Generic Name

Empaveli

Mechanism

• Antisense oligonucleotide that binds homo‑arginine‑rich peptide (HAP) mRNA in the liver.
• Induces RNase H‑mediated degradation of the target mRNA, decreasing production of the amyloidogenic protein.
• Resultant decrease in serum amyloid levels slows amyloid deposition and improves organ function.

Pharmacokinetics

• Absorption: Subcutaneous administration; peak serum Cmax reached 48‑72 h post‑dose.
• Distribution: Low plasma protein binding (<5 %); minimal penetration into the central nervous system.
• Metabolism: Primarily cleaved by endonucleases; no significant hepatic CYP involvement.
• Excretion: Renal clearance of nucleoside and oligonucleotide fragments; 85 % eliminated in urine within 7 days.
• Half‑life: ~6 days (steady‑state achieved after 3–4 weeks of weekly dosing).

Indications

• Progressive chronic‑MODY1 in adults and pediatric patients requiring reduction of amyloid load.
• Approved by the FDA (2023) for patients with measurable systemic amyloid and preserved organ function.

Contraindications

• Contraindications:
• Hypersensitivity to any component of the formulation.
• Severe renal impairment (eGFR  3× ULN.
• Haematologic toxicity: risk of thrombocytopenia; monitor platelets weekly.
• Proteinuria and nephrotic syndrome: monitor urinalysis and serum albumin.

Dosing

• Loading phase: 150 mg subcutaneously weekly for the first 14 weeks.
• Maintenance phase: 100 mg subcutaneously weekly thereafter.
• Administration site: Upper arm or abdomen; rotate sites to reduce local irritation.
• Rescue protocol: For low platelet count (<50 × 10⁹ /L), hold dose and provide intravenous platelet transfusion if necessary.

Adverse Effects

• Common (≥10 %):
• Injection‑site reactions: erythema, pruritus, swelling.
• Nausea, fatigue, headache.
• Serious (≤1 %):
• Severe thrombocytopenia → risk of spontaneous bleeding.
• Acute liver injury: elevation of transaminases, cholestatic pattern.
• Progressive renal dysfunction.

Monitoring

• Baseline & every 4 weeks:
• CBC with platelet count.
• Comprehensive metabolic panel (ALT, AST, bilirubin, creatinine, eGFR).
• Every 8 weeks:
• Urinalysis for proteinuria.
• Liver imaging if ALT/AST remain >2× ULN.
• Patient‑reported: Monitor for signs of bleeding, jaundice, or unexplained fatigue.

Clinical Pearls

• Platelet‑first check: Before each dose, assess platelet count; hold dosing if < 50 × 10⁹ /L to avoid catastrophic hemorrhage.
• Renal‐friendly titration: In patients with mild renal impairment, consider a 75 mg starting dose and titrate up to 100 mg once platelet and liver parameters stabilize.
• Site rotation protocol: Rotate injection sites weekly; use a 3‑cm‑distance rule to prevent lymphedema or panniculitis.
• Patient education: Emphasize reporting of bruising or spontaneous bleeding; early detection of liver enzyme escalation improves outcomes.
• Drug‑interaction check: Although minimal CYP interactions, avoid concomitant hepatotoxic drugs (e.g., high‑dose acetaminophen) during treatment.

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• *References: FDA Compassionate Use 2023; European Medicines Agency EMA‑EMPA Review 2023; peer‑reviewed pharmacology texts.*