Korsuva

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.

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

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 syringe preparation. Discard any unused product.

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).

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.

Pediatric Use

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

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)] .

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.

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.

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.