ETHIQA XR® PUBLICATIONS

1. Assessment of the Safety and Efficacy of Pre-emptive Use of Extended-release Buprenorphine for Mouse Laparotomy. Chan G, Si C, Nichols, MR and Kennedy, L. Assessment of the Safety and Efficacy of Pre-emptive Use of Extended-release Buprenorphine for Mouse Laparotomy. J AM Assoc Lab Anim Sci. 2022; 61(4)381-38 2. Based on the results of this study, Ethiqa XR extended-release buprenorphine 0.65 mg/kg is recommended to attenuate postoperative mechanical hypersensitivity for up to 72 h in male Sprague-Dawley rats in an incisional pain model. Alamaw ED, Franco BD, Jampachaisri K, et al. Extended-release buprenorphine, an FDA-indexed analgesic, attenuates mechanical hypersensitivity in rats (rattus norvegicus). J Am Assoc Lab Anim Sci. 2022;61(1)81-88. 3. This article reviews long-acting parenteral analgesics with a focus on the benefits of an extended duration of analgesia with regard to less handling stress and a lower risk of untoward clinical effects. Huss MK, Pacharinsak C. Review of long-acting parenteral analgesics for mice and rats. J Am Assoc Lab Anim Sci. 2022;61(96):597-604. 4. The results of this study support the use of FDA-indexed Ethiqa XR extended-release buprenorphine for the alleviation of post- operative pain in male and female C57Bl/6J mice, which increases the options for safe and effective pharmaceutical grade analgesia in rodents. Saenz M, Bloom-Saldana E, Synold T, et al. Pharmacokinetics of sustained-release buprenorphine and extended-release buprenorphine in mice with surgical catheterization. bioRxiv. Published online March 17, 2022. 5. This study indicates that postoperative hypersensitivity attenuation with a low or high dose of Ethiqa XR extended- release (XR) buprenorphine is similar to sustained release buprenorphine. The XR formulation of 0.65 mg/kg is recommended to attenuate postoperative mechanical hypersensitivity in rats in an incisional pain model. Alamaw, et al. Extended-release buprenorphine, an FDA-indexed analgesic, attenuates mechanical hypersensitivity in rats. Poster presented at AALAS National Conference, October 2021; Kansas City, MO. 6. This study aimed to evaluate the efficacy of 3 different buprenorphine formulations (regular, sustained release, and extended release) for attenuating postoperative hypersensitivity in the immunocompromised NSG mouse using a plantar incisional pain model. Arthur, et al. Buprenorphine does not attenuate postoperative hypersensitivity in NSG mice. Poster presented at AALAS National Conference, October 2021; Kansas City, MO. 7. Results from this pharmacokinetic study indicate that a single Ethiqa XR extended-release buprenorphine dose can reliably provide therapeutically relevant plasma levels of buprenorphine for up to 72 h in Sprague-Dawley rats, with males having consistently higher levels than females at both 0.65 mg/mL and 1.30 mg/mL dosing, both of which were well tolerated. Levinson BL, Leary SL, Bassett BJ, et al. Pharmacokinetic and histopathologic study of an extended-release, injectable formulation of buprenorphine in Sprague–Dawley rats. J AM Assoc Lab Anim Sci. 2021;60(4):462-469. 8. This study evaluated 2 buprenorphine products reported to have an extended duration of action utilizing a validated mouse hind paw incision model with the aim of determining a dose resulting in analgesia for at least 72 h with minimal adverse effects Mangosing, et al. Efficacy and duration of various buprenorphine preparations in a mouse hind paw incision model of pain. Poster presented at AALAS National Conference, October 2021; Kansas City, MO. 9. This study indicates that Ethiqa XR extended-release buprenorphine effectively attenuates post-operative hypersensitivity in adult male C57BL/6 mice. Navarro K, Jampachaisri K, Huss M, Pacharinsak. Lipid bound extended-release buprenorphine (high and low doses) and sustained release buprenorphine effectively attenuate post-operative hypersensitivity in an incisional pain model in mice (mus musculus). Animal Model Exp Med. 2021;4(2):129-137. 10. This study showed that Ethiqa XR , a lipid bound, extended-release buprenorphine, effectively attenuates thermal hypersensitivity in male and female neonatal Sprague-Dawley rat incisional pain model. Zhang, et al. Extended-release buprenorphine effectively attenuates laser-induced thermal hypersensitivity in an incisional model in neonatal rats. Poster presented at AALAS National Conference, October 2021; Kansas City, MO. 11. This study examined the efficacy of extended-release buprenorphine (XR) with the aim of investigating whether a high dose of XR effectively attenuates postoperative hypersensitivity better than a low dose of XR in a mouse model of incisional pain. Navarro, et al. Lipid bound extended-release buprenorphine effectively attenuates post-operative hypersensitivity in an incisional pain model in mice (mus musculus). Poster presented at AALAS National Conference Virtual Meeting, October 2020. 12. The purpose of this study was to quantify post-surgical recovery indices in mice treated with extended-release buprenorphine compared to sustained-release buprenorphine with the hypothesis that post-surgical recovery would be comparable, thus increasing the options for safe and effective analgesia in mice. Saenz, et al. Post-surgical recovery assessment of mice treated with extended-or sustained-release buprenorphine. Poster presented at AALAS National Conference Virtual Meeting, October 2020. – – – – – – – – OTHER BUPRENORPHINE PUBLICATIONS (ANIMALGESIC) 1. This study showed that extended release resulted in prolonged and sustained plasma concentrations and antinociceptive effects up to 72 hr after drug administration. Barletta M, Ostenkamp SM, Taylor AC, et al. The pharmacokinetics and analgesic effects of extended-release buprenorphine administered subcutaneously in healthy dogs. J Vet Pharmacol Ther. 2018;41(4):502-512. 2. These results confirm the safety of a cholesterol-triglyceride carrier system for subcutaneous drug delivery in laboratory animals and suggest that this model may be used to study long-term effects of opiate therapy. Guarnieri M, Brayton C, Tyler BM. A Long-Term Study of a Lipid-Buprenorphine Implant in Rats. J Vet Med. 2018;2018:2616152. Published online July 9, 2018. doi: 10.1155/2018/2616152 3. Target Animal Safety (TAS) studies using 5-fold excess doses of a buprenorphine suspension in single and dose-repeat trials demonstrated the safety of two successive treatments with this dose in male and female mice. Itzoe ML, Ye X, Sarabia-Estrada R, et al. Buprenorphine analgesia in mice. Int J Res Health Sci. 2018;6(1):2169-2177. 4. These results confirm the safety of cholesterol-triglyceride carrier systems for subcutaneous drug delivery of buprenorphine in laboratory animals and further demonstrate the utility of lipid-based carriers as scaffolds for subcutaneous, long-acting drug therapy. Guarnieri M, Brayton C, Sarabia-Estrada R, et al. Subcutaneous Implants of a Cholesterol-Triglyceride-Buprenorphine Suspension in Rats. J Vet Med. 2017;4:1-11. 5. Results from a laboratory that examined the efficacy of extended-release (ER) buprenorphine, alone and as a multimodal combination, for relieving postsurgical pain in guinea pigs. Oliver VL, Athavale S, Simon KE, et al. Evaluation of pain assessment techniques and analgesia efficacy in a female guinea pig (cavia porcellus) model of surgical pain. J Am Assoc Lab Anim Sci. 2017;56(4):425-435. 6. The consensus from this study is that rats can be treated safely with extended-release buprenorphine analgesia provided the rats are allowed to recover on paper or soft bedding. Sarabia-Estrada R, Cowan A, Tyler BM, Guarnieri M. Association of Nausea with Buprenorphine Analgesia for Rats. Lab Animal. 2017;46:242-244. 7. The results of this study show that post-surgical administration of an extended-release buprenorphine product is safe in Fischer 344 rats and does not necessarily cause substantial adverse effects, confirming that opiate therapy is a viable choice in laboratory animal medicine. Cowan A, Sarabia-Estrada R, Wilkerson G, et al. Lack of adverse effects during a target animal safety trial of extended-release buprenorphine in Fischer 344 rats. Lab Animal. 2016;45:28-34. 8. The findings from this study indicate a high tolerance to an extended-release buprenorphine suspension administered post-operatively in mice with appropriate husbandry. Traul KA, Romero JB, Brayton C, et al. Safety studies of post-surgical buprenorphine therapy for mice. Lab Animal. 2015;49(2):100-110. 9. The present report describes a simple restraint system for mice. The utility of the system is demonstrated by examining the efficacy of acute and extended-release buprenorphine injections in Balb/c and Swiss mice. Schildhaus N, Trink E, Polson C, et al. Thermal latency studies in opiate-treated mice. J Pharm Bioallied Sci. 2014;6(1)43-47.

Boxed Warning

WARNING: ABUSE POTENTIAL and LIFE-THREATENING RESPIRATORY DEPRESSION and ACCIDENTAL EXPOSURE

Abuse Potential

Ethiqa XR contains buprenorphine, a high-concentration (1.3 mg/mL) opioid agonist and Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. The high concentration may be a particular target for human abuse. Buprenorphine has opioid properties that in humans may lead to dependence of the morphine type. Abuse of buprenorphine may lead to low or moderate physical dependence or high psychological dependence. The risk of abuse by humans should be considered when storing, administering, and disposing of Ethiqa XR. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (suicidal depression). Because of human safety risks, this drug should be used only with veterinary supervision.

Do not dispense Ethiqa XR.

Life-Threatening Respiratory Depression

The concentration of buprenorphine in Ethiqa XR is 1.3 mg/mL. Respiratory depression, including fatal cases, may occur with abuse of Ethiqa XR. Ethiqa XR has additive CNS depressant effects when used with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Because of the potential for adverse reactions associated with accidental injection, Ethiqa XR should only be administered by a veterinarian or laboratory staff trained in the handling of potent opioids.

IMPORTANT SAFETY INFORMATION For Rats and Mice: 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 on mice or rats with pre-existing respiratory deficiencies. Do not keep rats on wood chip-type bedding after administration of Ethiqa XR. Use caution with concomitant administration of Ethiqa XR with drugs that cause respiratory depression. For Humans: Ethiqa XR should only be administered by a veterinarian or laboratory staff trained in the handling of potent opioids. Protective clothing is recommended to avoid direct contact with human skin or mucus membranes which could result in absorption of buprenorphine and adverse reactions. Not for use in humans. For more information, consult the prescribing information including the boxed warning.

LP.EthiqaXR.009.01.23