bupivacaine

For single-dose infiltration into the surgical site to provide local postoperative analgesia for cranial cruciate ligament surgery in dogs.

Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Nocita™

For use as a peripheral nerve block to provide regional postoperative analgesia following onychectomy in cats.

Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Nocita™

For single-dose infiltration into the surgical site to provide local postoperative analgesia for cranial cruciate ligament surgery in dogs.

FDA application 141-461

For use as a peripheral nerve block to provide regional postoperative analgesia following onychectomy in cats.

FDA application 141-461

Bupivacaine is an amide, non-opioid local anesthetic. It provides local analgesia by deactivating sodium channels on the nerve membrane, preventing the generation and propagation of nerve impulses. It is only present in small concentrations as uncharged molecules at tissue pH as it is a base with pKa of 8. This un-ionized form provides a lipophilicity that permits the drug to traverse across the nerve cell membrane and upon entering the cell, binds to the intracellular portion of voltage-gated sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. Without depolarization, no initiation or conduction of a pain signal can occur.

FDA application 141-461

Do not administer by intravenous or intra-arterial injection. If accidental intravascular administration occurs, monitor for cardiovascular (dysrhythmias, hypotension, hypertension) and neurologic (tremors, ataxia, seizures) adverse reactions. Do not use for intra-articular injection. In humans, local anesthetics administered into a joint may cause chondrolysis.

FDA application 141-461

Not for use in humans. Keep out of reach of children. NOCITA is an amide local anesthetic. In case of accidental injection or accidental topical exposure, contact a physician and seek medical attention immediately. Wear gloves when handling vials to prevent accidental topical exposure.

FDA application 141-461

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). Table C-2: Adverse Reactions Reported During the Study in the Safety Population (any cat that received treatment) 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. Adverse Reaction NOCITA (n = 120) Saline (n = 121) Elevated body temperature* 8 (6.7%) 5 (4.1%) Surgical site infection 4 (3.3%) 1 (0.8%) Chewing/licking of surgical site 3 (2.5%) 2 (1.7%) Diarrhea 2 (1.7%) 1 (0.8%) Injection site erythema 1 (0.8%) 0 (0.0%) Swelling of paw; erythematous digits 1 (0.8%) 0 (0.0%) 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.

FDA application 141-461

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). Table D-1. Adverse Reactions Reported During the Study in the Safety Population (any dog that received treatment) Note: If an animal experienced the same event more than once, only the first occurrence was tabulated. Adverse Reaction NOCITA (n = 123) Saline (n = 59) Discharge from the Incision 4 (3.3%) 0 (0.0%) Incisional Inflammation (erythema and/or edema) 3 (2.4%) 0 (0.0%) Vomiting 3 (2.4%) 0 (0.0%) Abnormalities on Urinalysis (isosthenuria ± proteinuria) 2 (1.6%) 0 (0.0%) Increased ALP 2 (1.6%) 0 (0.0%) Surgical Limb Edema ± Erythema 1 (0.8%) 3 (5.1%) Soft Stool/Diarrhea 1 (0.8%) 1 (1.7%) Inappetence 1 (0.8%) 1 (1.7%) Fever 1 (0.8%) 0 (0.0%)

FDA application 141-461

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.

Perineural, Infiltration

Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Nocita™

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.

Perineural, Infiltration

Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Nocita™

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/cat) as a 4-point nerve block (described below) prior to onychectomy. Administration prior to surgery may provide up to 72 hours of pain control. Prepare Dose(s): • Wear gloves when handling and administering NOCITA (see WARNINGS ). •NOCITA should not be allowed to come into contact with topical antiseptics. When a topical antiseptic such as povidone iodine or chlorhexidine is applied, the area should be allowed to dry before NOCITA is administered. • Do not shake vial. Invert the vial multiple times to re-suspend the particles immediately prior to withdrawal of the product from the vial. • Do not puncture the vial multiple times. Puncture the vial stopper once with a single 25 gauge or larger needle. Use aseptic technique to sequentially attach and fill sterile syringes. Each syringe should be prepared for single patient use only. Discard the vial after all doses are withdrawn. •Following withdrawal from the vial into a syringe, NOCITA may be stored at controlled room temperature of 68° F to 77° F (20° C to 25° C) for up to 4 hours. Because the formulation does not contain preservative, the syringe(s) must be discarded after 4 hours. •Do not dilute NOCITA prior to use as a nerve block in cats. Do not mix with water or other hypotonic solutions as it will result in disruption of the liposomal particles (see CLINICAL PHARMACOLOGY ). Do not mix NOCITA with other local anesthetics or other drugs prior to administration (see PRECAUTIONS ). •Use a 25 gauge or larger bore needle for administration. Dose Administration: •Aspirate prior to injecting to prevent intravascular administration (see CONTRAINDICATIONS ). Table C-1. Dose Administration for One Forelimb.1 Legend Abbreviations Needle insertion point Needle withdrawal + drug injection SpU - Styloid process of the ulna Needle advancement Drug injection point Needle redirection to a 90˚ angle to the palmar plane ACb - Accessory carpal bone Dose Volume per Injection (% of total 0.4 mL/kg/forelimb volume) and Description A. 0.14 mL/kg (35%) Superficial Branch of the Radial Nerve: At the center of the limb, on the dorsal aspect at the level of the antebrachiocarpal joint, insert the needle subcutaneously with the bevel up (•). Advance the needle subcutaneously as depicted by the dotted line and arrow and inject (ο) adjacent to the confluence of the accessory cephalic and cephalic veins. Dorsal B. 0.08 mL/kg (20%) Dorsal Branch of the Ulnar Nerve: Palpate a groove between the accessory carpal bone (ACb, in the base of the carpal pad) and the styloid process of the ulna (SpU). Distal to this groove, insert the needle subcutaneously with the bevel up and advance the needle proximally. Inject once the tip reaches the midpoint of the groove. Lateral C. 0.16 mL/kg (40%) Median Nerve and Superficial Branch of the Palmar Branch of the Ulnar Nerve: Insert the needle subcutaneously with the bevel up lateral to the distal tip of the accessory carpal pad and advance the needle medially 2/3 the width of the limb, until the tip is located near the base of the first digit. Inject 2/3 of the volume at this point and the remaining volume while withdrawing the needle (solid grey arrow). Gently massage for 5 seconds. Palmar D. 0.02 mL/kg (5%) Deep Branch of the Palmar Branch of the Ulnar Nerve: Orient the needle perpendicular to the long axis of the limb at the level of the ACb. Insert the needle subcutaneously and advance the needle laterally until it contacts the medial aspect of the ACb. Redirect the needle dorsally by rotating the needle 90°, advance it along the medial side of the ACb 2-3 mm until it penetrates the flexor retinaculum, and inject. Palmar

SUBCUTANEOUS

FDA application 141-461

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. Dosing Instructions: • Wear gloves when handling and administering NOCITA (see WARNINGS ). •NOCITA should not be allowed to come into contact with topical antiseptics. When a topical antiseptic such as povidone iodine or chlorhexidine is applied, the area should be allowed to dry before NOCITA is administered into the surgical site. • Do not shake vial. Invert the vial multiple times to re-suspend the particles immediately prior to withdrawal of the product from the vial. • Do not puncture the vial multiple times. Puncture the vial stopper once with a single 25 gauge or larger needle. Use aseptic technique to sequentially attach and fill sterile syringes for dosing. Each syringe should be prepared for single patient use only. Discard the vial after all doses are withdrawn. •Following withdrawal from the vial into a syringe, NOCITA may be stored at controlled room temperature of 68° F to 77° F (20° C to 25° C) for up to 4 hours. Because the formulation does not contain preservative, the syringe(s) must be discarded after 4 hours. •If the dose volume of NOCITA (0.4 mL/kg) is not sufficient to cover the surgical site, add up to an equal volume of normal (0.9%) sterile saline or Lactated Ringer’s solution. If saline or Lactated Ringer’s is added to the NOCITA dose, administer the entire volume by tissue infiltration into the surgical site. Do not mix with water or other hypotonic solutions as it will result in disruption of the liposomal particles (see CLINICAL PHARMACOLOGY ). Do not mix NOCITA with other local anesthetics or other drugs prior to administration (see PRECAUTIONS ). •Use a 25 gauge or larger bore needle for administration. •Administer by infiltration injection: Inject slowly into the tissues using an infiltration injection technique. To obtain adequate coverage, infiltrate all of the tissues in each surgical closure layer. Aspirate frequently to prevent intravascular administration (see CONTRAINDICATIONS ).

SUBCUTANEOUS

FDA application 141-461