetics of PHA-739521 4 mg/kg Orally by Tablet on Study Days 0, 14, 42 and 70.	10 November 2006	Metabolism and Kinetics	Target Animals	Applicant
35162	S	MC Savides.	70-Day Dose Proportionality Study of Mavacoxib (PHA-739521) in Dogs.	5 October 2006	Metabolism and Kinetics	Target Animals	Applicant
35137	S	R Seals.	PHA-739521: Local Tolerance Study in the Male Rabbit after Topical Dermal Administration.	26 September 2003	Toxicology	Acute Dermal Studies, Active	Applicant
35135	S	R Driscoll.	PHA-739,521: Acute Dermal Toxicity (Limit Test) in the Rat.	January 2004	Toxicology	Acute Dermal Studies, Active	Applicant
35139	S	R Seals.	PHA-739521: Local Tolerance Study in the Male Rabbit after Ocular Administration.	26 September 2003	Toxicology	Acute Eye Irritation Studies, Active	Applicant
35134	S	R Seals, C Sabaitis.	PHA-739521: Acute Oral Toxicity Study in the Rat.	11 November 2003	Toxicology	Acute Oral Studies, Active	Applicant
35140	S	W Seaman.	Acute oral (tablets) tolerance study of PHA-739521 in beagle and mongrel dogs.	24 August 2005	Toxicology	Acute Oral Studies, Product	Applicant
35138	S	JM Hurley.	Skin Sensitization Study of PHA-739,521 in albino guinea pigs (Modified Buehler Method).	27 March 2007	Toxicology	Acute Skin Sensitisation Studies, Active	Applicant
35148	S	PL Heard.	In Vivo Micronucleus Study of PHA-739521 (PF-716186) in Rats.	2006	Toxicology	Genotoxicity (Mutagenicity) Studies	Applicant
35147	S	RJ Mauthe.	In Vitro Structural Chromosome Aberration Assay of PHA-739521 (PF-716186) in Human Peripheral Lymphocytes.	13 April 2007	Toxicology	Genotoxicity (Mutagenicity) Studies	Applicant
35146	S	PW Thompson	PHA-739,521: Reverse Mutation Assay "Ames Test" using Salmonella typhimurium and Escherichia coli.	18 December 2003	Toxicology	Genotoxicity (Mutagenicity) Studies	Applicant
35204	S	RK Frank	Safety and Residues Expert Report	26 March 2007	Toxicology	Other Information	Applicant
35143	S	W Seaman.	PHA-739521 (SC-58500): 2-Month Oral Toxicity Study in the Dog.	July 2003	Toxicology	Short-term Studies	Applicant
35141	S	SR Cox.	1-Month Oral Toxicity Study of PHA-739521 in Rats with 1-Month of Recovery.	14 September 2006	Toxicology	Short-term Studies	Applicant
35136	S	R Driscoll.	PHA-739,521: Local Lymph Node Assay in the Mouse.	January 2004	Toxicology	Short-term Studies	Applicant
35144	S	W Seaman.	PHA-739521: 24-Week Oral Toxicity Study in the Dog Followed by an 8-Week Recovery Period.	2 June 2004	Toxicology	Sub-chronic Studies	Applicant

Australian Government Department of Environment, Water, Heritage and the Arts

The Department of the Environment, Water, Heritage and the Arts (DEWHA), now known as The Department of Sustainability, Environment, Water, Population and Communities (DSEWPAC), has conducted an assessment as per the Environment Impact Assessment (EAI) for Veterinary Medicinal Products, Phase 1 VICH Guideline 6, to assess the possible environmental aspects of mavacoxib in Trocoxil 95mg Chewable Tablets for Dogs (P64462),Trocoxil 75mg Chewable Tablets for Dogs (P64463), Trocoxil 30mg Chewable Tablets for Dogs (P64464), Trocoxil 20mg Chewable Tablets for Dogs (P64465) and Trocoxil 6mg Chewable Tablets for Dogs (P64466). The proposed product is for use under veterinary prescription in non-food producing animals, dogs, only. In considering the proposed use pattern and estimated levels of use, DEWHA has concluded that the use of the product as proposed is not likely to have an unintended effect that is harmful to animals, plants, things or the environment. The APVMA concur with the recommendations of DEWHA.

External Efficacy Reviewer

An external reviewer evaluated data presented by the applicant to support the safety and efficacy of the proposed new products Trocoxil 95mg Chewable Tablets for Dogs (P64462),Trocoxil 75mg Chewable Tablets for Dogs (P64463), Trocoxil 30mg Chewable Tablets for Dogs (P64464), Trocoxil 20mg Chewable Tablets for Dogs (P64465) and Trocoxil 6mg Chewable Tablets for Dogs (P64466). Studies of pharmacokinetics, dose determination, margin of safety, and clinical efficacy were provided for assessment.

The proposed products require a very specific dosing regimen. After the initial 2mg/kg dose, a period of 14 days must pass before administration of the second dose. Thereafter, the product must only been administered at one-monthly intervals, for up to a maximum of seven doses (6.5 months in total).

The pharmacokinetic studies provided demonstrated that oral bioavailability is maximised when the product is administered with food. Oral bioavailability for fed dogs was 87.4%, compared with 46.1% when given to fasted dogs. As a result, the product is to be administered with food.

Initial laboratory studies in young beagle dogs suggested that a dose rate of 4mg/kg with a regimen of 2 doses at a 14 days interval, followed by monthly dosing, would be appropriate. However, clinical studies in the target population (older dogs with osteoarthritis), indicated a longer mean elimination half-life in this population (mean approximately 39d) with a subpopulation (approximately 5%) with an elimination half-life of more than 80 days. The mean eliminations half-life in younger dogs was generally much shorter (approximately 20 days). Therefore, bioaccumulation during the treatment regimen at a dose rate of 4mg/kg and a lower safety margin were noted in the target class.

Generally the final population pharmacokinetics model describes the pharmacokinetics of mavacoxib in dogs well. Bodyweight is a major factor in predicting clearance and distribution volume for mavacoxib, therefore dosage adjustment based on bodyweight will significantly minimise the variability in drug exposure during treatment. Age is also identified as a significant factor affecting mavacoxib clearance. As the formulation is intended for use in older animals, the margin of safety of the treatment regimen was found to be improved by using a dose of 2mg/kg rather than 4mg/kg.

Several margin of safety studies were conducted to support this application. Study 35145 was a long duration study conducted in 32, young mongrel dogs. Dogs were dosed with 0mg/kg (placebo), 5mg/kg, 15mg/kg, or 25mg/kg at T=0, and 14 days later, followed by 5 doses with 28 day intervals between. The dose time is consistent with the proposed dosage regimen. From this study the NOAEL was found to be 5mg/kg, as vomiting and renal tubular changes were observed even at this dose. There was evidence for bioaccumulation and potential for fatal peritonitis at 25mg/kg.

Safety study 35164 was conducted in both beagles and mongrel dogs. Dogs received 25mg/kg, 50mg/kg or placebo, on one occasion, and were all euthanised on day 21. Negative effects were found to occur more frequently in mongrel compared to beagle dogs; this included dark, discoloured faeces at twice the prevalence, and almost three times as many cases of soft faeces and diarrhoea; and in the 50mg/kg group, a worse effect on food consumption and greater incidence of gastrointestinal tract ulceration and renal papillary necrosis. Pharmacokinetic parameters were not significantly different between breeds. The potential difference between breeds is indicated on the label to reflect these findings.

Study 35165 was conducted in 32 beagles of an appropriate target age. Dogs were dosed with 0mg/kg (placebo), 4mg/kg or 8mg/kg on two occasions, 15 days apart. Over 45 days, 4mg/kg and 8mg/kg doses induced elevations in blood urea nitrogen (BUN). Carprofen therapy was started on day 43 at 4mg/kg. Prior exposure of mavacoxib was shown to have no impact on the pharmacokinetics of carprofen in the following period. This supports the proposed 30-day washout period which is included on the product labelling. Two other studies were also conducted using the proposed formulation at high doses, followed by a standard dosing regimen with carprofen. These were also supportive of the proposed regimen.

Efficacy study 35190 was conducted in dogs of various breeds and ages (1-16 years). The study included a positive control (carprofen) and a negative control (placebo), as well as the test item, mavacoxib, which was dosed at 4mg/kg. The initial dose was followed by a second dose 14 days later, then 3 doses to follow at monthly intervals. It is noted that the duration of treatment was not identical the proposed (i.e. 2 doses less) and the dose used was 4mg/kg instead of 2mg/kg. Clinical cases of dogs with osteoarthritis were used. The inclusion criteria required evidence of osteoarthritis in at least one joint.

Eight assessment points were included in the study, which involved a veterinarian aspect and a patient owner aspect. Examinations ranged from between day zero to day 129, and included the following parameters: owner assessment form, physical examination, bodyweight, orthopaedic exam, blood sampling, and urine sampling.

The data demonstrated non-inferiority of the mavacoxib regimen compared to the carprofen regimen. Efficacy was found to be 78.8% in the mavacoxib and 82.6% in the carprofen group. Incidence of adverse effects was similar in both groups. A small number of animals (approximately 2%) experienced severe adverse effects in each treatment group. 2.15% of carprofen dogs exhibited serious adverse events including anorexia, apathy, anaemia, biliary stasis and gastrointestinal tract ulceration (oral). 2.2% of mavacoxib dogs exhibited serious adverse events including liver disease, azotaemia/renal failure and gastrointestinal tract ulceration (gastric and duodenal). Incidence of adverse events in dogs receiving mavacoxib did not increase with the duration of treatment. Vomiting, loose faeces, and various enteric conditions occurred in both groups, however the incidence of gastrointestinal tract and renal associated adverse events was low given the age of the dogs in the study. The data suggests that the applicant formulation used in the above regimen is relatively safe in older dogs but both mavacoxib and carprofen may exacerbate pre-existing hepatic, renal and gastrointestinal lesions.

Study 35193 was also used to compare mavacoxib to carprofen (Rimadyl) in clinical osteoarthritis cases. Dogs used in the study were an average age of 10 years. A 2mg/kg dose was administered orally as 2 initial doses at a 14 day interval followed by 3 doses at monthly intervals. Increased BUN levels for the mavacoxib group were higher than for the carprofen group, which seems to mirror the bioaccumulation of mavacoxib over time. There is some evidence of bioaccumulation of mavacoxib with this regimen and this is mirrored by a progressive increase in BUN during the course of the study. This suggests that setting a maximum treatment duration of approximately 6 months is appropriate. The same assessment points were used as for the study above. For the primary efficacy parameter – assessment of overall improvement at assessment point 5 (all parameters and administration of 3rd dose) – 93.4% of the dogs receiving mavacoxib improved compared to 89.7% of the dogs receiving carprofen. Incidence and frequency of adverse events were similar, as for the study above.

All parameters assessed by both the owner and the vet demonstrated improvement with rapid improvement evidenced by owner assessment point 2 (within 3 days of commencing dosing). The improvement increased over the first 6 weeks and was thereafter maintained. This was equally true for both the mavacoxib and carprofen treatments. There was a close correlation between improvement trends assessed by the owner and the vet. No cases were withdrawn from the study up to assessment point 5 for apparent lack of efficacy or inadequate improvement. The data demonstrates non-inferiority of the mavacoxib regimen (compared to daily carprofen at 4mg/kg).

The label is considered to contain adequate instructions and information regarding precautions, side effects, and other information to mitigate the risk of encountering adverse experiences with use of this product. Based on the advice of the external efficacy and safety reviewer, and the APVMA’s internal assessment, the APVMA concludes that the product will be safe and efficacious to target animals when used under the proposed use pattern and label instructions.