Generic Name

Yeztugo

Mechanism

Difelikefalin is a tetrapeptide (D–phenylalanine–D‑leucine–D‑lysine–D‑phenylalanine) that binds with high affinity to peripheral κ‑opioid receptors (KOR) while exhibiting minimal blood‑brain‑barrier penetrance.

* Receptor selectivity – >1,000‑fold greater affinity for KOR versus μ‑ and δ‑opioid receptors, reducing risk of euphoria or respiratory depression.
* Anti‑pruritic effect – KOR activation in dorsal root ganglia dampens itch signaling by inhibiting substance P release and modulating peripheral sensory neuron excitability.
* Minimal CNS activity – the peptide’s large polar structure and rapid degradation in plasma limit central nervous system (CNS) exposure.

Pharmacokinetics

Indications

* Pruritus associated with CKD requiring dialysis – Adults undergoing hemodialysis or peritoneal dialysis.

Contraindications

* Allergy – Contraindicated in patients with known hypersensitivity to any component of Yeztugo.
* Severe hypotension or bradycardia – May exacerbate.
* Pregnancy & Lactation – Not studied; potential risks outweigh benefits.
* CNS depression – Use cautiously with CNS depressants (benzodiazepines, opioids).

Warnings
* Hemodynamic instability – Monitor BP and heart rate during infusion; treat hypotension promptly.
* Potential for respiratory depression – Although rare, keep patients in a monitored setting.
* Infection risk – As with all IV therapies, ensure aseptic technique to reduce line‑associated infections.

Dosing

* Premedication – Not required; but anti‑emetics may be considered for patients with a history of nausea.

Adverse Effects

Common (≥10 %)
* Nausea
* Dizziness
* Headache
* Constipation
* Hypotension (often transient)

Serious (≤5 %)
* Bradyarrhythmias
* Severe respiratory depression (very rare)
* Anaphylactic reactions

Adverse reactions are generally mild to moderate and resolve upon completion of the infusion or dose adjustment.

Monitoring

* Vital signs – BP and HR before, during, and after infusion.
* Pruritus severity – Use validated scales (e.g., 5‑point itch severity scale) pre‑ and post‑dialysis.
* Renal function – Creatinine, eGFR; not necessary to modify dose in dialysis, but monitor for fluid shifts.
* Lab values – Complete metabolic panel periodically to detect electrolyte disturbances.
* Infusion site – Inspect for infiltration, phlebitis, or extravasation.

Clinical Pearls

1. Start low and titrate – Begin with a slow infusion (15 min) to assess tolerability, especially in patients with pre‑existing hypotension.

2. Avoid concurrent opioid analgesics – Though Yeztugo has low μ‑opioid activity, concurrent systemic opioids may synergistically depress CNS and respiratory centers.

3. Dialysis timing is critical – Infuse at the very beginning of the session to maximize exposure when fluid shifts are most pronounced; this reduces pruritus during the remainder of the session.

4. Monitor for paradoxical itch – In rare cases, patients report increased itching after stopping Yeztugo; ensure a tapering plan or switch to alternative anti‑itch therapies.

5. Patient education – Reinforce that Yeztugo does not replace dialysis; it treats the symptom of pruritus and should be paired with adequate fluid and toxin removal.

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• *This drug card is intended for educational purposes. Clinical decisions should be guided by the most current prescribing information and individualized patient factors.*