Bupivacaine: what the FDA reviewed for dog products
2 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Bupivacaine, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Cats; Dog.
Products
- Nocita™ (NADA/ANADA 141-461)
Nocita™ NADA 141-461, Supplemental approval, August 03, 2018; sponsor Elanco US Inc.; species: Cats; foi_id 3952; FDA PDF
Indication
Use as a peripheral nerve block to provide regional postoperative analgesia following onychectomy in cats.
Dose regimen
5.3 mg/kg per forelimb (0.4 mL/kg per forelimb; total 10.6 mg/kg per cat), Perineural; 4-point nerve block, once, prior to surgery, Administration prior to onychectomy may provide up to 72 hours of pain control
NOCITA® is for administration only once prior to surgery. Administer 5.3 mg/kg per forelimb (0.4 mL/kg per forelimb, for a total dose of 10.6 mg/kg per cat) as a 4-point nerve block prior to onychectomy. Administration prior to surgery may provide up to 72 hours of pain control.
Target-animal safety
dose multiples 0X (saline), bupivacaine HCl 5.3 mg/kg (active control), 2X, 4X, 6X; duration Single femoral nerve block injection every 9 days for 3 doses (Days 0, 9, 18); necropsy Day 21; animals Forty (20 males, 20 females).
Objective: To evaluate the safety of NOCITA®. The maximum labeled dose is 5.3 mg/kg for each forelimb. The study design resulted in administration of 10.6 mg/kg, 21.2 mg/kg, and 31.8 mg/kg NOCITA® per cat as a single injection for a femoral nerve block (which corresponds to 2X, 4X, and 6X the labeled dose per forelimb.) Study Animals: Forty domestic short-haired cats (20 males, 20 females), approximately 5 months old, with a bodyweight range of 2.00 – 3.75 kg, determined as healthy based on physical examination, clinical pathology, electrocardiogram, and fecal parasitology.
| Finding | Quote |
|---|---|
| Right hindlimb impairment in 23 of 24 NOCITA cats, persisting 1-5 days (2 negative-control cats for 1 day; none in active control). | Clinical observations and examinations: Right hindlimb impairment occurred in 23 of the 24 NOCITA® treated cats which persisted for 1-5 days; 2 negative control cats which persisted for 1 day; and none of the active control cats. |
| One female in the 31.8 mg/kg (6X) group euthanized on Day 15 for a progressive open necrotic self-trauma wound near the right stifle. | The other cat, a female in the 31.8 mg/kg group, was euthanized on Day 15 due to progression and discomfort associated with an open and necrotic wound near the right stifle. |
| One active-control (bupivacaine HCl) male died during anesthetic recovery after the second dose; cause undetermined. | One active control male died after the second dose was administered. This cat died during recovery from anesthesia despite resuscitation efforts. The definitive cause of death was not determined. |
| Subacute/chronic inflammation at the femoral nerve and at the injection site (inflammation, mineralization, myofiber degeneration, necrosis in skin/subcutis/muscle). | Histopathology: Treatment-related microscopic findings at the femoral nerve were subacute or chronic inflammation. Treatment-related microscopic findings at the injection site were subacute or chronic inflammation, mineralization, myofiber degeneration, and necrosis at the skin, subcutis, or muscle. |
| Table III.2a femoral nerve inflammation (columns: negative control, active control, NOCITA 10.6, 21.2, 31.8 mg/kg; N=8 each): 1 (12.5%), 0 (0%), 7 (87.5%), 8 (100%), 8 (100%). | Axonal degeneration 1 (12.5%) 1 (12.5%) 1 (12.5%) 1 (12.5%) 0 (0%) Inflammation 1 (12.5%) 0 (0%) 7 (87.5%) 8 (100%) 8 (100%) |
| No clinically relevant hematology, serum chemistry, urinalysis, ECG, body weight or organ weight findings; three cats (one each in active control, 10.6 and 21.2 mg/kg) had decreased platelets at termination. | Clinical Pathology: There were no clinically relevant findings for hematology, serum chemistry, and urinalysis variables in any of the treatment groups. One cat in the bupivacaine active control group, one cat in the 10.6 mg/kg group and one cat in the 21.2 mg/kg group had normal platelet counts prior to study start but decreased platelets at study termination (52,000, 83,000 and 50,000 platelets respectively, normal range 106,000-721,000/µL). |
| No systemic toxicity at 10.6, 21.2 and 31.8 mg/kg; acceptable margin of safety. | Conclusion: NOCITA® administered as an injection for femoral nerve block, every 9 days for 3 doses, at 10.6, 21.2, and 31.8 mg/kg did not produce systemic toxicity and had an acceptable margin of safety. |
Effectiveness
Pivotal study AT003-FCL-008: multicenter (8 sites), prospective, randomized, masked, placebo-controlled field study in cats undergoing bilateral forelimb onychectomy; NOCITA 5.3 mg/kg per forelimb (120 cats) vs saline 0.4 mL/kg per forelimb (121 cats) as a 4-point nerve block before surgery; all cats received a pre-operative short-acting opioid; pain scored with a modified UNESP-Botucatu composite scale to 72 h, rescue if score >=6; per-protocol analysis.; n = 236 cats per protocol (117 NOCITA, 119 saline); primary endpoint: Percent treatment successes (no rescue analgesia) over 0-24 hours post-surgery; secondary 0-48 h and 0-72 h tested hierarchically; result: 0-24 h success 88/117 (75.2%) NOCITA vs 48/119 (40.3%) saline, p=0.0252; 0-48 h 79/115 (68.7%) vs 41/118 (34.7%), p=0.0395; 0-72 h 78/114 (68.4%) vs 42/119 (35.3%), p=0.0452.
Effectiveness: Effectiveness was evaluated in 236 cats that underwent onychectomy (117 cats in the NOCITA® group and 119 in the saline group). The observed success rates for the 0-24 hour interval are summarized in Table II.3 below. Table II.3. Number of Cats and Percent Effectiveness for NOCITA® and Saline at the 0-24 Hour Time Interval Time Interval for Pain Assessment NOCITA® (n=117) Saline (n=119) 0-24 hours 88 (75.2%) 48 (40.3%) The difference in success rates for the 0-24 hour interval is significant at p=0.0252.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Elevated body temperature (>=103 F on Day 3, normal before surgery) | 8 (6.7%) | 5 (4.1%) | Elevated body temperature* 8 (6.7%) 5 (4.1%) |
| Surgical site infection | 4 (3.3%) | 1 (0.8%) | Surgical site infection 4 (3.3%) 1 (0.8%) |
| Chewing/licking of surgical site | 3 (2.5%) | 2 (1.7%) | Chewing/licking of surgical site 3 (2.5%) 2 (1.7%) |
| Diarrhea | 2 (1.7%) | 1 (0.8%) | Diarrhea 2 (1.7%) 1 (0.8%) |
| Injection site erythema | 1 (0.8%) | 0 (0.0%) | Injection site erythema 1 (0.8%) 0 (0.0%) |
| Swelling of paw; erythematous digits | 1 (0.8%) | 0 (0.0%) | Swelling of paw; erythematous digits 1 (0.8%) 0 (0.0%) |
Extraction notes: Supplemental NADA held under a dog application but this summary is for CATS (species recorded as stated). The 'n_dogs' field holds the cat count. Adverse reactions from Table II.5 (safety population NOCITA n=120, saline n=121; column order NOCITA n (%), saline n (%)). Target animal safety: GLP multi-dose femoral nerve block study 2175-007, 8 cats per group (4 male, 4 female); dose multiples 2X/4X/6X are per-cat totals of 10.6/21.2/31.8 mg/kg relative to the 5.3 mg/kg per-forelimb label dose. Four NOCITA and four saline cats in the field study had platelet counts below reference range on Day 3 without clinical signs. No pharmacokinetic data in this summary. A pilot field study (62 cats) supported dose selection.
Nocita™ NADA 141-461, Original approval, August 12, 2016; sponsor Elanco US Inc.; species: Dog; foi_id 947; FDA PDF
Indication
Single-dose infiltration into the surgical site to produce local postoperative analgesia for cranial cruciate ligament surgery in dogs.
Dose regimen
5.3 mg/kg (0.4 mL/kg), Infiltration injection into the tissue layers at the time of incisional closure, single dose only, A single dose administered during surgical closure may provide up to 72 hours of pain control
NOCITA is for single dose administration only. A dose of 5.3 mg/kg (0.4 mL/kg) is administered by infiltration injection into the tissue layers at the time of incisional closure. A single dose administered during surgical closure may provide up to 72 hours of pain control.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| half-life | 16.9 ± 6.05 hour | Bupivacaine HCl 9 mg/kg SC, Day 1 (toxicokinetics in the 4-week SC toxicity study). Table 9 row as flattened by PDF extraction; column order: dosing day, treatment, bupivacaine dose (mg/kg, bupivacaine HCl equivalent), AUC0-tlast ± SD (hour·ng/mL), AUC0-tlast/Dose ± SD, Cmax ± SD (ng/mL), Cmax/Dose ± SD, t1/2 ± SD (hour), tmax ± SD (hour). Subcutaneous injection, 3 dogs/sex/group (recovery subgroup). | 1 Bupiv. HCl 9 9,720 ± 1,860 1,080 ± 207 1,420 ± 355 158 ± 39.5 16.9 ± 6.05 0.5 ± 0.0 |
| cmax | 1,420 ± 355 ng/mL | Bupivacaine HCl 9 mg/kg SC, Day 1. Table 9 row as flattened by PDF extraction; column order: dosing day, treatment, bupivacaine dose (mg/kg, bupivacaine HCl equivalent), AUC0-tlast ± SD (hour·ng/mL), AUC0-tlast/Dose ± SD, Cmax ± SD (ng/mL), Cmax/Dose ± SD, t1/2 ± SD (hour), tmax ± SD (hour). Subcutaneous injection, 3 dogs/sex/group (recovery subgroup). | 1 Bupiv. HCl 9 9,720 ± 1,860 1,080 ± 207 1,420 ± 355 158 ± 39.5 16.9 ± 6.05 0.5 ± 0.0 |
| half-life | 59.5 ± 49.1 hour | NOCITA 9 mg/kg bupivacaine HCl equivalent (1.5X) SC, Day 1. Table 9 row as flattened by PDF extraction; column order: dosing day, treatment, bupivacaine dose (mg/kg, bupivacaine HCl equivalent), AUC0-tlast ± SD (hour·ng/mL), AUC0-tlast/Dose ± SD, Cmax ± SD (ng/mL), Cmax/Dose ± SD, t1/2 ± SD (hour), tmax ± SD (hour). Subcutaneous injection, 3 dogs/sex/group (recovery subgroup). | 1 NOCITAb 9 9,100 ± 4,460 1,010 ± 495 488 ± 335 54.2 ± 37.2 59.5 ± 49.1 |
| cmax | 488 ± 335 ng/mL | NOCITA 9 mg/kg bupivacaine HCl equivalent (1.5X) SC, Day 1. Table 9 row as flattened by PDF extraction; column order: dosing day, treatment, bupivacaine dose (mg/kg, bupivacaine HCl equivalent), AUC0-tlast ± SD (hour·ng/mL), AUC0-tlast/Dose ± SD, Cmax ± SD (ng/mL), Cmax/Dose ± SD, t1/2 ± SD (hour), tmax ± SD (hour). Subcutaneous injection, 3 dogs/sex/group (recovery subgroup). | 1 NOCITAb 9 9,100 ± 4,460 1,010 ± 495 488 ± 335 54.2 ± 37.2 59.5 ± 49.1 |
| auc | 9,100 ± 4,460 hour·ng/mL | AUC0-tlast. NOCITA 9 mg/kg bupivacaine HCl equivalent (1.5X) SC, Day 1. Table 9 row as flattened by PDF extraction; column order: dosing day, treatment, bupivacaine dose (mg/kg, bupivacaine HCl equivalent), AUC0-tlast ± SD (hour·ng/mL), AUC0-tlast/Dose ± SD, Cmax ± SD (ng/mL), Cmax/Dose ± SD, t1/2 ± SD (hour), tmax ± SD (hour). Subcutaneous injection, 3 dogs/sex/group (recovery subgroup). | 1 NOCITAb 9 9,100 ± 4,460 1,010 ± 495 488 ± 335 54.2 ± 37.2 59.5 ± 49.1 |
| tmax | 0.5 hr | NOCITA 9 and 18 mg/kg SC (first sampling time point) | The time to reach maximum concentration was rapid and occurred at the first time point (0.5 hr) for the 9 and 18 mg/kg doses. |
| tmax | 48.1 hours (Day 1) and 12.8 hours (Day 25) | NOCITA 30 mg/kg SC | For the 30 mg/kg dose group, the Tmax occurred at 48.1 and 12.8 hours on Day 1 and Day 25, respectively. |
| other | AUC0-t ratio Day 25 vs Day 1 of approximately 2 (accumulation) | NOCITA repeated SC dosing twice weekly, across 9, 18 and 30 mg/kg | The repeated dose of NOCITA resulted in moderate accumulation with AUC0-t ratio on Day 25 versus Day 1 of approximately 2 across the dose levels. |
Target-animal safety
dose multiples 0X (saline), bupivacaine HCl 9 mg/kg (active control), 1.5X, 3X, 5X; duration Subcutaneous injection twice weekly for 4 weeks (8 doses), followed by a 4-week recovery period in half the dogs; animals Sixty (30 males, 30 females).
Study Animals: Sixty Beagle dogs (30 males, 30 females), aged 5-6 months old at receipt, determined as healthy based on physical examination, clinical pathology, and fecal parasitology. Treatment Groups and Drug Administration: Dogs were randomized to saline (0.9% sodium chloride, USP), bupivacaine HCl, or NOCITA (bupivacaine liposome injectable suspension).
| Finding | Quote |
|---|---|
| No clinically relevant clinical, ECG, body weight, food consumption, clinical pathology or organ weight findings versus saline. | Clinical Observations and Examinations: There were no clinically relevant findings in the NOCITA and bupivacaine HCl groups compared to the saline group. |
| Swollen or thickened injection sites (granulomatous inflammation and/or edema) in one male and one female of the 30 mg/kg (5X) terminal group. | Swollen or thickened injection sites were noted in one male and one female dog in the NOCITA 30 mg/kg terminal group. |
| Minimal to moderate granulomatous inflammation in subcutaneous tissue at injection sites in all NOCITA groups (terminal and recovery dogs). | Minimal to moderate granulomatous inflammation was observed in the subcutaneous tissue of male and female terminal and recovery dogs receiving NOCITA. |
| Granulomatous inflammation not seen with saline or bupivacaine HCl; considered a tissue response to liposomes. | Subcutaneous granulomatous inflammation was not observed in terminal or recovery dogs receiving saline or bupivacaine HCl. |
| Table 7 (terminal group, Injection Site 1; columns NOCITA 9, 18, 30 mg/kg, n=6 each): edema 1/6, 2/6, N/A; granulomatous inflammation 3/6, 4/6, 3/6; mineralization 1/6, 3/6, 1/6. | Injection Site 1 Edema 1/6 2/6 N/A Granulomatous Inflammation 3/6 4/6 3/6 Mineralization 1/6 3/6 1/6 |
| No systemic toxicity at 9, 18 and 30 mg/kg twice weekly for 4 weeks; high margin of safety. | Conclusions: NOCITA administered as a subcutaneous injection, twice-weekly for 4 weeks, at 9, 18, and 30 mg/kg (bupivacaine base equivalent of 5.3, 16, and 26.6 mg/kg) did not produce systemic toxicity and had a high margin of safety. |
Effectiveness
Pivotal study AT003-CCL-14-003: multicenter (5 sites), prospective, randomized, masked, placebo-controlled field study; NOCITA 5.3 mg/kg (0.4 mL/kg, diluted up to 1:1 with saline as needed) vs saline 0.4 mL/kg infiltrated into tissue layers at closure after CCL stabilization surgery (extra-capsular repair, TPLO, TTA); 123 NOCITA / 59 placebo dogs enrolled; per-protocol analysis; CMPS-SF pain assessments to 72 h, rescue if score >=6.; n = 164 per protocol (112 NOCITA, 52 placebo); primary endpoint: Percent treatment successes (no rescue pain intervention) over 0-24 hours post-surgery; secondary 24-48 h and 48-72 h intervals tested hierarchically; result: 0-24 h success 77/112 (68.8%) NOCITA vs 19/52 (36.5%) placebo; model-estimated 68.3% vs 36.1%, P=0.0322. 24-48 h: 64.3% vs 34.6% (P=0.0402); 48-72 h: 61.6% vs 32.7% (P=0.0432). Treatment failures were carried forward.
Effectiveness: Effectiveness was evaluated in 164 dogs that underwent CCL surgery (112 dogs in the NOCITA group and 52 in the placebo group). Treatment success was defined for each dog as no pain intervention over the interval of 0-24 hours post-surgery. The observed success rates for the 0-24 hour interval are summarized in Table 3 below. Table 3. Number and Percent Effectiveness for NOCITA and Placebo at the 0-24 Hour Time Interval Time Interval for Pain Assessment NOCITA (n=112) Placebo (n=52) 0-24 hours 77 (68.8%) 19 (36.5%) Based on the statistical model, the estimated success rates are 68.3% and 36.1% for the NOCITA group and the placebo group, respectively. The difference in success rates is significant at P=0.0322.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Discharge from the incision | 4 (3.3%) | 0 (0.0%) | Discharge from the Incision 4 (3.3%) 0 (0.0%) |
| Incisional inflammation (erythema and/or edema) | 3 (2.4%) | 0 (0.0%) | Incisional Inflammation (erythema and/or edema) 3 (2.4%) 0 (0.0%) |
| Vomiting | 3 (2.4%) | 0 (0.0%) | Vomiting 3 (2.4%) 0 (0.0%) |
| Abnormalities on urinalysis (isosthenuria ± proteinuria) | 2 (1.6%) | 0 (0.0%) | Abnormalities on Urinalysis (isosthenuria ± proteinuria) 2 (1.6%) 0 (0.0%) |
| Increased ALP | 2 (1.6%) | 0 (0.0%) | Increased ALP 2 (1.6%) 0 (0.0%) |
| Surgical limb edema ± erythema | 1 (0.8%) | 3 (5.1%) | Surgical Limb Edema ±Erythema 1 (0.8%) 3 (5.1%) |
Extraction notes: Original NADA. Adverse reactions are from Table 5 (safety population: NOCITA N=123, placebo N=59; column order NOCITA n (%), placebo n (%)). PK values are toxicokinetic data from the GLP 4-week subcutaneous toxicity study (Table 9, flattened by PDF extraction; NOCITA doses expressed as bupivacaine HCl equivalents, where 5.3 mg/kg bupivacaine base = 6 mg/kg HCl); no PK were reported at the labeled infiltration route. Target animal safety design_quote combines the Study Animals and Treatment Groups sentences; dose multiples 1.5X/3X/5X correspond to 9/18/30 mg/kg HCl-equivalent (Table 6). Half-life for the 30 mg/kg groups was not calculable in several dogs. A pilot field study (46 dogs) supported dose selection.
Reproduce: foi_structured_search(query="Bupivacaine") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).