Advice summary application for registration of a chemical product

ADVICE

Pfizer Animal Health a Division of Pfizer Australia Pty Ltd has applied to the APVMA to register a new product, Trocoxil 95mg Chewable Tablets for Dogs (P64462). The proposed product, which has been treated as the primary application of a set of five, contains the new active constituent mavacoxib. Four secondary applications were submitted for the following products, containing the same active constituent: 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 products are to be used for the treatment of pain and inflammation associated with degenerative joint disease in dogs.

Australian Government Department of Health and Ageing, Office of Chemical Safety and Environmental Health

The Office of Chemical Safety and Environmental Health (OCSEH) has evaluated toxicological data to support the registration of the 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).

Mavacoxib is a compound belonging in the coxib class of non-steroidal anti-inflammatory drugs (NSAIDs). Mavacoxib is closely related to the human drug celecoxib. The mechanism of action for mavacoxib is through the selective inhibition of the cyclooxygenase-2 enzyme (COX-2), which plays a major role in the synthesis of prostaglandins responsible for mediating the pain and inflammatory response in tissues and organs.

Based on the findings of toxicological studies evaluated, mavacoxib is predicted to be of low acute oral toxicity and a low dermal toxicity. Mavacoxib is not predicted to be a skin irritant or a skin sensitiser, but is a slight eye irritant. No acute inhalational information was available, but given the acute toxicity profile, it is unlikely to be of significant inhalation toxicity. Mavacoxib is not mutagenic or genotoxic and is unlikely to be carcinogenic.

Upon administration, mavacoxib was absorbed and distributed extensively in dogs and rats. Total body plasma clearance was relatively low in both species, resulting in mavacoxib terminal elimination half-lives of 17.9–19.1 days in dogs, and 28-31 hours in rats. Mavacoxib was well absorbed in rats and has approximately 90% bioavailability following administration of the intended commercial tablet formulation to dogs. Mavacoxib was not metabolised extensively and parent mavacoxib accounted for nearly all of the drug-related material in the plasma of the dog.

In the repeat-dose studies, mavacoxib could not be administered any more frequently than one dose every 28 days because of the long elimination half-life of the compound. Daily administration of mavacoxib at 5 mg/kg bodyweight per day to rats resulted in death and moribundity after 13–15 days due to segmental gastrointestinal ulceration and secondary peritonitis. Gastrointestinal ulceration was also seen in the dog at 25 and 50 mg/kg bodyweight during an acute dose tolerance study. Due to the accumulation effects of mavacoxib, the following statements “harmful if swallowed” and “Do not swallow” are to be included in the label Safety Directions. These statements are considered to appropriately reflect the toxicity risks associated with bioaccumulation.

On the basis of the presented evidence, mavacoxib is classified as a potential developmental toxicant. To provide adequate warning regarding the potential risks associated with product use, the following warning statement has been recommended in addition to the Safety Directions.

WARNING/SAFETY PRECAUTION – Ingestion of Mavacoxib can be harmful to children, and prolonged gastrointestinal and pharmacological effects may be observed upon accidental ingestion. To avoid accidental ingestion administer the tablet to the dog immediately after removal from the blister package.

The OCSEH proposed that mavacoxib be included in Schedule 4 of the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP). The delegate to the Secretary of the Department of Health and Ageing sought advice from the Advisory Committee on Chemical Scheduling (ACCS) on the OCSEH’s proposal to include mavacoxib in Schedule 4 of the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP). The delegate agreed with the proposal of the OCSEH and the final decision was to include mavacoxib in Schedule 4 of the SUSMP.

The OCSEH report recommends that from a toxicological viewpoint there are no objections on human health grounds and that the approval of mavacoxib

and the registration of 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) is supported. No

Acceptable Daily Intake (ADI) or Acute Reference Dose (ArfD) were required to be set for mavacoxib as the product is for use in non-food producing species

only. The OCSEH has assessed the potential toxicological hazard, likelihood of handler and occupational exposure and has recommended First Aid Instructions and Safety

Directions. The APVMA agrees with the findings and recommendations of the OCSEH.