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Click below to see more information about NOCITA safety and efficacy studies.

NOCITA SAFETY STUDIES

NOCITA – Extended-Release Bupivacaine Safety

Local anesthetic toxicities affect the neurologic 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. Bupivacaine liposome injectable suspension has been studied in dog models as part of the development for human use.

Dose-Finding and Expanded Studies

In a study to determine the maximum tolerated doses after intravascular administration of bupivacaine liposome injectable suspension vs bupivacaine HCl, maximum doses at which no meaningful adverse events were observed were higher with bupivacaine liposome injectable suspension than with bupivacaine HCl after both intravenous and intra-arterial administration (Table 4).26 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.26

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Local Toxicity Studies

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

Study of Effects on Wound Healing

In a study evaluating bupivacaine liposome injectable suspension in a dog model of inguinal hernia repair, dogs given 9, 18, or 25 mg/kg bupivacaine liposome injectable suspension 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 bupivacaine liposome injectable suspension at doses higher than expected with clinical use.24

Repeat-Dose Local Toxicity Study

In a 4-week laboratory repeat-dose toxicity study, 60 healthy dogs aged 5 to 6 months were given bupivacaine liposome injectable suspension 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 for NOCITA).28 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.28

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 histopathology included minimal to moderate edema, granulomatous inflammation, and mineralization in the subcutaneous tissues in some dogs that received bupivacaine liposome injectable suspension.28

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

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 EFFICACY STUDY

NOCITA Efficacy Study

Clinical Effectiveness Study 30

The effectiveness of NOCITA in providing prolonged post-operative analgesia was evaluated in a multicenter, placebo-controlled, randomized, masked field study in client-owned dogs undergoing CCL stabilization surgery.

Study Design

In this study, 182 dogs were enrolled and randomized to treatment with NOCITA at a dose of up to 5.3 mg/kg (n = 123) or placebo (sterile saline, n = 59). The per-protocol population included 112 dogs treated with NOCITA and 52 dogs that received placebo. Dogs received an opioid analgesic just prior to general anesthesia and surgery. Surgical technique was at the discretion of the surgeon, and included extracapsular repair, tibial plateau–leveling osteotomy (TPLO), or tibial tuberosity advancement (TTA). Table 5 shows the number and percentage of surgical procedures by treatment group.

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Using a moving-needle infiltration injection technique, a single dose of NOCITA or placebo was infiltrated into the tissue layers during surgical closure. NOCITA or placebo was administered undiluted or diluted up to 2-fold (1:1) with sterile saline. Pain was assessed by trained observers using the short form composite measure pain score (CMPS-SF) for up to 72 hours following surgical closure. Pain assessments were conducted prior to surgery and at 0.5, 1, 2, 4, 8, 12, 24, 30, 36, 48, 56, and 72 hours after surgery. Dogs with a CMPS-SF score ≥ 6 or that were determined to be in pain by the investigator received rescue analgesic medication and were classified as treatment failures. No further CMPS-SF pain assessments were recorded for dogs that received rescue analgesia medication. The primary variable for effectiveness was evaluated over the first 24-hour time interval.

Dosing and Administration Video

Results

The percentage of treatment success for NOCITA was statistically significantly greater than placebo at the first 24-hour time interval (P = 0.0322). The 24-to-48-hour and 48-to-72-hour time intervals were evaluated as secondary variables and support effective use of NOCITA for up to 72 hours of analgesia (Table 6).

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Conclusions

The results of this study demonstrated that NOCITA administered at a dose of up to 5.3 mg/kg, provided effective post-operative analgesia for up to 72 hours following CCL surgery in dogs.

30. NOCITA Freedom of Information Summary, NADA 141-461