OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Naldemedine	916072-89-4	C32-H34-N4-O6

ANNOTATED BIBLIOGRAPHY

References updated: 15 April 2019

• Zimmerman HJ. Narcotic analgesics. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 710-11.

  (Expert review of hepatotoxicity published in 1999; mentions that trials of naltrexone have reported serum aminotransferase elevations in up to 30% of recipients, an effect that appeared to be partially dose dependent; naldemedine not discussed).
• Larrey D, Ripault MP. Illegal and recreational compounds. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 456-7.

  (Review of hepatotoxicity discusses buprenorphine, an orally available morphine analogue, which has been linked to cases of severe acute liver injury, usually as a result of intravenous administration; naldemedine is not discussed).
• Yaksh TL, Wallace MS. Opioids, analgesia, and pain management. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 355-86.

  (Textbook of pharmacology and therapeutics).
• https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2017/208854Orig1s000MedR.pdf .

  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy; rates of liver test abnormalities were similar with naldemedine [0.8%: 9 of 1163] as placebo [0.8%: 9 of 1165] and no convincing case of clinically apparent liver injury could be attributed to naldemedine).
• Webster LR, Yamada T, Arjona Ferreira JC. A phase 2b, randomized, double-blind placebo-controlled study to evaluate the efficacy and safety of naldemedine for the treatment of opioid-induced constipation in patients with chronic noncancer pain. Pain Med 2017; 18: 2350-60. [PMC free article: PMC5914456] [PubMed: 28371937]

  (Among 244 patients with non-cancer pain and opioid induced constipation, naldemedine [0.1,0.2 or 0.4 mg] was associated with a higher, dose dependent response rate, while changes in chemistry laboratory results from baseline “were similar for all treatment groups”).
• Hale M, Wild J, Reddy J, Yamada T, Arjona Ferreira JC. Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials. Lancet Gastroenterol Hepatol 2017; 2: 555-64. [PubMed: 28576452]

  (Among 1100 patients with opioid induced constipation enrolled in 2 placebo controlled 12 week trials, response rates were higher with naldemedine than placebo while adverse event rates were similar [22% vs 17%], diarrhea, nausea and abdominal pain being more frequent with naldemedine; no mention of ALT elevations or hepatotoxicity).
• Katakami N, Oda K, Tauchi K, Nakata K, Shinozaki K, Yokota T, Suzuki Y, et al. Phase IIb, randomized, double-blind, placebo-controlled study of naldemedine for the treatment of opioid-induced constipation in patients with cancer. J Clin Oncol 2017; 35: 1921-8. [PubMed: 28445097]

  (Among 227 patients with cancer and opioid induced constipation treated with naldemedine [0.1,0.2 or 0.4 mg] or placebo once daily for 14 days, response rates were higher with naldemedine and were dose related as were adverse event rates, diarrhea arising in 27%, 40% and 52% vs 25% in controls; no mention of ALT elevations or hepatotoxicity).
• Katakami N, Harada T, Murata T, Shinozaki K, Tsutsumi M, Yokota T, Arai M, et al. Randomized phase III and extension studies of naldemedine in patients with opioid-induced constipation and cancer. J Clin Oncol 2017; 35: 3859-66. [PubMed: 28968171]

  (Among 193 patients with cancer and opioid induced constipation treated with naldemedine or placebo for 2 weeks followed by naldemedine for 12 weeks, clinical responses were more frequent with naldemedine [71% vs 34%] as were adverse events [44% vs 26%], and one developed a severe adverse event described as “abnormal hepatic function” but no details given).
• Markham A. Naldemedine: first global approval. Drugs 2017; 77: 923-7. [PubMed: 28466424]

  (Summary of the structure, mechanism of action, pharmacology, clinical efficacy and safety of naldemedine; mentions that the most common adverse events are diarrhea, abdominal pain and nausea; no mention of ALT elevations or hepatotoxicity).
• Naldemedine (Symproic) for opioid-induced constipation. Med Lett Drugs Ther 2017; 9 (1535): 196-8. [PubMed: 29186083]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of naldemedine shortly after its approval in the US for opioid induced constipation; mentions adverse events of abdominal pain, nausea and diarrhea as well as hypersensitivity reactions, withdrawal symptoms and gastrointestinal perforation, but does not mention ALT elevations or hepatotoxicity).
• Webster LR, Nalamachu S, Morlion B, Reddy J, Baba Y, Yamada T, Arjona Ferreira JC. Long-term use of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: a randomized, double-blind, placebo-controlled phase 3 study. Pain 2018; 159: 987-94. [PMC free article: PMC5916485] [PubMed: 29419653]

  (Among 1246 patients with non-cancer pain and opioid induced constipation, overall adverse event rates were similar with naldemedine- [68%] as placebo-treatment [72%], while diarrhea was more frequent [11% vs 5%]; no mention of ALT elevations or hepatotoxicity).