Difelikefalin (Monograph)

Brand name: Korsuva
Drug class: Skin and Mucous Membrane Agents, Miscellaneous

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

A kappa opioid receptor agonist.

Uses for Difelikefalin

Pruritis Associated with Chronic Kidney Disease

Used for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD).

Not studied in patients on peritoneal dialysis; not recommended for use in this population.

Current guidelines from the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) and the Kidney Disease: Improving Global Outcomes (KDIGO) on management of CKD do not provide specific recommendations on treatment of CKD-aP.

Although several drugs (e.g., gabapentin, pregabalin, antihistamines, corticosteroids) have been used , poor tolerability and lack of antipruritic efficacy have limited use. Difelikefalin may provide a treatment option in patients with CKD-aP.

Difelikefalin Dosage and Administration

General

Pretreament Screening

• Evaluate patient use of centrally-acting depressant medications, sedating antihistamines, and opioid analgesics as concomitant use increases the risk of CNS effects.

Patient Monitoring

• Monitor for somnolence, dizziness, and mental status changes.

Administration

IV Administration

Administer by IV bolus injection into the venous line of the dialysis circuit at the end of each hemodialysis (HD) treatment. Administer dose either during or after rinse back of the dialysis circuit. If the dose is given after rinse back, follow the injection with at least 10 mL of normal saline flush. If the dose is given during rinse back, no additional normal saline is needed.

Do not mix or dilute solution. Administer dose within 60 minutes of syringe preparation. Discard any unused product.

If a HD treatment is missed, resume difelikefalin at the end of the next treatment.

Dosage

Adults

Pruritus Associated with CKD

IV

0.5 mcg/kg as an IV bolus injection into the venous line of the dialysis circuit at the end of each HD treatment.

The injection volume to be administered is based on the patent's target dry body weight as described below (see Table 1). For target dry body weights not listed, use the formula:

Total Injection Volume (mL) = Patient Target Dry Body Weight (kg) x 0.01, rounded to the nearest tenth (0.1 mL)

Special Populations

Hepatic Impairment

No dosage adjustment for mild to moderate hepatic impairment. Not studied and not recommended in patients with severe hepatic impairment.

Renal Impairment

Indicated for use in patients undergoing HD.

Geriatric Patients

No specific dosage recommendations.

Related/similar drugs

Korsuva

Cautions for Difelikefalin

Contraindications

• None.

Warnings/Precautions

CNS Effects

Dizziness, somnolence, mental status changes, and gait disturbances, including falls, have occurred and may subside over time. Incidence of somnolence is higher in patients ≥65 years of age.

Use caution when used concomitantly with centrally-acting depressant medications, sedating antihistamines, and opioid analgesics.

Risk of Driving and Operating Machinery

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 difelikefalin on a patient’s ability to drive or operate machinery is known.

Specific Populations

Pregnancy

Limited human data on use in pregnancy to evaluate a drug-associated risk for major birth defects or miscarriage. No adverse effects observed in animal reproduction studies.

Lactation

No data regarding presence of difelikefalin in human milk, effects on the breastfed infant, or on milk production. Distributed into milk of lactating rats. When a drug is present in animal milk, it is likely it will be present in human milk.

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for difelikefalin and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety or effectiveness observed between patients ≥65 years of age and younger patients, with the exception of a higher incidence of somnolence in geriatric patients.

Hepatic Impairment

Mild to moderate impairment: no significant pharmacokinetic differences observed.

Severe impairment: not studied and therefore not recommended.

Common Adverse Effects

Most common adverse reactions (≥2%): diarrhea, dizziness, nausea, gait disturbances (including falls), hyperkalemia, headache, somnolence, mental status changes.

Drug Interactions

No clinical studies evaluating drug interaction potential of difelikefalin.

Not a substrate of CYP enzymes.

Does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 3A, or 2D6 or induce CYP1A2, CYP2B6, or CYP3A.

Not an inhibitor of UGT1A3, 1A9, or 2B7.

Does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, OAT polypeptide (OATP)1B1, OATP1B3, multidrug and toxic compound extrusion (MATE)1, or MATE2-K.

Not a substrate of OAT1, OAT2, OAT3, OATP1A2, OCT2, OCT3, L-type amino acid transporter (LAT)1, peptide transporter (PEPT)1, PEPT2, apical sodium-dependent bile acid transporter (ASBT), bile salt export pump (BSEP), multidrug resistance protein (MRP)2, OATP1B1, OATP1B3, OATP2B1, OCT1, novel OCT (OCTN)1, OCTN2, P-gp, BCRP, organic solute transporter (OST)α/β, MATE1, or MATE2-K.

Difelikefalin Pharmacokinetics

Absorption

Bioavailability

Dose-proportional pharmacokinetics over single and multiple IV dosages in patients undergoing hemodialysis (HD)

Steady-state reached after second administered dose

Distribution

Plasma Protein Binding

23–28% in patients undergoing HD

Elimination

Elimination Route

Urine: 11%

Feces: 69%

Dialysate fluid: 20%; HD reduced plasma concentrations by 70 to 80%; difelikefalin concentrations undetectable after 2 dialysis cycles

Half-life

23 to 31 hours (prior to dialysis)

Special Populations

No clinically significant differences based on age (25–80 years), sex, race/ethnicity, or mild to moderate hepatic impairment

Stability

Storage

Parenteral

Injection

20–25°C (excursions permitted between 15–30°C).

Prepared syringe: 20–25°C until dosing. Dose must be administered within 60 minutes of syringe preparation.

Actions

• A selective kappa opioid receptor (KOR) agonist with greater affinity for KOR than mu opioid receptors.

• Alleviation of itching postulated to occur through activation of KOR on peripheral sensory neurons and immune cells as well as through a reduction in inflammatory markers.

• Due to its hydrophilicity, there is minimal penetration across the blood-brain barrier.

Advice to Patients

• Inform patients that dizziness, somnolence, mental status changes, and gait disturbances, including falls, can occur. Somnolence is more likely in patients who are ≥65 years of age. Inform patients that concomitant treatment with centrally-acting depressants, sedating antihistamines, and opioid analgesics may increase the likelihood of these adverse reactions and should be used with caution during treatment.

• Inform patients that difelikefalin may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to drive or operate machinery until they know how they react to treatment.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of the importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, and any concomitant illnesses.

• Inform patients of other precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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