Is difelikefalin FDA-approved, and what does the research show?

What is difelikefalin?

Difelikefalin is a synthetic peptide: a short, man-made chain of amino acids, the building blocks of proteins ¹. Its chemical name on the label shows four amino acids in their mirror-image "D" forms, joined to a small ring-shaped acid ¹. It is sold as Korsuva, a clear, colorless solution for injection into a vein ¹.

The label classes it as a "kappa opioid receptor agonist" ¹. A receptor is a docking site on a cell, and an agonist is a substance that switches that site on. Kappa is one type of opioid receptor, and FDA's review called the drug the "first in class kappa opioid treatment for uremic pruritus" ⁵. Uremic pruritus is another name for the itch that comes with kidney disease ⁵. Difelikefalin is not a wellness, weight-loss or performance peptide.

Is difelikefalin FDA-approved?

Yes, as a prescription drug for one kind of itch. FDA approved Korsuva (difelikefalin) injection on August 23, 2021, under NDA 214916 ². An NDA is a new drug application, the file a company submits to FDA for a new medicine. Drugs@FDA lists the product's marketing status as "Prescription" as of November 9, 2026, the date of the record's data ². The carton reads "Rx only," so it is dispensed only on a prescription ¹.

The label gives one indication: "the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD)" ¹. Pruritus is the medical word for itch. Hemodialysis is the treatment in which a machine filters the blood in place of the kidneys.

The label sets a limit on that use. Korsuva "has not been studied in patients on peritoneal dialysis and is not recommended for use in this population" ¹. Peritoneal dialysis is the form of dialysis done through the lining of the abdomen instead of a machine's filter. The label also says safety and effectiveness in children "have not been established" ¹.

Drugs@FDA lists a generic as well. FDA approved a difelikefalin acetate injection under ANDA 220919 on August 31, 2026, with the same "Prescription" status ⁴. An ANDA is an abbreviated new drug application, the route by which FDA approves a generic copy of an approved drug. Drugs@FDA's data of November 9, 2026, lists two difelikefalin applications, NDA 214916 and ANDA 220919, both for solutions given into a vein ², ⁴.

FDA's review of the application, completed on August 20, 2021, says: "Particular interest was placed on evaluation of drug abuse potential, overdose, and withdrawal and rebound" ⁵. The reviewers concluded that difelikefalin "is expected to have no meaningful abuse potential and no physical dependence" ⁵. They also wrote that it "will not be labeled as a scheduled drug," meaning one placed under federal controlled-substance rules ⁵. DailyMed's listing for the current Korsuva label reads "DEA Schedule: None" ¹.

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How does difelikefalin work?

The label states the mechanism in two short sentences ¹. Korsuva "is a kappa opioid receptor (KOR) agonist" ¹. The next sentence reads: "The relevance of KOR activation to therapeutic effectiveness is not known" ¹.

The authors of the first phase 3 trial give a fuller account, which is a proposed mechanism ⁶. They describe difelikefalin as "a peripherally restricted and selective agonist of kappa opioid receptors that are considered to be important in modulating pruritus in conditions such as chronic kidney disease" ⁶. "Peripherally restricted" means the drug acts mainly outside the brain and spinal cord. "Selective" means it favors one receptor type, here kappa, over others.

The label also describes how the body handles the drug. In patients on hemodialysis, its half-life, the time for half the drug to leave the blood, was 23 to 31 hours before dialysis ¹. Hemodialysis then lowered blood levels by 70 to 80 percent ¹. The label has the drug given once blood no longer circulates through the dialyzer, the machine's filter ¹. In lab tests on human liver cells and cell fractions, six cytochrome P450 enzymes, a family that processes many drugs, did not break it down ¹.

What does the research show?

FDA approved difelikefalin on two phase 3 trials, the large studies that come before an approval ¹. Both were randomized, double-blind and placebo-controlled, and together they enrolled 851 adults on hemodialysis with moderate-to-severe itch ¹. Randomized means patients were assigned to a group by chance. Double-blind means neither patients nor staff knew who received the drug and who received placebo, a dummy injection. Each patient received an injection into the dialysis line at the end of each session, three times a week for 12 weeks ¹.

Patients scored their worst itch each day on a scale from 0, "no itch," to 10, "worst itch imaginable" ¹. The average starting score was 7.1 in the first trial and 7.2 in the second ¹. The measure of success was a drop of at least 4 points in the weekly average score at week 12 ¹.

In Trial 1, 40 percent of the 189 patients given Korsuva reached that mark, against 21 percent of the 189 given placebo ¹. The difference was 19 percentage points, with a 95 percent confidence interval of 9 to 28 ¹. A confidence interval is the range in which the true difference probably lies. In Trial 2, 37 percent of the 237 patients given Korsuva reached the mark, against 26 percent of the 236 given placebo ¹. That difference was 12 percentage points, with an interval of 3 to 20 ¹.

Three details help in reading those results. In each trial, about six in ten patients on the drug did not reach the 4-point mark ¹. In Trial 1, 40 percent of patients were also using other anti-itch medicines, sedating antihistamines among them, and kept using them; in Trial 2, 36 percent were ¹. The placebo comparison ran for 12 weeks, and the label reports no controlled result beyond that point ¹. Within it, the label says, "Itch reduction was seen by Week 4 and sustained through Week 12" ¹.

The first trial, named KALM-1, was published online on November 8, 2019 ⁶. Studied in people: a randomized, double-blind, placebo-controlled phase 3 trial, 378 participants, itch intensity at week 12 ⁶. Its main outcome was a drop of at least 3 points on the same scale ⁶. In the observed data, 82 of 158 patients (51.9 percent) in the difelikefalin group reached it, against 51 of 165 (30.9 percent) in the placebo group ⁶. With missing scores filled in statistically, the figures were 49.1 and 27.9 percent, a difference unlikely to be chance (P<0.001) ⁶.

For a 4-point drop, the paper's estimate was 37.1 percent with difelikefalin against 17.9 percent with placebo ⁶. The label, analyzing the same trial with 189 patients in each group, reports 40 percent against 21 percent ¹. Itch-related quality of life, measured on two questionnaires, also improved more with the drug than with placebo ⁶. Cara Therapeutics funded the trial, and FDA's review names that company as the applicant for the approval ⁶, ⁵.

Outside the approved use, difelikefalin has been studied in people as a medicine taken by mouth ³. A phase 2 trial, an earlier and smaller stage of testing, enrolled 126 patients with moderate-to-severe itch caused by notalgia paresthetica ³. The authors describe that condition as "a neuropathic disorder characterized by pruritus in a circumscribed region of the upper back" ³. In plain terms, it is a nerve-related itch in one patch of the upper back.

The trial was double-blind, and patients took oral difelikefalin or placebo twice daily for 8 weeks ³. It was published on February 9, 2023, and Cara Therapeutics funded it ³. The main analyses covered 62 patients assigned to difelikefalin and 63 assigned to placebo ³. Both groups started at a mean itch score of 7.6 out of 10 ³.

At week 8 the score had fallen by 4.0 points with difelikefalin and by 2.4 points with placebo ³. The difference was 1.6 points in difelikefalin's favor, with a 95 percent confidence interval of 0.6 to 2.6 (P = 0.001) ³. The abstract adds a caution: "The results for the secondary outcomes generally did not support those of the primary analysis" ³. Its authors called the reductions "modestly greater" than with placebo and said the treatment "was associated with adverse events" ³. They concluded: "Larger and longer trials are needed to assess the efficacy and safety of difelikefalin treatment in this disorder" ³.

The label gives no result for body weight in people ¹. Its only weight findings are in pregnant rats and rabbits, in animal safety studies ¹. Neither trial abstract reports a weight, muscle or performance outcome ⁶, ³.

What are the side effects?

The label's side-effect figures pool the two phase 3 trials: 848 patients, 424 given Korsuva and 424 given placebo, followed for up to 12 weeks ¹. Diarrhea was reported by 9.0 percent of patients on the drug and 5.7 percent on placebo ¹. Dizziness was reported by 6.8 and 3.8 percent, nausea by 6.6 and 4.5 percent, and headache by 4.5 and 2.6 percent ¹. Trouble walking, a category that includes falls, was reported by 6.6 and 5.4 percent ¹. Sleepiness, which the label calls somnolence, was reported by 4.2 and 2.4 percent ¹.

Changes in mental status, confusion among them, were reported by 3.3 percent on the drug and 1.4 percent on placebo ¹. High blood potassium, called hyperkalemia, was found in 4.7 and 3.5 percent ¹. Among patients who were also taking opioids, it was found in 11.7 percent on Korsuva and 6.2 percent on placebo ¹. Of that gap the label says, "The clinical relevance of this is unknown" ¹.

Serious adverse reactions developed in 4.5 percent of patients on Korsuva and 2.8 percent on placebo ¹. Treatment was stopped because of an adverse reaction in 2.6 percent and 0.7 percent ¹. Across the phase 3 program, with and without a placebo group, 1,306 patients on hemodialysis received the drug ¹. Of these, 711 were treated for at least six months and 400 for at least a year ¹.

The label lists no contraindications: the section reads "None" ¹. It carries two warnings. The first reads: "Dizziness, somnolence, mental status changes, and gait disturbances, including falls, have occurred in patients taking KORSUVA and may subside over time with continued treatment" ¹.

In the two trials, 17.0 percent of patients given Korsuva reported at least one of these, against 12.0 percent given placebo ¹. Among patients on the drug, sleepiness was reported by 7.0 percent of those 65 or older and 2.8 percent of those younger ¹. The matching placebo rates were 3.0 and 2.1 percent ¹.

The same warning covers other medicines that sedate. It says: "Concomitant use of centrally-acting depressant medications, sedating antihistamines and opioid analgesics may increase the likelihood of these adverse reactions and should be used with caution during treatment with KORSUVA" ¹. Centrally-acting depressants are medicines that slow the brain, and opioid analgesics are opioid painkillers. The second warning concerns driving, and its instruction to prescribers reads: "Advise patients not to drive or operate dangerous machinery until the effect of KORSUVA on a patient's ability to drive or operate machinery is known" ¹.

The label does not recommend the drug in severe liver impairment, where it has not been evaluated ¹. Human data in pregnancy are, in the label's words, "not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage" ¹. There are no data on its presence in human milk, and no clinical studies of drug interactions were conducted ¹. For doses above the recommended one, given in clinical studies, the overdose section reads: "A dose-dependent increase in adverse reactions, including dizziness, somnolence, mental status changes, paresthesia, fatigue, hypertension, and vomiting, were observed" ¹. Paresthesia is tingling or numbness, and hypertension is high blood pressure.

The published trials add two notes. In KALM-1, diarrhea, dizziness and vomiting were more common with difelikefalin than with placebo ⁶. In the trial of the oral form, headache, dizziness, constipation and increased urine output were more frequent with difelikefalin than with placebo ³.

In sport

Difelikefalin is not named on the 2026 Prohibited List of WADA, the World Anti-Doping Agency ⁷. The list's section S7, "Narcotics," names thirteen entries, from buprenorphine to tramadol, one of them "fentanyl and its derivatives," as prohibited in competition ⁷. Difelikefalin is not among them ⁷. It is also not named in section S2, which covers peptide hormones, growth factors, related substances and mimetics ⁷.

The label has the drug given by intravenous injection ¹. The list's rule M2.2 prohibits "intravenous infusions and/or injections of more than a total of 100 mL per 12-hour period except for those legitimately received in the course of hospital treatments, surgical procedures or clinical diagnostic investigations" ⁷.

What JumpstartMD offers

JumpstartMD does not prescribe difelikefalin. Our peptide library covers it so you have the facts on its FDA status and the evidence, current as of November 10, 2026.

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Compounded medications are not FDA-approved, and FDA does not review their safety, effectiveness, or quality before they are marketed. A licensed clinician decides after an evaluation whether a peptide is appropriate for you, and not every patient will qualify.