Difelikefalin

In registration trials of difelikefalin, elevations in serum liver-associated enzyme levels were uncommon and no more frequent than in controls. Serum alkaline phosphatase elevations occurred in 12.7% vs 12.0% of participants, and there were no ALT elevations above 3 times the upper limit of normal (ULN). Since approval and more widespread use of difelikefalin, there have been no published reports of hepatotoxicity attributed to its use.

Phase 3 clinical trials involving patients with end-stage renal disease requiring dialysis suffering from uremic pruritus involved a study design. Patients received IV difelikefalin at weight-based doses of 1.0 mcg per kg 3 times a week in the venous circuit of their dialysis machine for 12 weeks. This study demonstrated the following most common adverse effects:

At supratherapeutic levels (15 mcg per mL), concern for respiratory depression or euphoric effects has not been demonstrated. Difelikefalin has been studied in rats and determined to cause diuresis by activating central kappa opioid receptors. Mild to moderate hypernatremia has been reported at supratherapeutic doses of 1.0, 2.0, and 5.0 mcg per kg. Any induced electrolyte imbalance observed during treatment should be managed per the standard of care in conjunction with the termination of medication administration and identification of any additional etiologies for the electrolyte disturbance. The adverse effects mentioned previously, including hypoesthesia, paresthesia, and somnolence, are self-limiting at supratherapeutic doses.

V - Various

QV - Various

Difelikefalin is administered to patients undergoing hemodialysis for chronic kidney disease (CKD) to prevent and treat the pruritus often associated with CKD. It is administered via bolus intravenous injection at the end of each hemodialysis treatment. As it works on opioid receptors, difelikefalin can cause dizziness, somnolence, and other CNS depressant effects that may impair mental or physical abilities - as such, patients should be advised to avoid operating dangerous machinery until the effect of difelikefalin on that patient is known.

Difelikefalin is a synthetic peptide and agonist of kappa opioid receptors (KORs), which have long been known to be involved with the itching sensation (in addition to playing some role in addiction). Endogenous KOR agonists - called dynorphins - have a neuroinhibitory effect on the itching sensation at the spinal cord level and mouse models have shown KOR agonist antipruritic activity when used to treat itching induced by different pruritogens. Although the specifics of the mechanism have yet to be elucidated, the administration of KOR agonists, like difelikefalin, in patients with uremic pruritus has proven an effective means to suppress scratching and improve their quality of life.

NA1U919MRO

DIFELIKEFALIN

Established Pharmacologic Class [EPC] - Kappa Opioid Receptor Agonist