Fentanyl: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Fentanyl, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- Recuvyra® (NADA/ANADA 141-337)
Recuvyra® NADA 141-337, Original approval, June 23, 2012; sponsor Elanco US Inc.; species: Dogs; foi_id 894; FDA PDF
Indication
Control of postoperative pain associated with surgical procedures in dogs.
Dose regimen
1.2 mg/lb (2.7 mg/kg), Topical (transdermal) to the dorsal scapular area, Single application, Applied 2 to 4 hours prior to surgery; a single application provides analgesia for 4 days
The dosage of RECUVYRA is 1.2 mg/lb (2.7 mg/kg) applied topically to the dorsal scapular area 2 to 4 hours prior to surgery. A single application provides analgesia for 4 days.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| other | Plasma fentanyl above 1 ng/mL over the 50 hour observation period | Dogs, pilot dose-finding study T8F1090406; 2.6 and 3.9 mg/kg transdermal doses applied about 12 hours before ACL transection surgery (n=8 per group); marked between- and within-subject variability | Plasma concentrations remained above 1 ng/mL for the 2.6 and 3.9 mg/kg doses over the 50 hour observation period. |
| other | Plasma fentanyl concentrations doubled from the first to the third dosing interval (accumulation with repeated dosing) | Dogs, margin-of-safety study ARDG01-C-03; 2.6, 5.2 and 7.8 mg/kg topical to ventral abdomen every 4 days for 3 doses | Plasma fentanyl concentrations doubled from the first to the third dosing interval. Fentanyl concentrations appeared to show accumulation with successive doses in all treated groups. |
| other | More rapid rise and decline in plasma fentanyl after dorsal scapular application than after ventral abdominal application | Dogs, pharmacokinetic application-site study 021591 (Figure 1; no numeric values given) | The results of a pharmacokinetic application site study (021591) showed that administration to the dorsal scapular region allows for a more rapid rise and decline in fentanyl plasma concentrations as compared to that seen when fentanyl transdermal solution is applied to the ventral abdominal region (Figure 1). |
| other | Half-life of 23.3 hours for the decline in fentanyl transferable from treated dog skin to a cotton glove (not a plasma half-life) | User-safety glove-transfer study in dogs; 4.25% of dose recovered immediately after application, about 2% at 24 h and 1% at 48 h | The amount of fentanyl transferred declined over time with an estimated half-life of 23.3 hours. |
| cmax | 0.318 ng/mL (arm), 0.0975 ng/mL (thigh), 0.545 ng/mL (fentanyl patch) | HUMAN volunteers (user safety section), exploratory human formulation of transdermal fentanyl solution vs DURAGESIC patch; not dog data | The mean fentanyl Cmax for arm, thigh, and patch were 0.318, 0.0975, and 0.545 ng/mL respectively. |
| tmax | 34 hours (range 18 to 96 hours) | HUMAN volunteers (user safety section), transdermal fentanyl solution applied to arm or thigh; not dog data | The mean time to reach maximal plasma concentration (Tmax) for transdermal fentanyl solution was 34 hours (ranged from 18 to 96 hours). |
Target-animal safety
dose multiples 0X, 1X, 2X, 3X; duration Every 4 days for a total of 3 doses (Days 0, 4, 8); 12-day study; animals 8 dogs per dose group (16 male, 16 female).
To evaluate the margin of safety of RECUVYRA when administered to healthy adult mongrel dogs (eight dogs per group) at 0, 2.6, 5.2, and 7.8 mg/kg (0, 1, 2, and 3 times the dose) as a topical application administered every 4 days for a total of 3 doses. b. Description of Test Animals: Thirty-two purpose bred laboratory mongrel dogs 1-2 years of age (16 male, 16 female), 8 dogs per dose group.
| Finding | Quote |
|---|---|
| Three deaths (two 2X dogs, one 3X dog) between the second and third doses from endotoxic shock secondary to severe gastrointestinal stasis with hypothermia and sedation | Three dogs died as a result of transdermal fentanyl administration. Death was due to endotoxic shock produced by severe gastrointestinal stasis complicated by continued hypothermia and sedation. All deaths occurred between the second and third doses. Two dogs (2X group) died on days 4 and 7, and the third dog (3X group) died on day 5. |
| Severe hypothermia (lowest 90.9-93.2 F), bradycardia and decreased respiratory rate in the dogs that died | All 3 dogs had severe hypothermia (body temperature < 98° F), with the lowest temperatures ranging from 90.9-93.2° F. The three dogs had bradycardia (heart rate < 60 beats per minute) and decreased respiratory rates. |
| Narrow margin of safety concluded | Administration of topical RECUVYRA every 4 days at 2.6, 5.2, and 7.8 mg/kg (1X, 2X, and 3X the clinical dose) for 3 doses showed a narrow margin of safety. |
| Spectrum of treatment effects: sedation, hypothermia, bradycardia, respiratory depression, dehydration, weight loss, decreased food consumption, GI signs | RECUVYRA caused variable levels of sedation that were sometimes profound, severe hypothermia, bradycardia, respiratory depression, dehydration, weight loss, decreased food consumption, blood in the feces, lack of feces, diarrhea, |
| Bone marrow changes suggestive of increased white blood cell demand (increased myeloid:erythroid ratios, most marked at 2X and 3X) | Results showed changes suggestive of an increased demand for white blood cells. |
| Naloxone reversal study (Study 021590, 24 Beagles, 5X = 13 mg/kg overdose): hourly IM naloxone temporarily reversed narcotic effects | Hourly administrations of 0.04 and 0.16 mg/kg IM naloxone were effective at temporarily reversing the narcotic effects of a 5X overdose (13 mg/kg) of a transdermal fentanyl solution applied to the ventral abdomen of dogs. |
Effectiveness
Active-controlled (oxymorphone hydrochloride SC before surgery, at extubation and every 6 h through 90 h), double-masked, multi-center non-inferiority field study in 251 client-owned dogs (124 fentanyl, 127 oxymorphone) undergoing cruciate repair surgery (ARDG01-C-01); a parallel soft tissue surgery study (ARDG01-C-02) enrolled another 251 dogs (125 fentanyl, 126 oxymorphone); primary endpoint: Dropout (treatment failure) rate due to lack of pain control (modified Glasgow Composite Pain Scale score of 8 or more) or opioid reversal with naloxone; non-inferiority if one-sided upper 95% bound of the RECUVYRA minus oxymorphone difference was below 15%; result: Orthopedic study: dropout 1.61% RECUVYRA vs 5.56% oxymorphone, upper bound -1.0%, non-inferior. Soft tissue study: dropout 1.60% vs 8.00%, upper bound -3.1%, non-inferior. Sedation score means were lower with RECUVYRA at all time points
The dropout rate in the RECUVYRA treatment group was 1.61%, and the dropout rate in the oxymorphone treatment group was 5.56%. The one-sided upper 95% confidence bound was -1.0%, which is less than 15%. Therefore, based on dropout rate, RECUVYRA is non-inferior to oxymorphone.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Any adverse reaction (orthopedic field study) | 13 (10.5%) | 32 (25.2%) | Adverse reactions were reported in 13 RECUVYRA-treated dogs (10.5%) and 32 oxymorphone-treated dogs (25.2%). |
| Emesis (orthopedic study, Table 4a; columns fentanyl n, %, oxymorphone n, %) | 5 (4.0%) | 18 (14.2%) | Emesis 5 4.0 18 14.2 |
| Hypothermia (orthopedic study, Table 4a) | 1 (0.8%) | 12 (9.4%) | Hypothermia 1 0.8 12 9.4 |
| Bradycardia (orthopedic study, Table 4a) | 1 (0.8%) | 6 (4.7%) | Bradycardia 1 0.8 6 4.7 |
| Diarrhea (orthopedic study, Table 4a) | 0 (0.0%) | 5 (3.9%) | Diarrhea 0 0.0 5 3.9 |
| Any adverse reaction (soft tissue field study) | 31 (24.8%) | 52 (41.3%) | Adverse reactions were reported in 31 RECUVYRA -treated dogs (24.8%) and 52 oxymorphone-treated dogs (41.3%). |
Extraction notes: Original approval (2012). The summary has no dedicated PK section; dog plasma data are descriptive only (no Cmax/AUC/half-life values in dogs), so the two numeric Cmax/Tmax entries are HUMAN volunteer data from the user-safety section and are flagged as such in conditions; the 23.3 h 'half-life' is the decline of fentanyl transferable to a glove from treated dogs, not a plasma half-life. Target animal safety quotes the margin-of-safety study (32 mongrel dogs, 0/1X/2X/3X every 4 days x3, ventral abdomen); a 16-week repeat-dose study (PRO01-C-01) and two field safety studies are also in the section but not extracted. Effectiveness: two active-controlled field studies of 251 dogs each; n_dogs is null because the quoted result sentence does not contain the enrolment number (251 appears in a separate sentence). Adverse-reaction table rows (Table 4a orthopedic study, N=124 fentanyl vs N=127 oxymorphone) are quoted as flattened rows with column order given in term.
Reproduce: foi_structured_search(query="Fentanyl") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).