ATCvet code: QN05CM99

Medetomidine is a potent and selective alpha-2 adrenoceptor agonist that inhibits the release of noradrenaline from noradrenergic neurons and produces sedation and analgesia. These effects are dose dependent in depth and duration. Medetomidine is a racemic mixture containing the active enantiomer dexmedetomidine and the inactive enantiomer levomedetomidine. Within the central nervous system, sympathetic neurotransmission is inhibited and the level of consciousness decreases. Respiratory rate and body temperature can also decrease. In the periphery, medetomidine stimulates alpha-2 adrenoceptors within vascular smooth muscle which induces vasoconstriction and hypertension, resulting in decreased heart rate and cardiac output. Dexmedetomidine also induces a number of other alpha-2 adrenoceptor mediated effects, which include piloerection, depression of motor and secretory functions of the gastrointestinal tract, diuresis and hyperglycaemia.

Vatinoxan is a peripherally selective alpha-2 adrenoceptor antagonist which poorly penetrates the central nervous system. Vatinoxan is administered as the active (RS) diastereomer. By limiting its effects to peripheral organ systems, vatinoxan will prevent or attenuate the cardiovascular and other effects of dexmedetomidine outside the central nervous system when administered simultaneously with the alpha-2 adrenoceptor agonist. The central effects of dexmedetomidine remain unaltered, although vatinoxan will reduce the duration of sedation and analgesia induced by dexmedetomidine, predominantly by increasing the clearance of the latter via improving the cardiovascular function. Vatinoxan stimulates insulin release and counteracts medetomidine’s hyperglycaemic effects.

The safety and efficacy of the veterinary medicinal product was tested in a multicentre clinical study, using 223 client-owned dogs. Dogs requiring a non-invasive, non-painful or mildly painful procedure or examination were treated with either the recommended dose of the veterinary medicinal product (test group), or dexmedetomidine (control group). Procedures included: radiographic examination or diagnostic imaging, ear examination and treatment, eye examination and treatment, anal sac treatment, dermatological examination and procedures, orthopaedic examination, dental examination and biopsy, fine needle aspiration/superficial biopsy, drain seroma or abscess, nail trimming, coat grooming and venous blood draw. One hundred and ten dogs received the test product. In this group, sedation sufficient to perform the procedure occurred on average in 14 minutes. Although duration of clinically-useful sedation varies substantially between individuals and intended procedure, 73% of test group cases had at least 30 minutes duration of sedation and the procedure was completed successfully in 94.5% of cases. Test group mean heart rate remained within the normal range (60–140 beats per minute) at all times after administration; however, 22% of dogs displayed tachycardia at some time point(s) after treatment (range 140–240 beats per minute). In the dexmedetomidine-treated control group, the average time to onset of sedation was 18 minutes and sedation lasted for at least 30 minutes in 80% of dogs. The procedure was completed successfully in 90.1% of control group cases.

After intramuscular administration of a pilot formulation of medetomidine (1 mg/m2) + vatinoxan (30 mg/m2), both medetomidine and vatinoxan were rapidly and highly absorbed from the injection site. Maximal plasma concentration was reached at 12.6±4.7 (mean ± standard deviation) minutes and 17.5±7.4 minutes for dexmedetomidine (the active enantiomer of medetomidine) and vatinoxan, respectively. Vatinoxan increased the volume of distribution and the clearance of dexmedetomidine. Thus, the clearance of dexmedetomidine was increased two-fold when given in combination with vatinoxan. The same phenomena were also seen with intravenous administration.

Concentrations of dexmedetomidine and vatinoxan in cerebrospinal fluid (CSF) were measured after intravenous administration of the final formulation of the veterinary medicinal product. Plasma unbound fraction:CSF ratio was approximately 50:1 for vatinoxan and 1:1 for dexmedetomidine.

Medetomidine plasma protein binding is high (85–90%). Medetomidine is mainly oxidised in the liver, a smaller amount undergoes methylation in the kidneys, and excretion is mainly via urine. Vatinoxan plasma protein binding is approximately 70%. Low levels are detectable in the central nervous system. Vatinoxan is metabolised to a very limited extent in the dog. Only a small amount (<5%) of vatinoxan dose has been found to be excreted via the urine. This suggests that vatinoxan is most likely eliminated in the faeces, although no data are available to confirm this.