Buprenorphine

For the control of postoperative pain associated with surgical procedures in cats.

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

Simbadol®

Ethiqa XR is indicated for the control of post-procedural pain in captive rodents, ferrets, laboratory rabbits, and non-human primates.

Ethiqa XR® (buprenorphine extended-release injectable suspension)

SIMBADOL is indicated for the control of postoperative pain associated with surgical procedures in cats.

Simbadol®

Buprenorphine is a potent, long-acting analgesic acting at opiate receptors in the central nervous system. Buprenorphine exerts its analgesic effect via high affinity binding to various subclasses of opiate receptors, particularly μ, in the central nervous system.1 Buprenorphine binds to opiate receptors with high affinity and high receptor avidity, such that its disassociation from the receptor is slow, as demonstrated in in vitro studies. This unique property of buprenorphine could account for its duration of activity.1 Following subcutaneous injection in cats, there is considerable inter-cat variability in plasma concentration and pharmacokinetic parameters.2 Formulated as an immediate release product, buprenorphine is quickly absorbed after subcutaneous injection. Pharmacological effects (e.g., mydriasis) may occur within minutes after injection. Buprenorphine plasma concentrations following subcutaneous injection did not appear to correlate to pharmacodynamics measurements (change in the thermal threshold data). In studies with SIMBADOL analgesic effects of buprenorphine appeared about one hour after injection with a 24 to 28 hour duration of action. Combined pharmacokinetic and pharmacodynamic studies have demonstrated a marked time delay between plasma concentrations and the onset and offset of the analgesic effect which is due to the slow equilibration between drug concentrations in the biophase and the slow association and dissociation of drug binding to the receptor. 2,3 Buprenorphine is metabolized in the liver. The major route of excretion of buprenorphine is in the feces. Buprenorphine undergoes oxidative metabolism by N-dealkylation to form norbuprenorphine (an active metabolite) via CYP3A4. Buprenorphine and norbuprenorphine subsequently form inactive glucuronide conjugates in the intestinal wall and the liver and its metabolites are excreted via the bile into the gastro-intestinal tract.4 The elimination half-life in cats is reported to be similar to that associated with humans and slower than that observed in dogs.5 It is also noted that because the cat is devoid of uridine diphosphate glucuronosyltransferase enzymes, conjugated metabolites may be absent.5

Simbadol®

Mechanism of Action: Buprenorphine exerts its analgesic effect via high affinity binding to various subclasses of opiate receptors particularly mu, in the central nervous system. Buprenorphine analgesic and adverse reactions are mediated by mu opioid receptor agonism. Due to its partial agonist activity, buprenorphine exhibits a ceiling affect to its actions and thus has a greater therapeutic index compared to full mu opioid receptor agonists such as morphine. Buprenorphine binds tightly to and dissociates slowly from the opioid receptor. Therefore, the pharmacological effects of buprenorphine are not directly related to plasma concentrations. Buprenorphine can act as an agonist and antagonist at different classes of opioid receptors. Agonism at the mu opioid receptor and, in some cases, antagonism at the kappa or delta opioid receptors are possible underlying mechanisms for the ceiling effect and bell-shaped dose-response curve of buprenorphine. Studies with knockout mice have shown that the antinociceptive effect of buprenorphine, which is mediated primarily by the mu opioid receptor, is attenuated by the ability of the drug to activate the opioid receptor like (ORL-1) receptor. The drug can be described as a ‘full’ and a ‘partial’ agonist at the same receptor depending on the specific assay. There appears to be no ceiling effect for analgesia, but there is a ceiling effect for respiratory depression. Pharmacokinetic studies with bolus injections of buprenorphine in mice and rats provide similar models. After bolus intravenous administration, plasma levels decline tri-exponentially. The drug is n-dealkylated in the liver to norbuprenorphine (NBN), an active metabolite. Studies have shown that glucuronide metabolites of buprenorphine and NBN are also metabolically active, and can approximate or exceed the concentration of the parent drug. Un-metabolized drug excreted in the urine and feces one week after injection was 1.9 and 22.4% of the dose, respectively, and 92% of the dose was accounted for in one week.3 See the dosing table under DOSAGE AND ADMINISTRATION section for information specific to each species regarding time to reach estimated therapeutic blood levels.

Ethiqa XR® (buprenorphine extended-release injectable suspension)

Mechanism of Action: Buprenorphine exerts its analgesic effect via high affinity binding to various subclasses of opiate receptors, particularly mu, in the central nervous system. Buprenorphine analgesic and adverse reactions are mediated by mu opioid receptor agonism. Due to its partial agonist activity, buprenorphine exhibits a ceiling effect to its actions and thus has a greater therapeutic index compared to full mu opioid receptor agonists such as morphine. Buprenorphine binds tightly to and disassociates slowly from the opioid receptor. Therefore, the pharmacological effects of buprenorphine are not directly related to plasma concentrations. Pharmacokinetics: Following application of ZORBIUM, solvent evaporation coupled with the permeation enhancer action results in rapid absorption and sequestration of the buprenorphine into the skin. ZORBIUM provides analgesia within 1 – 2 hours following administration and continually releases buprenorphine from the skin into the systemic circulation over a period of days. The mean (range) time to reach peak concentration (tmax) was 7.33 (1 – 24) hours. Due to buprenorphine elimination being faster than absorption from the skin, ZORBIUM exhibits flip-flop pharmacokinetics where the absorption determines its terminal half-life (mean 64.9 hours [range 39.1 – 85.7 hours]). The estimated absolute bioavailability (F) of transdermal administration was in the order of 16% [90% confidence interval (CI) =11.8% – 21.7%]. Buprenorphine is extensively metabolized by the liver in humans, the primary route being N-dealkylation to norbuprenorphine by cytochrome P450 enzymes. Both buprenorphine and norbuprenorphine form inactive glucuronide conjugates and are excreted by the bile into the gastrointestinal tract. The cat is devoid of uridine diphosphate glucuronosyltransferase enzymes (UGT1A6 and UGT1A9) responsible for conjugation and therefore conjugated metabolites may be absent. Norbuprenorphine is considered an active metabolite of buprenorphine, though it has one-fiftieth the analgesic activity of buprenorphine in rats. Buprenorphine extensively binds (95 – 98%) to plasma proteins.

ZorbiumTM (buprenorphine transdermal solution)

Only administer Ethiqa XR by subcutaneous injection. Ethiqa XR is not intended for intravenous, intra-arterial, intrathecal, intramuscular, or intra-peritoneal injection. Do not use in animals with pre-existing respiratory compromise. Do not house rats on wood chip-type bedding after administration of Ethiqa XR. Signs of nausea, including pica, have been observed in rats for up to 3 days post-treatment with Ethiqa XR. Pica involving wood chip type bedding can be lethal (see ADVERSE REACTIONS).

Ethiqa XR® (buprenorphine extended-release injectable suspension)

ZORBIUM is contraindicated in cats with known hypersensitivity to buprenorphine hydrochloride, any of the inactive ingredients of ZORBIUM, or known intolerance to opioids.

ZorbiumTM (buprenorphine transdermal solution)

SIMBADOL is contraindicated in cats with known hypersensitivity to buprenorphine hydrochloride or any of the components of SIMBADOL, or known intolerance to opioids.

Simbadol®

HUMAN SAFETY WARNINGS: Not for use in humans. Keep this and all medications out of reach of children and pets. Human User Safety While Handling ZORBIUM in the Hospital: Protective Covering: Do not come into direct contact with ZORBIUM. Wear impermeable latex or nitrile gloves, protective glasses, and a laboratory coat when applying ZORBIUM. Mucous Membrane or Eye Contact During Application: Direct contact of ZORBIUM with the eyes, oral, or other mucous membranes could result in absorption of buprenorphine and the potential for adverse reactions. If accidental eye, oral, or other mucous membrane contact is made during application, flush the area with water and contact a physician immediately. If wearing contact lenses, flush the eye first and then remove the contact lens. Skin Contact During Application: Following application to the cat, allow a minimum drying time of 30 minutes before direct contact with the application site. If human skin is accidentally exposed to ZORBIUM, wash the exposed area immediately with soap and water and contact a physician. Accidental exposure could result in absorption of buprenorphine and the potential for adverse reactions. Drug Abuse, Addiction, and Diversion of Opioids: Controlled Substance: ZORBIUM contains buprenorphine, a Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. Abuse: ZORBIUM contains buprenorphine, an opioid substance, that can be abused and is subject to misuse, abuse, and addiction, which may lead to overdose and death. This risk is increased with concurrent use of alcohol and other central nervous system depressants, including other opioids and benzodiazepines. ZORBIUM should be handled appropriately to minimize the risk of diversion, including restriction of access, the use of accounting procedures, and proper disposal methods, as appropriate to the clinical setting and as required by law. Prescription drug abuse is the intentional, non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Buprenorphine has been diverted for non-medical use into illicit channels of distribution. All people handling opioids require careful monitoring for signs of abuse. Storage and Disposal: ZORBIUM is a Schedule III opioid. Store in a locked cabinet according to federal and state controlled substance requirements/guidelines. Any unused or expired tubes must be destroyed by a reverse distributor; for further information, contact your local DEA field office or call Elanco US Inc. at 1-888-545-5973. Information for Physician: ZORBIUM transdermal solution contains a mu opioid partial agonist (20 mg buprenorphine/mL). In the case of an emergency, provide the physician with this package insert. Naloxone may not be effective in reversing respiratory depression produced by buprenorphine. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride has also been used as a respiratory stimulant. ANIMAL SAFETY WARNINGS: For topical use in cats only. This product should only be administered by veterinary personnel. Do not apply ZORBIUM if the application site at the dorsal cervical area has diseased or injured skin. Do not apply ZORBIUM to anatomic areas other than the dorsal cervical area because absorption characteristics may be different.

ZorbiumTM (buprenorphine transdermal solution)

Not for use in humans. Keep this and all medications out of reach of children and pets. Human User Safety While Handling Ethiqa XR in the Hospital: Ethiqa XR should only be handled and administered by a veterinarian, veterinary technician, or laboratory staff trained in the handling of potent opioids. To prevent human adverse reactions or abuse, at least 2 trained administrators should be present during injection of Ethiqa XR. Wear protective clothing when administering Ethiqa XR. Mucous Membrane or Eye Contact During Application: Direct contact of Ethiqa XR with the eyes, oral, or other mucous membranes could result in absorption of buprenorphine and the potential for adverse reactions. If accidental eye, oral, or other mucous membrane contact is made during application, flush the area with water and contact a physician immediately. If wearing contact lenses, flush the eye first and then remove the contact lens. Skin Contact During Application: If human skin is accidentally exposed to ETHIQA XR, wash the exposed area immediately with soap and water and contact a physician. Accidental exposure could result in absorption of buprenorphine and the potential for adverse reactions. Drug Abuse, Addiction, and Diversion of Opioids: Controlled Substance: Ethiqa XR contains buprenorphine, a Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. Abuse: Ethiqa XR contains buprenorphine, an opioid substance, that can be abused and is subject to misuse, abuse, and addiction, which may lead to overdose and death. This risk is increased with concurrent use of alcohol and other central nervous system depressants, including other opioids and benzodiazepines. Ethiqa XR should be handled appropriately to minimize the risk of diversion, including restriction of access, the use of accounting procedures, and proper disposal methods, as appropriate to the clinical setting and as required by law. Prescription drug abuse is the intentional, non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Buprenorphine has been diverted for non-medical use into illicit channels of distribution. All people handling opioids require careful monitoring for signs of abuse. Storage and Disposal: Ethiqa XR is a Schedule III opioid. Store in a locked cabinet according to federal and state controlled substance requirements/guidelines. Discard any broached vials after 90 days. Any unused or expired vials must be destroyed by a reverse distributor; for further information, contact your local DEA field office or call Fidelis Animal Health at 1-833-384-4729. Information for Physician: Ethiqa XR contains a mu opioid partial agonist (1.3 mg buprenorphine/mL). In the case of an emergency, provide the physician with this package insert. Naloxone may not be effective in reversing respiratory depression produced by buprenorphine. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride has also been used as a respiratory stimulant.

Ethiqa XR® (buprenorphine extended-release injectable suspension)

Human Safety: Not for use in humans. Keep out of reach of children. Adult Human User Safety while handling SIMBADOL in the hospital: Mucous membrane or eye contact during administration: Direct contact of SIMBADOL with the eyes, oral or other mucous membranes could result in absorption of buprenorphine and the potential for adverse reactions. If accidental eye, oral or other mucous membrane contact is made during administration, flush the area with water and contact a physician. Skin contact during administration: If human skin is accidentally exposed to SIMBADOL, wash the exposed areas with soap and water and contact a physician. Accidental exposure could result in absorption of buprenorphine and the potential for adverse reactions. Drug Abuse, Addiction, and Diversion of Opioids: Controlled Substance: SIMBADOL contains buprenorphine, a mu opioid partial agonist and Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. SIMBADOL can be abused and is subject to misuse, abuse, addiction, and criminal diversion. SIMBADOL should be handled appropriately to minimize the risk of diversion, including restriction of access, the use of accounting procedures, and proper disposal methods, as appropriate to the clinical setting and as required by law. Abuse: Abuse of SIMBADOL poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances including other opioids and benzodiazepines. Buprenorphine has been diverted for non-medical use into illicit channels of distribution. All people handling opioids require careful monitoring for signs of abuse. Drug abuse is the intentional non-therapeutic use of a prescription drug for its rewarding psychological or physiological effects. Abuse of opioids can occur in the absence of true addiction. Storage and Discard: SIMBADOL is a Class III opioid. Store in a locked, substantially constructed cabinet according to DEA and local controlled substance guidelines. Discard broached vials after 28 days. Any unused or expired vials must be destroyed by a DEA registered reverse distributor; for further information, contact your local DEA field office or call Zoetis Inc. at 1-888-963-8471. Information for physician: SIMBADOL injectable solution is a mu opioid partial agonist (1.8 mg buprenorphine/ mL). In the case of an emergency, provide the physician with the package insert. Naloxone may not be effective in reversing respiratory depression produced by buprenorphine. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride has also been used as a respiratory stimulant

Simbadol®

For subcutaneous (SQ) injectable use in cats.

Simbadol®

In two controlled field studies, a total of 450 male and female cats 4 months to 16 years old, weighing between 2.6 – 20.0 lb were included in the field safety analysis. In one study, cats underwent a soft tissue surgical procedure (soft tissue). In the other study, cats underwent onychectomy, onychectomy and castration, or onychectomy and ovariohysterectomy (orthopedic). The following tables (one table for each study) show the number of cats exhibiting each observation. Adverse Reactions in the Soft Tissue Field Study Adverse Reactiona Simbadol (N=109) Control (N=112) During Surgeryb After Surgery During Surgeryb After Surgery Hypotensionc 39 (35.8%) 29 (26.6%) 33 (29.5%) 24 (21.4%) Tachycardiad 26 (23.9%) 29 (26.6%) 15 (13.4%) 20 (17.9%) Hypothermia (≤98.0ºF) 30 (27.5%) 1 (0.9%) 31 (27.7%) 0 Hyperthermia (≥103.0ºF) 0 40 (36.7%) 0 19 (17.0%) Hypertensione 7 (6.4%) 20 (18.3%) 9 (8.0%) 6 (5.4%) Anorexia 0 18 (16.5%) 0 15 (13.4%) Hyperactivity 0 10 (9.2%) 0 4 (3.6%) Reduced Oxygen Saturation of Hemoglobin (pulse oximetry ≤90%) 5 (4.6%) 1 (0.9%) 8 (7.1%) 0 Bradycardia (≤90 beats/min) 2 (1.8%) 1 (0.9%) 1 (0.9%) 0 Tachypnea (≥72 breaths/min) 0 3 (2.8%) 0 2 (1.8%) Arrhythmia 1 (0.9%) 0 1 (0.9%) 0 Hyperesthesia 0 1 (0.9%) 0 0 Blindness 0 1 (0.9%) 0 0 Apnea/Death 0 1 (0.9%) 0 0 a. Cats may have experienced more than one type or occurrence of an adverse reaction. Cats experiencing the same reaction both during and after surgery are presented in both time periods. b. During surgery is the time from the administration of the anesthetic induction agent until discontinuation of the gas anesthetic. c. Hypotension is defined as a mean blood pressure of ≤60 mmHg during surgery and ≤90 mmHg after surgery. d. Tachycardia is defined as a heart rate ≥180 beats per minute during surgery and ≥200 beats per minute after surgery. e. Hypertension is defined as a mean blood pressure of ≥120 mmHg during surgery and ≥160 mmHg after surgery. Adverse Reactions in the Orthopedic Field Study Adverse Reactiona Simbadol (N=115) Control (N=114) During Surgeryb After Surgery During Surgeryb After Surgery Tachycardiac 29 (25.2%) 44 (38.3%) 15 (13.2%) 24 (21.1%) Hypotensiond 29 (25.2%) 22 (19.1%) 27 (23.7%) 16 (14.0%) Hyperthermia (≥103.0ºF) 1 (0.9%) 51 (44.3%) 0 14 (12.3%) Anorexia 0 22 (19.1%) 0 20 (17.5%) Hypertensione 3 (2.6%) 20 (17.4%) 8 (7.0%) 12 (10.5%) Hypothermia (≤98.0ºF) 8 (7.0%) 0 16 (14.0%) 0 Hyperactivity 0 16 (13.9%) 0 7 (6.1%) Bradycardia (≤90 beats/min) 3 (2.6%) 0 3 (2.6%) 1 (0.9%) Tachypnea (≥72 beats/min) 0 2 (1.8%) 1 (0.9%) 4 (3.5%) Reduced Oxygen Saturation of Hemoglobin (pulse oximetry ≤90%) 3 (2.6%) 0 3 (2.6%) 0 Arrhythmia 0 1 (0.9%) 1 (0.9%) 0 Blindness 0 1 (0.9%) 0 1 (0.9%) Ataxia 0 1 (0.9%) 0 0 Apnea/Death 1 (0.9%) 0 0 0 a. Cats may have experienced more than one type or occurrence of an adverse reaction. Cats experiencing the same reaction both during and after surgery are presented in both time periods. b. During surgery is the time from the administration of the anesthetic induction agent until discontinuation of the gas anesthetic. c. Tachycardia is defined as a heart rate ≥180 beats per minute during surgery and ≥200 beats per minute after surgery. d. Hypotension is defined as a mean blood pressure of ≤60 mmHg during surgery and 90 mmHg after surgery. e. Hypertension is defined as a mean blood pressure of ≥120 mmHg during surgery and ≥160 mmHg after surgery. The two cats with apnea in the SIMBADOLTM (buprenorphine injection) group died from the adverse reaction. The cat in the soft tissue study underwent a necropsy and a specific cause of death was not found, although other remarkable findings included metastatic neoplasia affecting multiple systems. The cat in the orthopedic study experienced apnea during endotracheal intubation. The cat was healthy and a specific cause of death was not found. Two cats in the SIMBADOL group and one cat in the placebo control group were reported with presumptive post-anesthetic cortical blindness. Both cats in the SIMBADOL group received blood pressure intervention during surgery for low blood pressure. All cats regained vision within 7 to 84 days after surgery; however, one cat in the SIMBADOL group continued to have some visual and balance deficits. One cat in the SIMBADOL group in the soft tissue study was euthanized after completion of the study due to pulmonary complications. The complications were considered likely related to the severity of the cat’s injuries prior to surgery. Post-Approval Experience (July, 2017): The following adverse events are based on post-approval adverse drug experience reporting. Not all adverse events are reported to FDA/CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data. he following adverse events reported for cats are listed in decreasing order of reporting frequency for SIMBADOL: Abnormal behaviors (e.g., hyperactivity, agitation, disorientation, hiding), mydriasis, hyperthermia, anorexia, lethargy, ataxia, and sedation.

Simbadol®

In a randomized, multi-centered, double-masked, field study, ZORBIUM™ (buprenorphine transdermal solution) (N=113) or vehicle control (N=109) was administered to cats prior to elective surgical reproductive sterilization (castration/ovariohysterectomy) in conjunction with forelimb onychectomy. Cats enrolled in the study were 4 months to 5 years of age and weighed 1.1 to 5.7 kg (2.5 to 12.5 lb). Clinical observations and physiological parameters were monitored prior to, during, and after surgery for 96 hours after sternal recumbency. Supplemental heat and fluids were allowed. There were no deaths during the study and no cats received an opioid reversal agent. Three ZORBIUM and 2 vehicle control cats were removed due to hyperthermia suspected to be treatment related. One ZORBIUM cat was removed due to fractious behavior 30 minutes following surgery. Adverse reactions were defined as any single excursion outside the normal range, as defined: 100.5 – 102.5 ˚F body temperature; 60 – 120 mmHg mean arterial pressure; 88 – 180 beats per minute for heart rate; 24 – 44 breaths per minute for respiratory rate. A summary of adverse reactions during anesthesia (from anesthetic induction through recovery defined as sternal recumbency) is provided in Table 1. Table 1. Adverse Reactions During Anesthesia: Adverse Reaction* ZORBIUM (N=113) Vehicle Control (N=109) Hypothermia 37 (32.7%) 29 (26.6%) Hypotension 31 (27.4%) 28 (25.7%) Hypertension 27 (23.9%) 18 (16.5%) Tachycardia 14 (12.4%) 14 (12.8%) Sedation 12 (10.6%) 7 (6.4%) Oxygen saturation ≤ 90% 6 (5.3%) 2 (1.8%) Bradycardia 4 (3.5%) 2 (1.8%) Hyperthermia 3 (2.7%) 4 (3.7%) *Physiological adverse reactions were defined as any single excursion outside the normal range at any 10 minute interval during the entire duration of anesthesia. After recovery, cats were observed in the hospital and underwent physiological assessments that included indirect mean arterial blood pressure, heart rate, respiratory rate, body temperature, lung auscultation, heart auscultation, and assessments of urination, defecation, and appetite. A summary of adverse reactions after anesthetic recovery (sternal recumbency) in all cats is reported in Table 2. Table 2. Adverse Reactions After Anesthetic Recovery: Adverse Reaction* ZORBIUM (N=113) Vehicle Control (N=109) Hypothermia 107 (94.7%) 105 (96.3%) Hyperthermia 84 (74.3%) 62 (56.9%) Sedation 64 (56.6%) 48 (44.0%) Tachypnea 56 (49.6%) 70 (64.2%) Hypotension 50 (44.2%) 51 (46.8%) Hypertension 42 (37.2%) 34 (31.2%) Bradycardia 34 (30.1%) 45 (41.3%) Tachycardia 32 (28.3%) 39 (35.8%) Anorexia 25 (22.1%) 32 (29.4%) Dysphoria 20 (17.7%) 29 (26.6%) Diarrhea 11 (9.7%) 11 (10.1%) Bradypnea 11 (9.7%) 7 (6.4%) Leukocytosis 6 (5.3%) 4 (3.7%) Hyperactivity 2 (1.8%) 9 (8.3%) *Physiological adverse reactions were defined as any single excursion outside the normal range following anesthetic recovery (sternal recumbency) through 4 days postoperatively. Hyperthermia was the only adverse event observed in more than 10% of cats in the ZORBIUM group after the day of surgery (24 – 96 hours). The percentage of cats in the ZORBIUM group with hyperthermia decreased over time from 66.4% on Day 0 to 28.3% on Day 1, and to 6.2% by Day 4. A summary of adverse reactions (from anesthetic recovery through 96 hours after recovery) in cats in the ZORBIUM group by study day is reported in Table 3. Table 3. Adverse Reactions in ZORBIUM Cats (N=113) by Day: Adverse Reaction* Day 0 Day 1 Day 2 Day 3 Day 4 Hypothermia 106 (93.8%) 2 (1.8%) 2 (1.8%) 2 (1.8%) 2 (1.8%) Hyperthermia 75 (66.4%) 32 (28.3%) 18 (15.9%) 14 (12.4%) 7 (6.2%) Sedation 64 (56.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Tachypnea 51 (45.1%) 5 (4.4%) 2 (1.8%) 3 (2.7%) 4 (3.5%) Hypotension 42 (37.2%) 2 (1.8%) 1 (0.9%) 4 (3.5%) 2 (1.8%) Hypertension 28 (24.8%) 2 (1.8%) 1 (0.9%) 1 (0.9%) 1 (0.9%) Anorexia 25 (22.1%) 3 (2.7%) 1 (0.9%) 0 (0.0%) 0 (0.0%) Bradycardia 24 (21.2%) 3 (2.7%) 2 (1.8%) 3 (2.7%) 5 (4.4%) Tachycardia 24 (21.2%) 4 (3.5%) 0 (0.0%) 1 (0.9%) 1 (0.9%) Dysphoria 20 (17.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Bradypnea 8 (7.1%) 2 (1.8%) 0 (0.0%) 0 (0.0%) 1 (0.9%) Hyperactivity 1 (0.9%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.9%) *Physiological adverse reactions were defined as any single excursion outside the normal range following anesthetic recovery (sternal recumbency) through 96 hours postoperatively.

ZorbiumTM (buprenorphine transdermal solution)

See the dosing table under the DOSAGE AND ADMINISTRATION section for species-specific adverse reactions.

Ethiqa XR® (buprenorphine extended-release injectable suspension)

Administer topically to the dorsal cervical area at the base of the skull a single dose of 1.2 to 3.1 mg/lb (2.7 to 6.7 mg/kg) approximately 1 to 2 hours before surgery.

Topical

Zorbium™

Administer 0.24 mg/kg (0.11 mg/lb) by subcutaneous injection once daily for up to 3 days. Administer the first dose approximately 1 hour prior to surgery.

Subcutaneous

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

Simbadol®

Wear protective clothing when administering Ethiqa XR. Do not dispense Ethiqa XR for administration at home by the pet owner (see HUMAN SAFETY WARNINGS). Dosing Administer Ethiqa XR subcutaneously according to the dose listed in the table for the appropriate species. Doses were derived either from published literature or using allometric principles. Consider the time to reach estimated therapeutic blood levels when administering Ethiqa XR for post-procedural pain. If needed, a single repeat dose may be administered subcutaneously 72 hours after the initial dose. Definitive therapeutic blood levels of Ethiqa XR have not been established for all species. The times to reach blood levels thought to be therapeutic is presented below and is representative of what has been found in published literature. For more information, consult the published literature referenced at the end of this package insert. DOSING TABLE FOR SUBCUTANEOUS INJECTION OF ETHIQA XR Species Ethiqa XR Dose (mg/kg body weight) Time to reach estimated therapeutic blood levels Precautions/ Adverse Events Mice 3.25 mg/kg10 30 minutes10 • Death has been reported when non-steroidal anti-inflammatory drugs (NSAIDs such as meloxicam and carprofen) and Ethiqa XR have been administered concomitantly.5 • Granulomatous inflammatory nodules have been observed in naked-skinned mice and rats administered Ethiqa XR.4,5 • In one study, two male mice died following the third surgery and redosing; weight loss.11 Naked mole rats (NMR) 3.25 mg/kg* • No published data available administering Ethiqa XR to naked mole rats. Gerbils 1 mg/kg13 30 minutes13 • Granulomatous inflammation at injection site.13 Hamsters 0.8 mg/kg* • No published data available administering Ethiqa XR to hamsters. Rats 0.65 mg/kg12 4 hours16 • Nausea within 24 hrs of dosing, self-licking, self-gnawing and efforts to eat wood-chip bedding, one out of 36 rats exposed to wood bedding died3,12, 3 of 222 rats bled profusely from jugular vein, which was used for obtaining blood samples, and died. • Granulomatous inflammatory nodules have been observed in naked-skinned mice and rats administered Ethiqa XR.4,5 Chinchillas 0.48 mg/kg* • No published data available administering Ethiqa XR to chinchillas. Guinea pigs 0.48 mg/kg17* 8 hours17 • Decrease in body weight14,17and fecal output.14 Increase in passive behavior, such as eyes closed or squinting, subtle body movement, and incomplete movement.17 Prairie dogs 0.48 mg/kg* • No published data available administering Ethiqa XR to prairie dogs. Ferrets 0.6 mg/kg9 30 minutes9 • No adverse reactions observed.9 Non-human primates 0.2 mg/kg6 15 minutes6 • Injection site reactions including inflammation and necrosis have been observed in common marmosets.6 • Mild sedation, decreased body weight, increased cage movements, acute necrosis and inflammation at the injection site.6 Laboratory rabbits 0.15 mg/kg19 • 60 minutes19 • 30 minutes in female and 60 minutes in male rabbits20 • Reduced fecal output post-operatively. Returned to normal at 72 hours.19 *These doses are based on allometric principles. Allometric principles (i.e., animals among closely related species and of similar body size should have similar metabolic rates) can be used to determine the dose of Ethiqa XR for rodent species not listed in the table above and where no published data is available. For example, doses for hamsters and guinea pigs were calculated using published allometric scaling factors (see Nair21 and FDA22 for detailed discussion and how to apply allometric scaling). The dose of Ethiqa XR can also be estimated by using the known dose for a rodent species of similar size (the doses listed in the table above for NMR, chinchillas, and prairie dogs were calculated using this approach). Based upon the time to reach estimated therapeutic blood levels, Ethiqa XR can be administered 30 minutes prior to painful stimulus in mice10 and gerbils13, 8-12 hours prior in guinea pigs17, 60 minutes prior in laboratory rabbits19, and 15 minutes prior in non-human primates.6 Administration Shake the vial well before each use to ensure uniform suspension. If stored refrigerated, bring to room temperature before use. Use aseptic technique to subcutaneously administer Ethiqa XR by utilizing minimally stressful restraint techniques or sedation. An oily sheen may be observed in the fur after injection due to leakage of Ethiqa XR, which is an oil-based drug suspension, from the injection site. The oily sheen may last for 4 to 5 days post-injection. Leakage from the injection site can be minimized by slowly injecting Ethiqa XR into the subcutaneous space. Do not return any unused drug suspension from the syringe back into the vial. The animal can be returned to its cage immediately after receiving Ethiqa XR. (See CONTRAINDICATIONS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION for additional information on bedding.)

SUBCUTANEOUS

Ethiqa XR® (buprenorphine extended-release injectable suspension)

This product should only be administered by veterinary personnel. ZORBIUM is for administration only once for the surgical procedure. ZORBIUM should be applied 1 to 2 hours before surgery. A single application provides analgesia for 4 days. ZORBIUM should only be applied topically to the dorsal cervical area at the base of the skull. Do not apply if dorsal cervical skin is diseased or injured. The dosage of ZORBIUM is 1.2 – 3.1 mg/lb (2.7 – 6.7 mg/kg) administered topically as the entire tube contents according to the following dosing table: Pounds of Body Weight Kilograms of Body Weight Dose of ZORBIUM 2.6 to 6.6 1.2 to 3 0.4 mL (8 mg) pink tube >6.6 to 16.5 >3 to 7.5 1 mL (20 mg) green tube Dose Application Wear impermeable latex or nitrile gloves, protective glasses, and a laboratory coat to prevent direct solution contact with human skin, eyes, or mucosa when handling and applying the solution. Do not dispense ZORBIUM for administration at home by the pet owner (see HUMAN SAFETY WARNINGS). Figure 1 - Diagram of tube components. Figure 2 – Proper grasp of the applicator tube: To prepare to open the tube for application, the tube must be held in an upright position to avoid spilling contents. Grasp the tube just beneath the ribbed portion of the tip. Figure 3 – Opening the applicator tube: Keeping the tube upright, grasp the ribbed portion of the tip, and turn the applicator tip in either direction at least 180° to open the tube. The applicator tip is designed to stay on the tube and should not be removed. The tube is ready for application when a breaking of the seal is felt. Figure 4 – Solution application: Fur should not be clipped. Do not apply to injured or diseased skin. Gently hold the cat both before and after application to prevent the cat from shaking or rubbing. Part the fur and apply the tip of the tube directly onto the skin at the base of the head. Squeeze the tube 2 – 3 times to empty the contents without moving the tube or the tip. Lift the tube directly away from the skin, avoiding contact of the tip with the cat’s fur.

TRANSDERMAL

ZorbiumTM (buprenorphine transdermal solution)

The dosage of SIMBADOL is 0.24 mg/kg (0.11 mg/lb) administered subcutaneously once daily, for up to 3 days. Administer the first dose approximately 1 hour prior to surgery. Do not dispense SIMBADOL for administration at home by the pet owner (see Human Safety).

SUBCUTANEOUS

Simbadol®