Korsuva Drug Information

Korsuva is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD). Limitation of Use Korsuva has not been studied in patients on peritoneal dialysis and is not recommended for use in this population.

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. If a regularly scheduled HD treatment is missed, resume KORSUVA at the end of the next HD treatment.

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 2

Administration Instructions KORSUVA is removed by the dialyzer membrane and must be administered after blood is no longer circulating through the dialyzer. Administer KORSUVA by intravenous bolus injection into the venous line of the dialysis circuit at the end of each HD session. The dose may be given either during or after rinse back of the dialysis circuit.

If the dose is given after rinse back, administer KORSUVA into the venous line followed by at least 10 mL of normal saline flush. If the dose is given during rinse back, no additional normal saline is needed to flush the line. The dose must be administered within 4 hours of the syringe preparation.

Discard any unused product.

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). Of the total subjects, 61% were White, 29% were Black or African American, and 5% were Asian.

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 percentage of subjects who developed serious adverse reactions was 4.5% in the KORSUVA group and 2.8% in the placebo group. 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. 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.

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.

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).

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

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.