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Referred scheduling proposal
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to create a new entry for cimicoxib in Schedule 4 with no exemption or cut-off in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
Scheduling application
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 4 – New Entry
CIMICOXIB
The applicant’s reasons for the request are:
- Cimicoxib, an imidazole derivative, is a non-steroidal anti-inflammatory drug (NSAID) belonging to the coxib group whose mode of action is the selective inhibition of the enzyme cyclo-oxygenase 2 (COX-2).
- Cimicoxib has low acute oral toxicity; the product has low acute oral, dermal, and inhalational toxicity, is a slight skin irritant, a moderate eye irritant, and is a skin sensitiser.
- The product Cimalgex 80 mg Chewable Tablets for Dogs, containing 80 mg cimicoxib, is intended to treat pain in dogs and requires veterinary diagnosis and management (i.e. prescription).
- The Committee has previously considered a number of other NSAID COX-2 inhibitors, such as celecoxib, mavacoxib, rofecoxib and valdecoxib.
Current scheduling status
Cimicoxib is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.
Related selective COX-2 inhibitors with similar properties are listed in Schedule 4, such as celecoxib, lumiracoxib, mavacoxib and meloxicam.
Australian regulatory information
Cimicoxib is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017, or PubCRIS, and is not an excipient or active in any medicines on the ARTG.
Due to the withdrawal of rofecoxib from the market in 2004, the COX-2 inhibitors have been reviewed by the TGA to address safety concerns.
International regulations
European Union (EU)
Cimicoxib was registered by EMA/CVMP in February 2011 under the trade name Cimalgex. In March 2015, as part of a veterinary pharmacovigilance initiative, it was recommended to add the following warnings to address relatively high number of reports that include renal disorders and renal failure: 'In very rare cases, increases in renal biochemistry parameters were noted. Furthermore, in very rare cases, renal failure has been reported. As for any long term NSAID treatment, renal function should be monitored'.
- CIMICOXIB was approved for use in certain EU countries in 2011 (Cimalgex, tablets, 8, 30 and 80 mg) as a treatment for pain and inflammation in dogs.
- Marketing Authorisation Numbers EU/2/10/119/001 – EU/2/10/119/012; the Scientific Discussion of the European Public Assessment Report (EPAR) is here: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_asse….
United Kingdom (UK)
Cimicoxib is approved for use in the UK for the treatment of pain and inflammation associated with osteoarthritis, and the management of peri-operative pain due to orthopaedic or soft tissue surgery, in dogs.
Other
Cimicoxib could not be found as being available in the USA or Canada or New Zealand.
Substance summary
| Property | CIMICOXIB |
|---|---|
| CAS name | Benzenesulfinamide, 4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl] |
| CAS numbers |
265114-23-6 |
| Chemical structure |  |
| Molecular formula | C16H13ClFN3O3S |
| Molecular formula | 381.8 g/mol |
| IUPAC, CAS and/or common and/or other names | IUPAC: 4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl]benzenesulfonamide;
UR-8880 |
The following information was extracted from the Human Health Risk Assessment – Technical Report for cimicoxib.
| Toxicity | Species | Cimicoxib | Product | SPF (2015) Classification |
|---|---|---|---|---|
| Acute oral toxicity LD50 (mg/kg bw) | Mouse Rat |
>2000 (1/6 deaths) >2000 (no deaths) |
>5000 (rat) | Schedule 5 |
| Acute dermal toxicity LD50 (mg/kg bw) | Rat | No data | >5000 | Schedule 5 |
| Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | No data | - | - |
| Skin irritation | Rabbit | No data | Slight | Schedule 5 |
| Eye irritation | Rabbit | No data | Moderate | Schedule 5 |
| Skin sensitisation (GPMT)n | Guinea pig | No data | Sensitiser | Schedule 6 |
In response to the above tables the applicant stated:
- Acute toxicity endpoints have been provided against Schedules 5 and 6 of the Scheduling Policy Framework (SPF), but cimicoxib would be more appropriately listed under Schedule 4.
- For the purposes of the APVMA risk assessment, the product toxicity of all three proposed dosage forms of the product was considered under the 80 mg dose as this has the highest concentration of the active constituent of all three products.
- Cimicoxib, an imidazole derivative, is a non-steroidal anti-inflammatory drug (NSAID) whose mode of action is the selective inhibition of the enzyme cyclo-oxygenase 2 (COX-2). The product the product, containing 80 mg cimicoxib is intended to treat pain in dogs and requires veterinary diagnosis and management (i.e. prescription). The Committee has previously considered a number of other NSAID COX-2 inhibitors, such as celecoxib, mavacoxib, rofecoxib and valdecoxib.
- Oral gavage studies in rats indicated that absorption of cimicoxib was essentially complete at a low dose; ≥93%. Cimicoxib was widely distributed to tissues and extensively metabolised undergoing demethylation and subsequent glucuronidation. Excretion was rapid, predominantly in faeces with lesser amounts in urine. Saturation of absorption was observed in rats, rabbits and dogs as well as in a human clinical trial in male adults at oral doses >75 mg cimicoxib. Tissue accumulation did not occur following repeat dosing in dogs.
Acute toxicity
Based on the available oral and dermal data, cimicoxib has low acute toxicity.
Repeat-dose toxicity
In short-term repeat-dose oral (gavage) studies in rats and dogs, the primary target organ was the gastrointestinal tract. In rats, deaths were seen that were associated with inflammation/perforation of the small intestine and gastrointestinal adhesions, with secondary septic peritonitis seen at higher dose levels. Clinical signs such as hunched posture, swollen abdomen that was hard to the touch and decreased motor activity were observed. In dogs, emesis, soft faeces/diarrhoea and hidden blood in the faeces were seen, with adverse decreases also seen in RBC count, haemoglobin, haematocrit, total protein and albumin at higher dose levels.
There was no evidence that cimicoxib was neurotoxic or immunotoxic.
Genotoxicity
Cimicoxib was tested for genotoxicity in an adequate range of in vitro and in vivo assays and was negative. It was concluded that cimicoxib is unlikely to pose a carcinogenic risk to humans.
Carcinogenicity
No studies investigating the chronic toxicity or carcinogenic potential of cimicoxib are available.
Reproduction and developmental toxicity
In a one-generation rat study, a decrease in the fertility index at the low dose and greater that lacked a dose response and did not obtain statistical significance was considered incidental, compared to controls. A decrease was also seen in the mean number of corpora lutea. No historical control data were provided, although obtained data on the background incidence of corpora lutea in rats indicated that it was likely to be incidental to treatment. A treatment-related and adverse decrease was seen in uterus weight, the number of implantations and live foetuses, and an increase in the percentage of resorptions and pre- and post-implantation loss in the absence of parental toxicity.
In a study of developmental toxicity in rats, a slight increase was seen in the foetal and litter incidence of haemorrhagic liver, pale liver, malpositioned kidneys and misaligned sternebrae at the top dose level, compared to controls. No historical control data were provided, although data on the background incidence of misaligned sternebrae in rat foetuses indicated it was likely incidental to treatment. No historical control data were identified for haemorrhagic liver, pale liver and malpositioned kidneys in rat foetuses. However, noting that these minor visceral abnormalities were observed in control foetuses and the slight increase seen at the top dose level (that produced deaths and adhesion and perforation in the small intestine of dams) did not obtain statistical significance, it is considered they were likely incidental to treatment.
In a study of developmental toxicity in rabbits, an increased incidence of total external and internal (visceral) macroscopic abnormalities was seen in foetuses at the low dose and greater in the absence of maternal toxicity at the low and mid dose, compared to controls. At the mid and greater doses, a decrease was seen in uterus weight, increase in percentage post-implantation loss and resorptions and decrease in the number of live foetuses. At the top dose compared to controls, an increase was seen in the foetal incidence of cleft palate, gastroschisis, enlarged fontanelle, absence of 1 or 2 sternebrae and fused sternebrae along with an increase in the litter incidence of enlarged fontanelle and fused sternebrae were seen in the presence of maternal toxicity (mortality, decreased bodyweight gain and gastric perforation and gastrointestinal fibrous adherences in dams). It was concluded that cimicoxib is a reproductive toxicant in rats and teratogenic in rabbits but not rats.
Observation in humans
In a human clinical trial study in males (aged 18-45 years), cimicoxib was safe and well tolerated following a single oral does up to 600 mg, the highest dose administered.
Pre-meeting public submissions
No public submissions were received for cimicoxib.
Summary of ACCS-ACMS advice to the delegates
Schedule 4 – New Entry
CIMICOXIB.
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; and (c) the toxicity of a substance.
The reasons for the recommendation comprised the following:
- the risks and benefits of the use of a substance:
- The benefit of cimicoxib is that it is an additional anti-inflammatory pain relief option for veterinary use.
- The risk posed by cimicoxib is that if it is used inappropriately (e.g. without health professional prescribing) it may cause serious adverse effects and death.
- Risk and benefit profile consistent with other COX-2 inhibitors and NSAIDs.
- the purposes for which a substance is to be used and the extent of use of a substance:
- It will be used for pain relief in dogs, the management of which requires veterinary intervention.
- Currently not in use in Australia.
- the toxicity of a substance:
- Cimicoxib shows low acute oral, dermal, and inhalational toxicity. Cimicoxib is a slight skin irritant, a moderate eye irritant and is a skin sensitiser.
- Repeat dose toxicity causes ulcerative gastritis in doses close to recommended dose. Reproductive toxicity and teratogenicity (at all doses tested in rabbits) has also been demonstrated.
- Toxicity is consistent with a Schedule 5 or 6 listing, however a Schedule 4 listing is considered appropriate due to the need for veterinary intervention for management of pain in dogs.
- the dosage, formulation, labelling, packaging and presentation of a substance:
- Nil.
- the potential for abuse of a substance:
- Nil.
- any other matters that the Secretary considers necessary to protect public health
- Nil.
Delegate's considerations
The delegate considered the following in regards to this proposal:
- Scheduling proposal
- ACCS-ACMS advice
- Section 52E of the Therapeutic Goods Act 1989
- Scheduling Policy Framework (SPF 2015)
Delegate's interim decision
The delegate’s interim decision is create a new Schedule 4 entry for cimicoxib. The proposed Schedule entry is:
Schedule 4 – New Entry
CIMICOXIB.
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.
The reasons for the recommendation comprised the following:
- the risks and benefits of the use of a substance:
- The benefit of cimicoxib is that it is an additional anti-inflammatory pain relief option for veterinary use.
- The risk posed by cimicoxib is that if it is used inappropriately (e.g. without health professional prescribing) it may cause serious adverse effects and death.
- Risk and benefit profile consistent with other COX-2 inhibitors and NSAIDs.
- the purposes for which a substance is to be used and the extent of use of a substance:
- It will be used for pain relief in dogs, the management of which requires veterinary intervention.
- Currently not in use in Australia.
- the toxicity of a substance:
- Cimicoxib shows low acute oral, dermal, and inhalational toxicity. Cimicoxib is a slight skin irritant, a moderate eye irritant and is a skin sensitiser.
- Repeat dose toxicity causes ulcerative gastritis in doses close to recommended dose. Reproductive toxicity and teratogenicity (at all doses tested in rabbits) has also been demonstrated.
- Toxicity is consistent with a Schedule 5 or 6 listing, however a Schedule 4 listing is considered appropriate due to the need for veterinary intervention for management of pain in dogs.
- the dosage, formulation, labelling, packaging and presentation of a substance:
- Nil.
- the potential for abuse of a substance:
- Nil.
- any other matters that the Secretary considers necessary to protect public health
- Nil.