Difelikefalin

KORSUVA is a kappa opioid receptor (KOR) agonist. The relevance of KOR activation to therapeutic effectiveness is not known.

• KORSUVA is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD). KORSUVA is a kappa opioid receptor agonist indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD).ICD-10: N18.9

• None Nonecontraindicated

Recommended dosage is 0.5 mcg/kg. ( 2.1 ) Administer by intravenous bolus injection into the venous line of the dialysis circuit at the end of each HD treatment. ( 2.1 ) Do not mix or dilute KORSUVA prior to administration. ( 2.2 ) Administer within 4 hours of syringe preparation. ( 2.3 ) See full prescribing information for additional recommendations on preparation and administration of KORSUVA. ( 2.2 , 2.3 ) 2.1 Dosage The recommended dosage of KORSUVA is 0.5 mcg/kg administered by intravenous bolus injection into the venous line of the dialysis circuit at the end of each HD treatment [see Dosage and Administration (2.3) ] . If a regularly scheduled HD treatment is missed, resume KORSUVA at the end of the next HD treatment. 2.2 Preparation Instructions Do not mix or dilute KORSUVA prior to administration. Inspect KORSUVA for particulate matter and discoloration prior to administration. The solution should be clear and colorless. Do not use KORSUVA vials if particulate matter or discoloration is observed. KORSUVA is supplied in a single-dose vial. Discard any unused product. Injection volume to be administered is determined by patient's target dry body weight in kilograms (one patient may use less than the full contents of the vial or use more than one vial). See Table 1 . Table 1. KORSUVA Injection Volumes Based on Target Dry Body Weight Target Dry Body Weight Range (kg) Injection Volume (mL) Total Injection Volume (mL) = Patient Target Dry Body Weight (kg) x 0.01, rounded to the nearest tenth (0.1 mL).

Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances: Dizziness, somnolence, mental status changes, and gait disturbances, including falls, have occurred. Centrally-acting depressant medications, sedating antihistamines, and opioid analgesics should be used with caution during treatment with KORSUVA. ( 5.1 ) Risk of Driving and Operating Machinery: May impair mental or physical abilities. 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. ( 5.2 ) 5.1 Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances Dizziness, somnolence, mental status changes, and gait disturbances, including falls, have occurred in patients taking KORSUVA and may subside over time with continued treatment [see Adverse Reactions (6.1) ] . In Trial 1 and Trial 2, 17.0% of patients randomized to receive KORSUVA reported at least one of these adverse reactions, compared to 12.0% of patients who received placebo. The incidence of somnolence was higher in KORSUVA-treated subjects 65 years of age and older (7.0%) than in KORSUVA-treated subjects less than 65 years of age (2.8%). 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. 5.2 Risk of Driving and Operating Machinery Dizziness, somnolence, and mental status changes have occurred in patients taking KORSUVA.

The following clinically significant adverse reactions are described elsewhere in the labeling: Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances [see Warnings and Precautions (5.1) ] The most common adverse reactions (incidence ≥2% and ≥1% higher than placebo) were diarrhea, dizziness, nausea, gait disturbances, including falls, hyperkalemia, headache, somnolence, and mental status change. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Vifor (International) Inc. at 1-844-835-8277 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 1306 subjects undergoing HD who had moderate-to-severe pruritus were treated with KORSUVA in placebo-controlled and uncontrolled Phase 3 clinical trials. Of these, 711 were treated for at least 6 months and 400 were treated for at least one year. Two placebo-controlled Phase 3 trials (Trial 1 and Trial 2), in subjects undergoing HD who had moderate-to-severe pruritus were pooled to evaluate the safety of KORSUVA in comparison to placebo up to 12 weeks. In total, 848 subjects were evaluated (424 in KORSUVA group and 424 in placebo group). The mean age of the subjects was 59 years (range 22 to 88 years), and 59% of the subjects were male.

Severe Hepatic Impairment: Not recommended in patients with severe hepatic impairment. ( 8.6 ) 8.1 Pregnancy Risk Summary The limited human data on use of KORSUVA in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. In animal reproduction studies, intravenous injection of difelikefalin to pregnant rats and rabbits during the period of organogenesis at doses 711 and 10 times the maximum recommended human dose (MRHD), respectively, resulted in no adverse effects in either rats or rabbits (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryofetal development study, difelikefalin was administered by intravenous injection to pregnant rats at doses of 0.25, 2.5, and 25 mg/kg/day during the period of organogenesis. Difelikefalin was not associated with embryofetal lethality or fetal malformations. Difelikefalin increased the incidences of skeletal variations (wavy ribs and incompletely ossified ribs) at the dose of 25 mg/kg/day (711 times the MRHD based on AUC comparison).

Metabolism

The pharmacokinetics of difelikefalin is dose proportional over a single dosage range from 1 to 3 mcg/kg (2 to 6 times the recommended dosage) and multiple intravenous dosage range from 0.5 to 2.5 mcg/kg (1 to 5 times the recommended dosage) in chronic kidney disease patients undergoing HD. Steady-state was reached after the second administered dosage and the mean accumulation ratio was up to 1.6.

Single doses of KORSUVA up to 12 times and multiple doses of KORSUVA up to 5 times the recommended dosage of 0.5 mcg/kg were administered in clinical studies in subjects undergoing HD. A dose-dependent increase in adverse reactions, including dizziness, somnolence, mental status changes, paresthesia, fatigue, hypertension, and vomiting, were observed. In the event of overdosage, provide the appropriate medical attention based on patient's clinical status. Difelikefalin is primarily eliminated by the kidneys with a low plasma protein binding of approximately 23% to 28% in dialysis patients. Hemodialysis for 4 hours using a high-flux dialyzer effectively cleared approximately 70% to 80% of difelikefalin from plasma, and difelikefalin was not detectable in plasma at the end of the second of two dialysis cycles. [see Clinical Pharmacology (12.3) ].

• Aug 23, 2021NDANDA214916Vifor Intl

1. 1Dizziness4211%
2. 2Somnolence369.3%
3. 3Fall348.8%
4. 4Death287.2%
5. 5Drug Ineffective246.2%
6. 6Mental Status Changes235.9%
7. 7Confusional State194.9%
8. 8Nausea184.7%
9. 9Hallucination164.1%
10. 10Asthenia153.9%
11. 11Pruritus153.9%
12. 12Drug Reaction With Eosinophilia And Systemic Symptoms143.6%
13. 13Off Label Use133.4%
14. 14Gait Disturbance112.8%
15. 15Hypotension112.8%

The 10 most recently updated of 23 ClinicalTrials.gov registrations naming Difelikefalin as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• Safety and Tolerability of Difelikefalin in Adolescents on Haemodialysis With Moderate-to-Severe Pruritus
  Recruiting · Phase 2 · Interventional · 18 enrolled · Vifor Fresenius Medical Care Renal Pharma
  NCT06593392updated 2026-06-11
• Difelikefalin for Itching in Hemodialysis Patients With Chronic Kidney Disease
  Not yet recruiting · Interventional · 106 enrolled · Chittagong Medical College
  NCT07526324updated 2026-04-13
• Phase 3 Study of Difelikefalin in Haemodialysis Chinese Adult Subjects With Moderate-to-Severe Pruritus
  Completed · Phase 3 · Interventional · 260 enrolled · Vifor Fresenius Medical Care Renal Pharma
  NCT05885737updated 2025-09-12
• Pharmacokinetics of Intravenous Difelikefalin in Chinese Adult Subjects on Haemodialysis
  Completed · Phase 1 · Interventional · 30 enrolled · Vifor Fresenius Medical Care Renal Pharma
  NCT05885763updated 2025-02-14
• Study to Evaluate the Efficacy and Safety of Oral Difelikefalin for Moderate to Severe Pruritus in Subjects With Notalgia Paresthetica
  Terminated · Phase 2 · Phase 3 · Interventional · 214 enrolled · Cara Therapeutics, Inc.
  NCT05978063updated 2024-06-21
• A Study to Evaluate the Safety and Efficacy of Difelikefalin in Advanced Chronic Kidney Disease Patients With Moderate-to-Severe Pruritus
  Terminated · Phase 3 · Interventional · 286 enrolled · Cara Therapeutics, Inc.
  NCT05342623updated 2024-05-07
• CR845-310302: A Study to Evaluate the Safety and Efficacy of Difelikefalin in Advanced Chronic Kidney Disease Patients With Moderate-to-Severe Pruritus
  Terminated · Phase 3 · Interventional · 105 enrolled · Cara Therapeutics, Inc.
  NCT05356403updated 2024-05-07
• Study to Evaluate the Efficacy and Safety of Oral Difelikefalin as Adjunct Therapy to a Topical Corticosteroid for Moderate to Severe Pruritus in Subjects With Atopic Dermatitis
  Terminated · Phase 3 · Interventional · 287 enrolled · Cara Therapeutics, Inc.
  NCT05387707updated 2024-02-22
• A Study to Evaluate the Safety and Efficacy of CR845 in Chronic Kidney Disease Patients With Moderate-to-Severe Pruritus
  Completed · Phase 2 · Interventional · 269 enrolled · Cara Therapeutics, Inc.
  NCT03617536updated 2024-01-24
• Study to Evaluate the Safety and Efficacy of Oral CR845 (Difelikefalin) in Patients With Primary Biliary Cholangitis (PBC) and Moderate-to-Severe Pruritus
  Terminated · Phase 2 · Interventional · 14 enrolled · Cara Therapeutics, Inc.
  NCT03995212updated 2023-07-03

Frequently asked questions

How does Difelikefalin work?

KORSUVA is a kappa opioid receptor (KOR) agonist. The relevance of KOR activation to therapeutic effectiveness is not known.

What is Difelikefalin used for?

According to FDA labeling, Difelikefalin carries indications including: KORSUVA is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD). KORSUVA is a kappa opioid receptor agonist indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD).. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Difelikefalin?

Difelikefalin is classified as Other therapeutic products, Kappa Opioid Receptor Agonist, Opioid Agonists, Opioid kappa Receptor Agonists, Peripheral Nervous System Activity Alteration.

What are the brand names for Difelikefalin?

Difelikefalin is marketed under brand names including Korsuva.

What are the contraindications for Difelikefalin?

Difelikefalin labeling lists contraindications including: None None. Always consult the full prescribing information and a clinician.