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Click below to see more information about NOCITA® (bupivacaine liposome injectable suspension) safety studies.

NOCITA SAFETY STUDIES IN DOGS

NOCITA – Safety in Dogs

Local anesthetic toxicities affect the neurological or cardiovascular systems, manifest from high plasma levels of the local anesthetic, and commonly are a result of the accidental intravascular injection of the drug or the administration of an overdose. Extended-release bupivacaine has been studied in dog models as part of the development for human use.

Pilot Dose-Finding and Expanded Studies in Dogs26

In a pilot study to determine the maximum tolerated doses after intravascular administration of bupivacaine liposome injectable suspension (liposome bupivacaine) vs bupivacaine HCl, maximum doses at which no meaningful adverse events were observed were higher with liposome bupivacaine than with bupivacaine HCl after both intravenous and intra-arterial administration (Table 5). In a subsequent expanded study of systemic adverse effects and pharmacokinetics following intravascular administration of liposome bupivacaine at 9.0 mg/kg intravenous and 4.5 mg/kg intra-arterial, there were no observed changes in pathology and no mortality; adverse clinical signs included convulsions, lying on side, and decreased muscle tone, all of which were transient.

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Local Toxicity Studies in Dogs

Additional studies have centered on the local safety and tolerability of liposome bupivacaine following tissue infiltration.

Study of Effects on Wound Healing 24

In a study evaluating liposome bupivacaine in a dog model of inguinal hernia repair, dogs given 9, 18, or 25 mg/kg liposome bupivacaine experienced similar incidence and severity of histological changes at day 15 compared with controls who received bupivacaine HCl or saline, and there were no observed differences in local toxicity or delays in wound healing between the study groups. The authors concluded that there were no significant adverse effects on wound healing using liposome bupivacaine at higher doses than expected with clinical use.

Target Animal Safety Study 28

In a 4-week laboratory repeat-dose toxicity study, 60 healthy dogs aged 5 to 6 months were administered NOCITA at 8, 16, and 26.6 mg/kg bupivacaine base (corresponding to 1.5, 3, and 5 times the maximum label dose, respectively, of 5.3 mg/kg bupivacaine base). The active control group was administered 9 mg/kg bupivacaine HCl (equivalent to 8 mg/kg bupivacaine base), and the placebo group was administered 1.2 mL/kg saline. All dogs were dosed by subcutaneous injection twice weekly for 4 weeks, for a total of 8 injections. Doses alternated between 2 injection sites to the right or left of dorsal midline near the scapula. There were 6 dogs of each sex per group for the first 4 weeks, and then 3 dogs of each sex per group were maintained and monitored during a treatment-free 4-week recovery period.

All dogs survived the study, and there were no clinically relevant treatment-related effects on clinical observations, physical examination, body weight, electrocardiograms, hematology, serum chemistry, urinalysis, coagulation, or organ weights. Injection-site reactions upon histopathological examination included minimal to moderate edema, granulomatous inflammation, and mineralization in the subcutaneous tissues in some dogs that received NOCITA.

Adverse Reactions 21

Safety was evaluated in 123 NOCITA treated dogs and 59 saline (placebo) treated dogs in a field study in dogs that underwent cranial cruciate ligament stabilization surgery. Dogs enrolled in the study were 1-13 years of age, and weighed 3.4 to 61.3 kg. NOCITA was administered by infiltrative injection at the surgical site at a dose of 5.3 mg/kg (0.4 mL/kg).

Please note charts are best viewed on a larger screen or desktop.

Note: If an animal experienced the same event more than once, only the first occurrence was tabulated.

21. NOCITA® [package insert]. Leawood, KS: Aratana Therapeutics, Inc.; 2018.

24. Richard BM, Ott LR, Haan D, et al. The safety and tolerability evaluation of DepoFoam bupivacaine (bupivacaine extended-release liposome injection) administered by incision wound infiltration in rabbits and dogs. Expert Opin Investig Drugs. 2011;20(10):1327-1341.

26. Joshi GP, Patou G, Kharitonov V. The safety of liposome bupivacaine following various routes of administration in animals. J Pain Res. 2015;8(781):789.

28. Richard BM, Rickert DE, Newton PE. Safety evaluation of EXPAREL (DepoFoam bupivacaine) administered by repeated subcutaneous injection in rabbits and dogs: Species comparison. J Drug Deliv. 2011;2011:467429.

NOCITA SAFETY STUDIES IN CATS

NOCITA – Safety in Cats

Target Animal Safety Study 29

In a 22-day laboratory study, 40 healthy cats (4 cats/sex/group) aged 5 to 6 months were administered NOCITA 10.6, 21.2, or 31.8 mg/kg; active control (bupivacaine HCl 5.3 mg/kg); or negative control (2.37 mL/kg saline) by injection using a suprainguinal approach for a femoral nerve block of the right hindlimb on Days 0, 9, and 18. These NOCITA doses correspond to 1, 2, and 3 times the maximum labeled total dose of 10.6 mg/kg/cat (representing 2, 4, and 6 times the maximum labeled dose of 5.3 mg/kg/forelimb).

Two cats died during the study. One male in the active control group died during recovery from anesthesia after the second dose despite resuscitation efforts, and no definitive cause of death was determined. One female in the NOCITA 31.8 mg/kg group was euthanized on Day 15 due to progression of and discomfort associated with an open and necrotic wound near the right stifle.

This cat developed hindlimb motor impairment, as well as a suppurative, open, necrotic wound over the region of the right stifle after the second dose administration. Pain medication, antibiotics, subcutaneous fluids, and wound care were provided. However, the area with the punctures progressed to discoloration and edema, ultimately resulting in sloughing of the affected area such that the joint capsule was visible. Histopathology findings at the stifle wound included inflammation, ulcer, cavitation, necrosis, and fibrosis. Histopathology findings of inflammation at the injection site and femoral nerve were similar to those in other NOCITA-treated cats.

In the 38 cats that survived the study, there were no clinically relevant treatment-related effects on electrocardiograms, hematology, serum chemistry, urinalysis, coagulation, or organ weights. Right hindlimb impairment was expected because the entire dose was administered as a femoral nerve block. Right hindlimb impairment occurred in 23 of the 24 cats administered NOCITA, which persisted for 1 to 5 days; 2 cats administered negative control, which persisted for 1 day; and none of the cats administered active control. Left hindlimb impairment was observed the day after the first dose in 1 cat administered NOCITA 21.2 mg/kg. NOCITA treatment-related effects were observed on histopathological examination of soft tissue and the femoral nerve at the injection sites. Injection-site histopathology findings in the soft tissue included subacute or chronic inflammation, mineralization, myofiber degeneration, and myofiber necrosis. Injection-site histopathology findings in the femoral nerve included subacute or chronic inflammation.

Among the NOCITA, active control, and negative control groups, sporadic clinical observations included soft or watery or mucoid stool, inguinal swelling on the right hindlimb after only the first dose, and abrasions or scabbing at the right abdominal and inguinal regions as well as on the right hindlimb and at the right stifle; histopathology findings at or near the injection site or right stifle included ulceration and suppurative crusts on the skin; and histopathology findings at the injection site included subcutaneous foreign material and fibrosis, and myofiber regeneration.

Adverse Reactions 21

Safety was evaluated in 120 NOCITA treated cats and 121 saline (placebo) treated cats in a field study in cats undergoing onychectomy. Cats enrolled in the study were 5 months to 10 years of age, and weighed 2.0 to 9.3 kg. NOCITA was administered as a 4-point peripheral nerve block at a dose of 5.3 mg/kg per forelimb (0.4 mL/kg per forelimb).

Please note charts are best viewed on a larger screen or desktop.

Note: If an animal experienced the same event more than once, only the first occurrence was tabulated.

*Elevated body temperature was defined as temperature ≥ 103° F on Day 3 and normal before surgery. One of the NOCITA treated cats had an infection of one surgical site. No other cat with elevated body temperature showed evidence of infection or illness.

Eight cats, 4 in each group, had normal platelet counts before treatment on Day 0 and platelet counts below the reference range (155,000-641,000/μL) on Day 3. The 4 cats treated with NOCITA had platelet counts of 42,000 to 100,000/μL, and the 4 cats in the saline group had platelet counts of 114,000 to 149,000/μL. Decreased platelet counts were not associated with clinical signs.

In a pilot study with 62 cats undergoing onychectomy (31 cats treated with NOCITA and 31 with saline), one NOCITA treated cat had a motor deficit (unilateral knuckling) which resolved by the next morning following surgery. Another NOCITA treated cat had bruising at the injection sites.

21. NOCITA® [package insert]. Leawood, KS: Aratana Therapeutics, Inc.; 2018.

29. NOCITA Freedom on Information Summary, Supplemental NADA 141-461, 03 AUG 2018.

The aforementioned studies were all performed in healthy dogs and cats. Patient factors, such as cardiac, renal, or hepatic disease, may increase the incidence of adverse events. No known long-term safety issues  associated with liposome bupivacaine have been identified to date.