Medetomidine hydrochloride: what the FDA reviewed for dog products
2 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Medetomidine hydrochloride, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- Domitor® (NADA/ANADA 140-999)
- Placadine™ (NADA/ANADA 200-610)
Domitor® NADA 140-999, Original approval, March 19, 1996; sponsor Orion Corp.; species: Dogs; foi_id 554; FDA PDF
Indication
Sedative and analgesic in dogs over 12 weeks of age to facilitate clinical examinations, clinical procedures, minor surgical procedures not requiring muscle relaxation, and minor dental procedures not requiring intubation.
Dose regimen
750 mcg IV or 1000 mcg IM per square meter of body surface, Intravenous or intramuscular injection, single injection, dose volume taken from a body-weight chart (1 mg/mL solution); the dog should be allowed to rest quietly for 15 minutes after injection; IV route more efficacious for dental care
Domitor should be administered at the rate of 750 mcg IV or 1000 mcg IM per square meter of body surface.
Target-animal safety
dose multiples 2X, 6X, 10X; duration daily intramuscular injection for 28 consecutive days; animals Twenty-four (four groups of three males and three females).
Purpose: To assess the toxicity of medetomidine hydrochloride when administered by daily intramuscular injection for 28 days. b. Test Animals: Twenty-four young adult beagle dogs, weighing 9 - 15 kg at study initiation, were randomly divided into four groups containing three males and three females per group.
| Finding | Quote |
|---|---|
| Doses were 0, 80, 240 and 400 µg/kg IM, approximately 0, 2X, 6X and 10X the optimal IM dose. | Medetomidine hydrochloride was administered at dosages of 0 µg/kg (test formulation vehicle containing no active), 80 µg/kg, 240 µg/kg and 400 µg/kg. These doses are approximately equivalent to 0, 2X, 6X and 10X the optimal intramuscular dose. |
| No mortality; no effects on body weight or food consumption. | Mortalities: No mortalities were observed in any dose group. b. Body Weights: No significant differences between any treatment group and controls. c. Food Consumption: No significant differences between any treatment group and controls. |
| Dose-related sedation lasting into the evening at 10X (400 µg/kg) with staggering/recumbency at the last observation; dogs normal the next morning. Vomiting occurred in all treated groups. | Dogs in the high dose group (400 µg/kg), were sedated after dosage and sedation was evident during the last observation about five or six hours after dosing. At the last observation the dogs staggered or were lying down. However, the next morning the dogs were always normal. |
| Only drug-related histopathology: corneal changes (cysts, minimal horizontal central corneal opacity) in high-dose females and one medium-dose female, attributed to eye drying from prolonged repeated sedation. | The only drug related changes were seen in the eyes of females of the high dose group. In two animals small cysts were observed in the corneal epithelium of one eye. In all females of the high dose level and in one female of the medium dose level minimal horizontal opacity at the central area of the cornea was observed in the ophthalmological studies. The histological changes that were observed in the cornea were possibly due to the drying of eyes caused by long-lasting repeated sedation. |
| Blood glucose lower after dosing in treated groups (dose-related). | After dosing, blood glucose values were lower in the low dose female group than in controls (p<0.05), significantly lower in the medium dose groups of males and females, highly significantly lower in the high dose groups of males and significantly lower in females. |
| Conclusion of the 28-day IM study: well tolerated up to 400 µg/kg; effects minor and secondary to prolonged sedation. | Medetomidine hydrochloride is well tolerated by dogs when administered by the i.m. route at doses up to 400 µg/kg for 28 days. Drug- related effects under these conditions are considered to be of minor toxicological or clinical importance and are primarily a consequence of long- lasting repeated sedation. |
| Second pivotal TAS study (IV): 0, 1X, 3X, 5X daily for three days and 10X once; no mortalities, considered safe up to 10X the IV dose. | Doses of medetomidine were given intravenously for three days at 0X, 1X, 3X, or 5X, (corresponding to 0, 750, 2250, or 3750 µg/m²) or one day at 10X (7500 µg/m²). This study found that medetomidine appears to be safe when administered up to 10X the recommended i.v. dosage in that no mortalities were reported. |
| IV study: dose-related marked bradycardia (to 40 beats/minute) lasting about 4 hours, resolved by 24 hours; transient apnea, pale mucous membranes, hypothermia, ECG changes (QT/QRS prolongation, AV block) also seen. | A dose related bradycardia was observed in beagles which lasted in most dogs for 4 hours after dosing. This decrease in heart rate was marked, decreasing to 40 beats/minute in some cases. In all instances the rate had returned to normal levels by 24 hours after dosing. |
Effectiveness
Fourth pivotal study: controlled clinical evaluation vs xylazine (positive control) at two sites (Cornell NYSCVM; Hudson Highland Vet. Med. Group), letter-coded (blinded), randomized to four groups: medetomidine 750 mcg/m2 IV or 1000 mcg/m2 IM vs xylazine 1.1 mg/kg IV or 2.2 mg/kg IM; sedation/analgesia scores over 180 minutes.; n = 65 enrolled (41 analysed for time-course variables); primary endpoint: Sedation (posture, response to noise) and analgesia (pedal reflex, procedure score) scores over 180 minutes, heart rate, times to recumbency/standing, investigator ratings of applicability, sedation and analgesia; result: Both medetomidine and xylazine were found safe and effective; medetomidine was consistently rated more efficient as a sedative and analgesic (applicability p=0.019, analgesia p=0.017), medetomidine IV ranked highest and xylazine IM lowest. Side-effect occurrence did not differ between groups (p=0.954).
For 24 of the 65 dogs in this study, time 0 was taken to be the time at which sedative effects were first observed rather than the time immediately prior to injection. Consequently, data on response variables taken over time (i.e. over the 180 minute observation period for posture score, pedal reflex score, response to noise, heart rate and procedure scores) were not included in the statistical analysis. The following results are based on data from the remaining 41 dogs.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Vomiting (fifth pivotal study, dental subset of 54 dogs) | 7.1% (medetomidine IV), 25% (medetomidine IM) | 7.6% (xylazine IV), 20.0% (xylazine IM) | Vomiting was the most noticeable side effect, occurring in 7.1% and 25% of all dogs treated with medetomidine i.v. and i.m., and 7.6% and 20.0% of all dogs treated with xylazine i.v. and i.m, respectively. |
| Side effects present (Table 15, fourth pivotal study; columns: medetomidine IM, medetomidine IV, xylazine IM, xylazine IV; n (%)) | 4 (28.6%) medetomidine IM; 4 (22.2%) medetomidine IV | 4 (22.2%) xylazine IM; 3 (20.0%) xylazine IV | Side Effects – Present 4 (28.6) 4 (22.2) 4 (22.2) 3 (20.0) |
| Profound bradycardia (fifth pivotal study) | Profound bradycardia was also a common side effect, however, the overall level of all side effects was low and not significantly different between groups. None was lasting or required medication. |
Extraction notes: Original NADA (1996). No pharmacokinetic data in the summary. Effectiveness section holds five pivotal studies (dose-response study in 48 dogs establishing 750 µg/m² IV and 1000 µg/m² IM; clinical comparison vs Innovar; two clinical comparisons vs xylazine; dental-care subset of 54 dogs); the fourth (field comparison vs xylazine, 65 dogs) is recorded here, with the conclusion quoted from the summary: 'Regardless of age, breed, body weight or health status of dogs at admission, both medetomidine and xylazine were found to be safe and effective for the procedures for which they were used. Medetomidine, however, was consistently rated more efficient as a sedative and analgesic than xylazine, with medetomidine i.v. rated highest, and xylazine i.m. rated lowest.' TAS section holds four pivotal studies plus an IM irritation study; the 28-day IM study (0/2X/6X/10X, 24 beagles) is recorded as the margin-of-safety study and the 3-day IV study (1X/3X/5X/10X, 34 dogs) is summarised in findings. Table 15 group sizes were 14, 18, 18 and 15 dogs (medetomidine IM, medetomidine IV, xylazine IM, xylazine IV).
Placadine™ NADA 200-610, Original approval, May 25, 2017; sponsor Modern Veterinary Therapeutics, LLC; species: Dogs; foi_id 1461; FDA PDF
Indication
Sedative and analgesic in dogs over 12 weeks of age to facilitate clinical examinations, clinical procedures, minor surgical procedures not requiring muscle relaxation, and minor dental procedures not requiring intubation.
Dose regimen
750 mcg IV or 1000 mcg IM per square meter of body surface, Intravenous or intramuscular injection, single injection, dose volume from the body-weight table (1 mg/mL); dog should rest quietly for 15 minutes after injection
Medetomidine Hydrochloride should be administered at the rate of 750 mcg IV or 1000 mcg IM per square meter of body surface.
Extraction notes: Generic (ANADA) of Domitor (NADA 140-999). Waiver from demonstrating bioequivalence granted on formulation characteristics (same active ingredient, concentration and dosage form; no inactive ingredients affecting bioavailability). No effectiveness, target animal safety or PK studies in the summary ('CVM did not require effectiveness studies for this approval'; 'CVM did not require target animal safety studies for this approval'). Proprietary name in the summary is 'Medetomidine Hydrochloride'; the catalogue lists Placadine™.
Reproduce: foi_structured_search(query="Medetomidine hydrochloride") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).