Approved & therapeutic
Difelikefalin
Korsuva
Difelikefalin is a peripherally restricted kappa opioid receptor agonist approved in the US for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. It is given intravenously into the dialysis circuit at the end of each dialysis session.
- Status
- Difelikefalin is approved by the U.S. FDA and has official prescribing information.
- Evidence
- Approved labeling. Official prescribing information exists, based on clinical trials in people.
- Half-life
- Approximately 23 to 31 hours in subjects on hemodialysis when measured before dialysis (label section 12.3). The label does not report a half-life in subjects with normal renal function. The prolonged half-life reflects the absence of renal clearance between dialysis sessions; hemodialysis reduces plasma concentrations by 70 to 80 percent per session, and in hemodialysis patients about 59 percent of a dose is recovered in feces, 20 percent in dialysate and 11 percent in urine.
- How it's taken
- Intravenous bolus injection into the venous line of the hemodialysis circuit
- Mechanism
- Other
How Difelikefalin works
Difelikefalin is a synthetic D-amino acid tetrapeptide that agonises kappa opioid receptors. Its hydrophilic peptide structure limits penetration of the blood-brain barrier, so activity is largely confined to peripheral sensory neurons and immune cells. It has no meaningful activity at the mu opioid receptor. The precise mechanism of its antipruritic effect in chronic kidney disease-associated pruritus is not fully established.
What research has looked at
- The primary efficacy endpoint in the US label is the proportion of patients achieving at least a 4-point improvement from baseline in the weekly mean 24-hour worst itching numerical rating scale at week 12. In Trial 1 this was 40 percent on difelikefalin versus 21 percent on placebo; in Trial 2 it was 37 percent versus 26 percent.
- The trials' own protocol-specified primary outcome used a 3-point threshold. In KALM-1 as published, at least a 3-point improvement was achieved by 51.9 percent versus 30.9 percent on placebo. FDA review designated the 4-point threshold as the primary outcome for labeling, so the 3-point result should not be read as the approved efficacy standard.
- Pre-specified secondary endpoints in KALM-1 showed statistically significant improvement in two itch-related quality-of-life instruments: the 5-D itch scale (change from baseline -5.0 versus -3.7 on placebo) and Skindex-10 (-17.2 versus -12.0).
- Efficacy was established over 12 weeks. Long-term efficacy beyond 12 weeks has not been characterised.
- An oral formulation was tested for pruritus in notalgia paresthetica and the study was terminated because it did not demonstrate a meaningful clinical benefit at any dose compared with placebo; the program was discontinued in 2024. That negative result concerns the oral formulation in a different indication and does not apply to the approved intravenous product.
Evidence level: Approved labeling. Official prescribing information exists, based on clinical trials in people. These are areas studied or reported, not promised effects.
Reported side effects and risks
- The label lists no contraindications and no boxed warning.
- Dizziness, somnolence, mental status changes and gait disturbances including falls; the label notes additive risk with centrally acting depressants, sedating antihistamines and opioid analgesics.
- Risk when driving or operating machinery until the effect on the individual is known.
- Adverse reactions more frequent than placebo were diarrhea (9.0 percent versus 5.7 percent), dizziness (6.8 percent versus 3.8 percent), nausea (6.6 percent versus 4.5 percent), gait disturbances including falls (6.6 percent versus 5.4 percent), hyperkalemia (4.7 percent versus 3.5 percent), headache (4.5 percent versus 2.6 percent), somnolence (4.2 percent versus 2.4 percent) and mental status change (3.3 percent versus 1.4 percent).
- Patients 65 years and older had a higher incidence of somnolence (7.0 percent) than patients under 65 (2.8 percent), with no comparable difference on placebo.
- The effect of severe hepatic impairment on the pharmacokinetics of difelikefalin is unknown and use is not recommended in that population. No dosage adjustment is needed for mild-to-moderate hepatic impairment.
- It has not been studied in patients on peritoneal dialysis and is not recommended in that population.
Sources
- PubMed research on Difelikefalin · NIH · National Library of Medicine
- DrugBank record for Difelikefalin · DrugBank
- Active clinical trials for Difelikefalin · U.S. National Library of Medicine
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Difelikefalin FAQ
What is Difelikefalin?
Difelikefalin is a peripherally restricted kappa opioid receptor agonist approved in the US for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. It is given intravenously into the dialysis circuit at the end of each dialysis session.
How does Difelikefalin work?
Difelikefalin is a synthetic D-amino acid tetrapeptide that agonises kappa opioid receptors. Its hydrophilic peptide structure limits penetration of the blood-brain barrier, so activity is largely confined to peripheral sensory neurons and immune cells. It has no meaningful activity at the mu opioid receptor. The precise mechanism of its antipruritic effect in chronic kidney disease-associated pruritus is not fully established.
Is Difelikefalin FDA approved?
Yes. Difelikefalin is approved by the U.S. FDA and has official prescribing information. Evidence level: approved labeling. Official prescribing information exists, based on clinical trials in people.
What is the half-life of Difelikefalin?
Reported half-life: Approximately 23 to 31 hours in subjects on hemodialysis when measured before dialysis (label section 12.3). The label does not report a half-life in subjects with normal renal function. The prolonged half-life reflects the absence of renal clearance between dialysis sessions; hemodialysis reduces plasma concentrations by 70 to 80 percent per session, and in hemodialysis patients about 59 percent of a dose is recovered in feces, 20 percent in dialysate and 11 percent in urine.
How is Difelikefalin taken?
Intravenous bolus injection into the venous line of the hemodialysis circuit.
What side effects have been reported with Difelikefalin?
Reported in the sources: The label lists no contraindications and no boxed warning; Dizziness, somnolence, mental status changes and gait disturbances including falls; the label notes additive risk with centrally acting depressants, sedating antihistamines and opioid analgesics; Risk when driving or operating machinery until the effect on the individual is known; Adverse reactions more frequent than placebo were diarrhea (9.0 percent versus 5.7 percent), dizziness (6.8 percent versus 3.8 percent), nausea (6.6 percent versus 4.5 percent), gait disturbances including falls (6.6 percent versus 5.4 percent), hyperkalemia (4.7 percent versus 3.5 percent), headache (4.5 percent versus 2.6 percent), somnolence (4.2 percent versus 2.4 percent) and mental status change (3.3 percent versus 1.4 percent); Patients 65 years and older had a higher incidence of somnolence (7.0 percent) than patients under 65 (2.8 percent), with no comparable difference on placebo; The effect of severe hepatic impairment on the pharmacokinetics of difelikefalin is unknown and use is not recommended in that population. No dosage adjustment is needed for mild-to-moderate hepatic impairment; It has not been studied in patients on peritoneal dialysis and is not recommended in that population.
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