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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].
Show detailsOVERVIEW
Introduction
Difelikefalin is a synthetic tetrapeptide agonist of the kappa opioid receptor that is used to treat pruritus in adults with chronic kidney disease undergoing hemodialysis. Difelikefalin has not been associated with serum enzyme elevations during therapy or with episodes of clinically apparent liver injury.
Background
Difelikefalin (dye fel” i kef’ a lin) is a synthetic, D-amino acid tetrapeptide agonist of the kappa opioid receptor that is involved in sensory pathways causing pruritus. Pruritus is common in persons with end-stage renal disease and can be severe and have adverse effects on quality of life. Approximately 60% of patients with chronic renal disease on hemodialysis have pruritus which is moderate-to-severe in 20% to 40%. Medications typically used for itching such as skin creams, antihistamines, gabapentin, and corticosteroids, are only partially effective and can be associated with further troublesome symptoms. The cause of pruritus in chronic renal failure is not well defined, but an imbalance of kappa and mu opioid activity appears to play a role. Difelikefalin is a specific agonist of the kappa opioid receptor which has been shown to decrease scratching behavior in animal models. In several randomized, placebo controlled trials, difelikefalin given intravenously at the end of hemodialysis sessions 3 times weekly was shown to decrease itching scores significantly in at least 40% of patients. Long term treatment led to improvements in quality of life in a proportion of patients. Difelikefalin was approved for use in the United States in 2021 and is available under the brand name Korsuva in solution in single use vials of 65 μg/1.3 mL (50 μg/mL). The recommended dose regimen in adults is 0.5 μg/kg given intravenously at the end of each hemodialysis session (usually 3 times weekly). It has not been approved as therapy of itching in patients on peritoneal dialysis, or those with chronic renal disease not on dialysis, or in other conditions associated with moderate-to-severe pruritus. However, both intravenous and an oral formulation of difelikefalin are under evaluation as therapy of pruritus due to other conditions (atopic dermatitis, primary biliary cholangitis). Therapy is generally well tolerated but side effects can include diarrhea, nausea, dizziness, headache, somnolence, gait disturbance, falls, and changes in mental status. Despite being an opioid receptor agonist, difelikefalin has no abuse potential and does not cause psychological or physical dependence. Severe adverse events include daytime somnolence with gait disturbances, falls, and impairment in driving and operation of heavy machinery.
Hepatotoxicity
In registration trials of difelikefalin, elevations in serum liver-associated enzyme levels were uncommon and no more frequent than in controls. Serum alkaline phosphatase elevations occurred in 12.7% vs 12.0% of participants, and there were no ALT elevations above 3 times the upper limit of normal (ULN). Since approval and more widespread use of difelikefalin, there have been no published reports of hepatotoxicity attributed to its use.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism by which difelikefalin might cause liver injury is unknown. It is a tetrapeptide and is not metabolized by the cytochrome P450 system. It has no significant drug-drug interactions other than contribution to excess somnolence and changes in mental status in persons also receiving antidepressants or other sedating medications. The lack of liver injury from difelikefalin may be due, in part, to the low doses used, generally in microgram amounts and well below 1 mg daily.
Outcome and Management
There is little evidence that difelikefalin causes serum enzyme elevations or liver injury. It has not been evaluated in patients with advanced liver disease and is not recommended in patients with decompensated cirrhosis (Child Pugh scores of B or C). Because difelikefalin is an opioid receptor agonist and can induce somnolence, it may like other opioid agonists cause or worsen hepatic encephalopathy in patients with moderate or severe liver dysfunction.
Drug Class: Renal Disease Agents
Other Drugs for Pruritus: Antihistamines, Corticosteroids, Gabapentin, Rifampin
PRODUCT INFORMATION
REPRESENTATIVE TRADE NAMES
Difelikefalin – Korsuva®
DRUG CLASS
Renal Disease Agents
Product labeling at DailyMed, National Library of Medicine, NIH
CHEMICAL FORMULA AND STRUCTURE
| DRUG | CAS REGISTRY NUMBER | MOLECULAR FORMULA | STRUCTURE |
|---|---|---|---|
| Difelikefalin | 1024828-77-0 | C36-H53-N7-O6 |
|
ANNOTATED BIBLIOGRAPHY
References updated: 30 January 2025
- Zimmerman HJ. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.(Expert review of hepatotoxicity published in 1999 before availability of difelikefalin).
- Sewell MJ, Burkhart C, Morrell D. Dermatological pharmacology. 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. 1271-96.(Textbook of pharmacology and therapeutics).
- FDA. Multi-Discipline Review. 2021. https://www
.accessdata .fda.gov/drugsatfda_docs /nda/2021/214916Orig1s000MultidisciplineR.pdf (FDA website with product labels and clinical review of the data on efficacy and safety submitted by the sponsor in support of approval for difelikefalin in the US; among 851 patients in two randomized, placebo controlled trials of difelikefalin, common side effects included diarrhea, nausea, dizziness, gait disturbance, falls, hypokalemia, headache, somnolence, and changes in mental status, while alkaline phosphatase elevations arose in 12.7% vs 12.0% but no patient had ALT elevations above 3 times ULN or liver enzyme elevations with jaundice). - Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F; KALM-1 Trial Investigators. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. N Engl J Med. 2020;382:222-232. [PubMed: 31702883](Among 378 adults with chronic renal disease on hemodialysis with moderate-to-severe pruritus treated with difelikefalin [0.5 mcg/kg] or placebo at the end of each dialysis session 3 times weekly for 12 weeks, symptom scores for pruritus decreased more frequently with difelikefalin [37% vs 18%], while adverse events were more frequent [69% vs 62%], mostly due to diarrhea, dizziness, nausea, and vomiting; no mention of ALT elevations or hepatotoxicity).
- Steele DJR. Difelikefalin for the treatment of uremic pruritus. N Engl J Med. 2020;382:289-290. [PubMed: 31940704](Editorial in response to publication by Fishbane [2020]).
- Deeks ED. Difelikefalin: first approval. Drugs. 2021;81:1937-1944. [PubMed: 34674115](Review of the mechanism of action, history of development, pharmacology, clinical efficacy, and safety of difelikefalin shortly after its approval in the US, discusses common side effects but does not mention ALT elevations or hepatotoxicity).
- Difelikefalin (Korsuva) for chronic kidney disease-associated pruritus. Med Lett Drugs Ther. 2022;64:18-19. [PubMed: 35134047](Concise review of the mechanism of action, clinical efficacy, safety, and costs of difelikefalin shortly after its approval for use in the US, discusses common side effects; no mention of ALT elevations or hepatotoxicity).
- Fishbane S, Wen W, Munera C, Lin R, Bagal S, McCafferty K, Menzaghi F, et al. Safety and tolerability of difelikefalin for the treatment of moderate to severe pruritus in hemodialysis patients: pooled analysis from the phase 3 clinical trial program. Kidney Med. 2022;4:100513. [PMC free article: PMC9418597] [PubMed: 36039153](In a pooled analysis of two randomized, placebo controlled trials of difelikefalin in adults with chronic kidney disease on hemodialysis with moderate-to-severe pruritus, side effects more frequent with drug were diarrhea [9% vs 5.7%], dizziness [6.8% vs 3.8%], nausea [6.6% vs 4.5%], gait disturbance [6.6% vs 5.4%], headache [4.5% vs 2.6%], somnolence [4.2% vs 2.4%], and mental status changes [3.3% vs 1.4%]; no mention of ALT elevations or hepatotoxicity).
- Yosipovitch G, Awad A, Spencer RH, Munera C, Menzaghi F. A phase 2 study of oral difelikefalin in subjects with chronic kidney disease and moderate-to-severe pruritus. J Am Acad Dermatol. 2023;89:261-268. [PubMed: 37059302](Among 269 adults with chronic kidney disease and moderate-to-severe pruritus treated with oral difelikefalin [0.25, 0.5, and 1.0 mg] or placebo daily for 12 weeks, a higher proportion of participants receiving the highest dose of difelikefalin [1.0 mg daily] had significant decreases in pruritus symptom scores [39% vs 14%], while adverse events were generally mild and “there were no clinically relevant abnormalities of laboratory values”).
- Guttman-Yassky E, Facheris P, Da Rosa JC, Rothenberg-Lausell C, Del Duca E, David E, Estrada Y, et al. Oral difelikefalin reduces moderate to severe pruritus and expression of pruritic and inflammatory biomarkers in subjects with atopic dermatitis. J Allergy Clin Immunol. 2023;152:916-926. [PubMed: 37453614](Among 401 adults with atopic dermatitis and moderate-to-severe pruritus treated with oral difelikefalin [0.25, 0.5, or 1.0 mg] vs placebo once daily for 12 weeks, improvement in pruritus scores was only slightly better with drug, the results not reaching statistical significance; no mention of ALT elevations or hepatotoxicity).
- PMCPubMed Central citations
- PubChem SubstanceRelated PubChem Substances
- PubMedLinks to PubMed
- Impact of renal impairment on the pharmacokinetic profile of intravenous difelikefalin, a kappa opioid receptor agonist for the treatment of pruritus.[BMC Nephrol. 2024]Impact of renal impairment on the pharmacokinetic profile of intravenous difelikefalin, a kappa opioid receptor agonist for the treatment of pruritus.Spencer RH, Noonan PK, Marbury T, Menzaghi F. BMC Nephrol. 2024 Oct 14; 25(1):351. Epub 2024 Oct 14.
- Review Difelikefalin: A New κ-Opioid Receptor Agonist for the Treatment of Hemodialysis-Dependent Chronic Kidney Disease-Associated Pruritus.[Ann Pharmacother. 2023]Review Difelikefalin: A New κ-Opioid Receptor Agonist for the Treatment of Hemodialysis-Dependent Chronic Kidney Disease-Associated Pruritus.Fugal J, Serpa SM. Ann Pharmacother. 2023 Apr; 57(4):480-488. Epub 2022 Aug 9.
- Review Difelikefalin in the Treatment of Chronic Kidney Disease-Associated Pruritus: A Systematic Review.[Pharmaceuticals (Basel). 2022]Review Difelikefalin in the Treatment of Chronic Kidney Disease-Associated Pruritus: A Systematic Review.Wala K, Szepietowski JC. Pharmaceuticals (Basel). 2022 Jul 28; 15(8). Epub 2022 Jul 28.
- Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients.[Kidney Int Rep. 2020]Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients.Fishbane S, Mathur V, Germain MJ, Shirazian S, Bhaduri S, Munera C, Spencer RH, Menzaghi F, Trial Investigators. Kidney Int Rep. 2020 May; 5(5):600-610. Epub 2020 Jan 28.
- Review Difelikefalin: First Approval.[Drugs. 2021]Review Difelikefalin: First Approval.Deeks ED. Drugs. 2021 Nov; 81(16):1937-1944.
- Difelikefalin - LiverToxDifelikefalin - LiverTox
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