Avatrombopag

Avatrombopag is a second-generation, orally administered thrombopoietin receptor agonist (TPO-RA) that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in increased platelet production. It does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production.

Avatrombopag is indicated for thrombocytopenia in patients with chronic liver disease scheduled for a procedure and for chronic immune thrombocytopenia in patients with insufficient response to previous treatment. Dosage is based on platelet count.

Common side effects include pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema. Caution is required regarding thrombotic/thromboembolic complications.

• Thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure
• Thrombocytopenia in patients with chronic immune thrombocytopenia who have had insufficient response to previous treatment

Avatrombopag is an orally bioavailable, small molecule TPO receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in increased platelet production. Avatrombopag does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production.

Avatrombopag results in dose- and exposure-dependent elevations in platelet counts. Platelet count increase is observed within 3-5 days of starting a 5-day course, with peak effect at 10-13 days. Platelet counts return to near baseline after 35 days.

Avatrombopag activates the TPO receptor on bone marrow progenitor cells, stimulating megakaryocyte proliferation and differentiation. This leads to increased platelet production and elevated platelet counts, reducing the risk of bleeding.

Chronic Liver Disease (CLD) - Pre-procedure:

• Platelet count <40 × 10⁹/L: 60 mg (3 tablets) once daily for 5 days with food
• Platelet count 40 to <50 × 10⁹/L: 40 mg (2 tablets) once daily for 5 days with food
• Initiate dosing 10-13 days prior to procedure; perform procedure 5-8 days after last dose

Chronic Immune Thrombocytopenia (ITP):

• Initial dose: 20 mg (1 tablet) once daily with food
• Dose level adjustments (based on platelet count):
  • <50 × 10⁹/L after ≥2 weeks: Increase 1 dose level
  • 200-400 × 10⁹/L: Decrease 1 dose level
  • >400 × 10⁹/L: Stop Avatrombopag; monitor twice weekly

ITP Dose Levels: Level 6: 40 mg/day; Level 5: 40 mg 3x/week + 20 mg remaining 4 days; Level 4: 20 mg/day; Level 3: 20 mg 3x/week; Level 2: 20 mg 2x/week OR 40 mg weekly; Level 1: 20 mg weekly

Take with food. For CLD: Once daily for 5 consecutive days with food. For ITP: Once daily with food.

If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and continue with your regular schedule. Do not double the dose.

Chronic Liver Disease (CLD):

• Pyrexia (8-11%)
• Abdominal pain (6-7%)
• Nausea (6-7%)
• Headache (4-7%)
• Fatigue (3-4%)
• Peripheral edema (3-4%)

Chronic ITP:

• Headache, fatigue, confusion, epistaxis, upper respiratory tract infection, arthralgia, gingival bleeding, petechiae, nasopharyngitis

Rare (<1%): Hyponatremia (0.7%)

Serious Precautions:

• TPO receptor agonists are associated with thrombotic and thromboembolic complications
• Portal vein thrombosis reported in patients with chronic liver disease
• Caution in patients with known risk factors for thromboembolism (Factor V Leiden, Prothrombin 20210A, Antithrombin deficiency, Protein C or S deficiency)
• Do not use in an attempt to normalize platelet counts
• Monitor for signs and symptoms of thromboembolic events
• May cause fetal harm during pregnancy
• Breastfeeding not recommended during treatment and for 2 weeks after the last dose

• Hypersensitivity to Avatrombopag or any component

• Moderate or strong dual inhibitors of CYP2C9 and CYP3A4: Increase Avatrombopag AUC, may increase toxicity risk. Reduce starting dose.
• Moderate or strong dual inducers of CYP2C9 and CYP3A4: Decrease Avatrombopag AUC, may reduce efficacy. Increase starting dose.

Take with food for better absorption.

[CONSULT YOUR DOCTOR] Pregnancy Category C. Animal studies showed adverse developmental outcomes during organogenesis. Advise pregnant women of potential risk to the fetus.

[CONSULT YOUR DOCTOR] No data on presence in human milk. Avatrombopag was present in milk of lactating rats. Breastfeeding not recommended during treatment and for at least 2 weeks after the last dose.

Safety and effectiveness in pediatric patients have not been established.

No differences in responses between elderly and younger patients were identified.

Mild-moderate renal impairment (CrCl ≥30 mL/min): No dose adjustment needed (minimally renally excreted).

Severe renal impairment (CrCl <30 mL/min) or hemodialysis: Unknown.

Hepatic impairment (Child-Pugh A, B, C or MELD 4-23): No clinically meaningful effects on pharmacokinetics.

Overdose may cause excessive platelet count increase and thrombotic/thromboembolic complications. Monitor patient and platelet count. Treat thrombotic complications per standard of care. No specific antidote. Hemodialysis is not expected to enhance elimination (only ~6% renally excreted, highly protein-bound).

Keep below 30°C, away from light and moisture. Keep out of reach of children.

Avatrombopag (C₂₉H₃₄Cl₂N₆O₃S₂)