Difelikefalin

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). ( 1 ) Limitation of Use Korsuva has not been studied in patients on peritoneal dialysis and is not recommended for use in this population. ( 1 ) Limitations of Use KORSUVA has not been studied in patients on peritoneal dialysis and is not recommended for use in this population.

Injection: 65 mcg/1.3 mL (50 mcg/mL) of difelikefalin as a clear, colorless solution in a single-dose glass vial. Injection : 65 mcg /1.3 mL (50 mcg/mL) of difelikefalin ( 3 )

None None

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. KORSUVA may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car and operating machinery. 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 .

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. Of the total subjects, 61% were White, 29% were Black or African American, and 5% were Asian. Table 2 summarizes the adverse reactions that occurred at a rate of ≥2% in the KORSUVA group and ≥1% higher than that of the placebo group during the 12-week placebo-controlled period of Trials 1 and 2. The percentage of subjects who discontinued treatment due to any adverse reaction was 2.6% for subjects taking KORSUVA and 0.7% for subjects taking placebo. The most common adverse reactions (≥0.5% of subjects) leading to discontinuation were dizziness (0.9% for KORSUVA and 0.2% for placebo), mental status change (0.7% and 0.2%, respectively), nausea (0.5% and 0%, respectively), and headache (0.5% and 0%, respectively). The percentage of subjects who developed serious adverse reactions was 4.5% in the KORSUVA group and 2.8% in the placebo group. Table 2: Adverse Reactions in ≥ 2% of KORSUVA-Treated Subjects with Moderate-to-Severe CKD-aP Undergoing HD and ≥ 1% Higher Than Placebo in Trials 1 and 2 Adverse Reactions Placebo (N=424) n (%) KORSUVA (N=424) n (%) Diarrhea 24 (5.7) 38 (9.0) Dizziness 16 (3.8) 29 (6.8) Nausea 19 (4.5) 28 (6.6) Gait Disturbances Gait disturbances includes: preferred terms of falls and gait disturbances 23 (5.4) 28 (6.6) Hyperkalemia 15 (3.5) 20 (4.7) Headache 11 (2.6) 19 (4.5) Somnolence 10 (2.4) 18 (4.2) Mental Status Change Mental Status Change includes: preferred terms of confusional state and mental status change. 6 (1.4) 14 (3.3) Description of Selected Adverse Reactions Gait Disturbances, including Falls Gait disturbances, including falls, were reported in 6.6% of subjects receiving KORSUVA compared to 5.4% of subjects who received placebo. Falls were reported as serious adverse reactions in < 1% of subjects receiving KORSUVA and placebo, with one subject discontinuing KORSUVA due to gait disturbance. Dizziness Dizziness was reported in 6.8% of subjects randomized to KORSUVA compared to 3.8% of subjects who received placebo. Dizziness occurred within the first 3 weeks of treatment and was generally transient. Dizziness was serious in 0.2% of KORSUVA-treated subjects compared to 0% of subjects who received placebo and led to discontinuation in 0.9% of KORSUVA-treated subjects compared to 0.2% of subjects who received placebo. Somnolence Somnolence was reported in 4.2% of subjects randomized to receive KORSUVA compared to 2.4% of subjects who received placebo. Somnolence occurred within the first 3 weeks of treatment and tended to subside with continued dosing. Somnolence was serious in 0.2% of KORSUVA-treated subjects compared to 0% of subjects who received placebo. There were no subjects who discontinued KORSUVA due to an adverse reaction of somnolence. Mental Status Change Mental status change (including confusional state) was reported in 3.3% of subjects randomized to receive KORSUVA compared to 1.4% of subjects who received placebo. Most events tended to subside with continued dosing. Mental status change adverse reactions were serious in 1.4% of KORSUVA-treated subjects compared to 0.5% of subjects who received placebo and led to discontinuation in 0.7% of KORSUVA-treated subjects compared to 0.2% of subjects who received placebo. Hyperkalemia Hyperkalemia was found in 4.7% of subjects who received KORSUVA compared to 3.5% of subjects who received placebo. The incidence of hyperkalemia was higher in subjects who took concomitant opioids regardless of treatment and was almost doubled in the KORSUVA group (11.7%) compared to the placebo group (6.2%). The clinical relevance of this is unknown.

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). In an embryofetal development study, difelikefalin was administered by intravenous injection to pregnant rabbits at doses of 0.025, 0.05, and 0.1 mg/kg/day during the period of organogenesis. Maternal toxicity evidenced by decreased maternal body weight gain was noted in all dose groups. Difelikefalin was not associated with embryofetal lethality or fetal malformations at doses up to 0.1 mg/kg/day (10 times the MRHD based on AUC comparison). In a prenatal and postnatal development study, difelikefalin was administered by intravenous injection to pregnant rats at doses of 0.6, 2.5, and 10 mg/kg/day beginning on gestation day 7 and continuing through lactation day 20. Persisting effects on decreased maternal body weight and/or maternal body weight gain as well as food consumption were noted at doses greater than or equal to 2.5 mg/kg/day (68 times the MRHD based on AUC comparison). No maternal effects were observed at 0.6 mg/kg/day (14 times the MRHD based on AUC comparison). No difelikefalin-related effects on postnatal developmental, neurobehavioral, or reproductive performance of offspring were noted at doses up to 10 mg/kg/day (282 times the MRHD based on AUC comparison).

8.2 Lactation Risk Summary There are no data regarding the presence of KORSUVA in human milk or effects on the breastfed infant or on milk production. Studies in rats showed difelikefalin was transferred into the milk in lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KORSUVA and any potential adverse effects on the breastfed child from KORSUVA or from the underlying maternal condition. Data Animal Data Difelikefalin was administered to lactating rats by intravenous injection at doses of 0.6, 2.5, or 10 mg/kg/day from gestation day 7 through lactation day 14. Difelikefalin was detected in the milk of the lactating rats with the concentration ratio for milk:plasma of 0.04 to 0.05 across the doses. There was no measurable difelikefalin in the plasma of nursing pups.

8.4 Pediatric Use The safety and effectiveness of KORSUVA in pediatric patients have not been established.

8.5 Geriatric Use Of the 848 subjects in the placebo-controlled studies who received KORSUVA, 278 subjects (32.8%) were 65 years of age and older and 98 subjects (11.6%) were 75 years of age and older. No overall differences in safety or effectiveness of KORSUVA have been observed between patients 65 years of age and older and younger adult subjects, with the exception of the incidence of somnolence which 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%), and was comparable in both placebo age groups (3.0% and 2.1%, respectively). No differences in plasma concentrations of KORSUVA were observed between subjects 65 years of age and older and younger adult subjects [see Clinical Pharmacology (12.3) ] .

8.6 Hepatic Impairment The influence of mild-to-moderate hepatic impairment on the pharmacokinetics of KORSUVA was evaluated in a population pharmacokinetic analysis which concluded that no KORSUVA dosage adjustments are needed in these populations [see Clinical Pharmacology (12.3) ] . The influence of severe hepatic impairment on the pharmacokinetics of KORSUVA in subjects undergoing HD has not been evaluated; therefore, use of KORSUVA in this population is not recommended.

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