Medetomidine hydrochloride and vatinoxan hydrochloride: what the FDA reviewed for dog products

1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Medetomidine hydrochloride and vatinoxan hydrochloride, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dog.

Products

Zenalpha® (NADA/ANADA 141-551)

Zenalpha® NADA 141-551, Original approval, March 30, 2022; sponsor Dechra Veterinary Products LLC; species: Dog; foi_id 12187; FDA PDF

Indication

Sedative and analgesic in dogs to facilitate clinical examination, clinical procedures and minor surgical procedures.

Dose regimen

1 mg medetomidine/m2 BSA, Intramuscular, single injection, fixed 1:20 combination (0.5 mg/mL medetomidine HCl + 10 mg/mL vatinoxan HCl), i.e. 20 mg vatinoxan/m2 BSA; dosed by body-surface area or the label dosing table (mg/kg dosage decreases as body weight increases)

Calculate the dose using 1 mg medetomidine /m2 BSA or use the dosing table below.

Pharmacokinetics

Parameter	Value	Conditions	Quote
cmax	Cmax and C0 less than dose-proportional for vatinoxan; approximately dose-proportional for dexmedetomidine and levomedetomidine	toxicokinetics in the TAS study; IV bolus at 1X, 3X, 5X (1, 3, 5 mg medetomidine/m2 with 20, 60, 100 mg vatinoxan/m2), Day 1, Beagles	The maximum observed concentration (Cmax) and estimated concentration at time zero (C0) were less than dose-proportional for vatinoxan, and approximately dose-proportional for dexmedetomidine and levomedetomidine after one dose on Day 1.
auc	AUC0-8h approximately dose-proportional for vatinoxan; more than dose-proportional for dexmedetomidine and levomedetomidine	same toxicokinetic data, Day 1; systemic exposure similar in males and females	The area under the plasma concentration-time curve from time zero to 8 hours (AUC0-8h) was approximately dose-proportional for vatinoxan and was more than dose-proportional for both dexmedetomidine and levomedetomidine after one dose on Day 1.
other	plasma unbound fraction : CSF ratio approximately 36:1 for vatinoxan and close to 1:1 for dexmedetomidine	after 1X IV dose for 4 consecutive days, adjusted for plasma protein binding; CSF collected at necropsy on Day 4	Following administration of the 1X dose for 4 consecutive days, adjusted for plasma protein binding, the plasma unbound fraction: CSF ratio was approximately 36:1 for vatinoxan, and close to 1:1 for dexmedetomidine.
other	urinary excretion of vatinoxan approximately 2% (1X) to 5% (3X and 5X) of the Day 3 dose	urine collected between Day 3 and Day 4 doses in the TAS study	Taking into account the urine volumes collected and total dose of vatinoxan received in each dog, the amount of the Day 3 dose detected in the urine was approximately 2% (1X group) to 5% (3X and 5X groups).
other	PK/PD simulation: medetomidine:vatinoxan ratio 1:20 kept mean heart rate closest to 70 beats per minute over 2 hours	PK/PD modeling report (Study No. 14-322-06) used for dose-ratio selection	The medetomidine to vatinoxan ratio that maintained the mean heart rate closest to 70 beats per minute over a 2-hour period post dose was 1:20.

Target-animal safety

dose multiples 1X, 3X, 5X; duration once daily for 4 days (IV bolus; label route is IM); animals Thirty-two (16 males, 16 females).

Objective: To evaluate the safety of Zenalpha® (medetomidine and vatinoxan hydrochlorides injection) when administered IV once a day for 4 days. Study Animals: Thirty-two Beagle dogs (16 males, 16 females), aged 4.5 to 6.5 months old, with a bodyweight range 5.4 to 10 kg, determined as healthy based on physical examination and clinical pathology. Experimental Design: The study was masked, placebo-controlled, and conducted according to Good Laboratory Practices (GLP).

Finding	Quote
No deaths or clinically significant illness.	Mortality and Morbidity: There were no deaths or clinically significant illness during the study.
Mucoid/soft/watery feces in 1X (1 dog), 3X (2 dogs), 5X (3 dogs); one 3X female had explosive diarrhea; one 5X female vomited once.	Dogs administered Zenalpha® had reported mucoid, soft, or watery feces in the 1X (1 dog), 3X (2 dogs), and 5X (3 dogs) groups post-dose. One 3X female had explosive diarrhea 1 hour after dosing. One 5X female vomited once 4 hours after dosing.
Heart rate decreased after dosing (lowest at 1 hour) then rose above baseline by 2 hours; mean HR above 140 bpm at 2-4 hours in 3X and 5X groups (sinus tachycardia).	The mean heart rate was increased above 140 bpm on Days 1 and 2 at 2 or 4 hours post-dose in the 3X group and on Days 1, 2, and 3 at 2 or 4 hours post-dose in the 5X group.
Second-degree AV block infrequent (5 instances in 3 dogs), not dose related.	Second-degree atrioventricular (AV) block occurred infrequently (5 instances in 3 dogs) and was not dose related.
Hypothermia requiring supplemental heat support at 1-4 hours post-dose in treated groups.	As a result of clinical observations and body temperature recordings, dogs in the Zenalpha® groups were often provided supplemental heat support which began at either 1 or 2 hours post-dose and was discontinued at 4 hours post-dose.
Blood pressure decreased between 15 minutes and 1.5 hours and recovered by 2-4 hours post-dose.	Blood pressure generally decreased between 15 minutes and 1.5 hours post-dose, and fully recovered to baseline/control values by 2 to 4 hours post-dose.
Two 5X males had serum glucose below 65 mg/dL on Day 3 (56 and 62 mg/dL).	Two male dogs in the 5X group had serum blood glucose less than 65 mg/dL on Day 3 at 3 hours post-dose (56 mg/dL and 62 mg/dL).
Duration of lateral recumbency increased with dose (pooled means 67.1, 91.2, 121.8 minutes for 1X, 3X, 5X); no treatment-related histopathology or organ-weight effects.	The mean duration of time in lateral recumbency for the Zenalpha® groups increased as the dose increased.
Conclusion: no systemic toxicity, acceptable margin of safety; sedation, hypotension, hypothermia, initial bradycardia then tachycardia all resolved before the next dose.	Zenalpha® administered as an intravenous injection once daily for 4 days at doses of 1 mg medetomidine and 20 mg vatinoxan/m2 BSA, 3 mg medetomidine and 60 mg vatinoxan/m2 BSA, or 5 mg medetomidine and 100 mg vatinoxan/m2 BSA did not produce systemic toxicity and had an acceptable margin of safety. The administration of Zenalpha® resulted in sedation, decreased blood pressure, hypothermia, and initial sinus bradycardia and later sinus tachycardia that all resolved prior to the next scheduled dose.

Effectiveness

Multicenter (6 US clinics), double-masked, randomized, active-controlled field study (Study No. 14-420-01) in client-owned dogs: Zenalpha 1 mg/m2 medetomidine + 20 mg/m2 vatinoxan IM once (n=110) vs dexmedetomidine 0.5 mg/m2 IM (n=113); 223 dogs enrolled (safety population).; n = 208 (109 Zenalpha, 99 control); primary endpoint: (1) ability to complete the planned examination/procedure while sedated (non-inferiority, NI margin 25%); (2) heart rate during the first 3 hours (superiority); result: Success rate 94.5% Zenalpha vs 90.9% control (non-inferior). Zenalpha group mean heart rate stayed within 60-140 bpm while control mean HR was below normal from 5-180 min (superior, p<0.0001 from 15 min); HR <40 bpm in 8.3% vs 52.4% of dogs. Mean onset of sedation 14 vs 18 min; mean duration 38 vs 90 min. Comparable analgesia (mechanical nociceptive threshold).

Effectiveness was evaluated in 208 dogs (109 in the Zenalpha® group and 99 in the control group). Ability to complete procedure: The success rate for the ability to complete the procedure was 94.5% in the Zenalpha® group and 90.9% in the control group.

Adverse reactions

Term	Treated	Control	Quote
Diarrhea	4 (3.6%)	0 (0%)	Diarrhea 4 (3.6) 0 (0)
Muscle tremor	2 (1.8%)	0 (0%)	Muscle tremor 2 (1.8) 0 (0)
Colitis	2 (1.8%)	0 (0%)	Colitis 2 (1.8) 0 (0)
Hypothermia (requiring external heat source)	1 (0.9%)	13 (11.5%)	Hypothermia* 1 (0.9) 13 (11.5)
Vomiting	1 (0.9%)	6 (5.3%)	Vomiting 1 (0.9) 6 (5.3)
Sedation (prolonged)	0 (0%)	3 (2.7%)	Sedation (prolonged) 0 (0) 3 (2.7)

Extraction notes: Original NADA. Adverse reaction rows quote Table II.10 (field study; columns: Zenalpha n (%) with N = 110, control dexmedetomidine n (%) with N = 113). Species/Class is stated as 'Dog' in the summary. No conventional PK parameter values (half-life, absolute Cmax) are reported; PK rows are toxicokinetic dose-proportionality statements, the plasma:CSF ratio, urinary excretion and a PK/PD simulation result. TAS study used IV bolus dosing (to avoid large IM volumes) at 1X/3X/5X of the IM label dose; n_animals is written as in the summary ('Thirty-two'). Dose-selection laboratory studies (8 Beagles each) and an atipamezole reversal study (8 Beagles; 5 mg/m2 IM reversed sedation within 10-20 minutes) are also described.

Reproduce: foi_structured_search(query="Medetomidine hydrochloride and vatinoxan hydrochloride") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).