Avalet

Approved Indications:

• Thrombocytopenia in Chronic Liver Disease (CLD):
  Indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a medical or dental procedure.
• Chronic Immune Thrombocytopenia (ITP):
  Indicated for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment (e.g., corticosteroids, immunoglobulins, or splenectomy).

Important Off-label or Investigational Uses:

• Myelodysplastic Syndrome (MDS)-associated thrombocytopenia (under clinical investigation)
• Chemotherapy-induced thrombocytopenia (not yet FDA-approved; under trial)

Chronic Liver Disease–Associated Thrombocytopenia (Adults):

• Recommended Dose:
  60 mg orally once daily for 5 consecutive days in patients with baseline platelet count <40×10⁹/L.
  40 mg orally once daily for 5 consecutive days in patients with baseline platelet count between 40×10⁹/L and 50×10⁹/L.
• Timing: Start 10–13 days prior to the procedure; perform procedure 5–8 days after last dose.

Chronic Immune Thrombocytopenia (Adults):

• Starting Dose: 20 mg orally once daily with food.
• Titration: Adjust in increments of 20 mg every 2 weeks to achieve and maintain platelet counts ≥50×10⁹/L (maximum: 40 mg/day).
• Discontinuation: If platelet count remains <50×10⁹/L after 4 weeks at 40 mg/day, discontinue.

Special Populations:

• Renal Impairment: No dosage adjustment required.
• Hepatic Impairment: No adjustment for Child-Pugh A or B. Use caution in Child-Pugh C.
• Pediatric Use: Safety and efficacy not established in children.

Administration Tips:

• Administer with food to enhance absorption.
• Tablets should not be split or chewed.

Avatrombopag is an orally active small molecule thrombopoietin (TPO) receptor agonist. It binds to and activates the human TPO receptor (c-Mpl) on the surface of megakaryocyte progenitor cells in the bone marrow. This receptor activation stimulates the proliferation and differentiation of these progenitor cells into mature megakaryocytes, thereby increasing platelet production. Unlike endogenous TPO, Avatrombopag does not compete for the same binding site, thus reducing the risk of neutralizing antibody formation.

• Absorption: Oral bioavailability is enhanced with food. Time to peak concentration (Tmax): ~6–8 hours with food.
• Distribution: Highly protein bound (~96%).
• Metabolism: Metabolized primarily by CYP2C9 and CYP3A4 hepatic enzymes.
• Elimination Half-life: Approximately 19 hours (range: 15–28 hours).
• Excretion: Primarily via feces (~88%), minor urinary excretion (~6%).
• Steady-State: Achieved within 5–7 days of once-daily dosing.

• Pregnancy:
  There is insufficient data in pregnant women to establish risk. Animal studies have shown embryo-fetal toxicity at high doses. Avatrombopag should only be used during pregnancy if the potential benefit justifies the risk to the fetus.
• FDA Category: Not formally assigned post-2015. Use caution; consult physician.
• Lactation:
  Unknown whether Avatrombopag is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, a decision should be made whether to discontinue nursing or discontinue the drug.

• Primary Class: Thrombopoietin Receptor Agonist (TPO-RA)
• Sub-class: Non-peptide, small-molecule TPO receptor stimulant

• Known hypersensitivity to Avatrombopag or any of its excipients
• History of thromboembolic disease where risk outweighs benefit
• Use in patients with myelodysplastic syndrome (MDS) not recommended due to potential for leukemic progression

• Thromboembolism Risk:
  Increased platelet counts may elevate risk of thrombotic events, including portal vein thrombosis—particularly in patients with liver disease.
• Monitoring Platelet Count:
  Monitor platelet count prior to initiation, during dose adjustment, and periodically during therapy.
• Hepatic Impairment:
  Use with caution in severe hepatic impairment; risk of overproduction of platelets and thromboembolic complications.
• Discontinuation Risk:
  Upon discontinuation, thrombocytopenia may recur. Monitor for bleeding.
• Malignancy:
  Not indicated for use in myelodysplastic syndromes due to progression to acute myeloid leukemia in some trials.

Common Side Effects:

• Gastrointestinal: Nausea, diarrhea, abdominal pain
• Hematologic: Increased platelet count, fatigue
• Hepatic: Elevated liver enzymes (ALT, AST)
• Neurologic: Headache, dizziness

Serious Side Effects:

• Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, portal vein thrombosis)
• Hepatotoxicity
• Hypersensitivity reactions (rash, pruritus)
• Worsening of underlying hematologic malignancies (in off-label use)

Rare Effects:

• Pancytopenia if used in MDS patients
• Visual disturbances

• CYP450 Enzyme Involvement:
  Avatrombopag is metabolized by CYP2C9 and CYP3A4.
• Strong CYP2C9 or CYP3A4 Inhibitors (e.g., fluconazole, ketoconazole): May increase Avatrombopag exposure.
• CYP Inducers (e.g., rifampin, carbamazepine): May reduce efficacy.
• No Significant Food Interactions:
  Taking with food is recommended to improve bioavailability.
• Alcohol Interaction:
  No direct interaction, but caution advised in patients with liver dysfunction.

• FDA (2020): Approved for chronic ITP following insufficient response to previous therapy.
• EMA: Authorized for the same indications as FDA, with updated guidance on hepatic safety monitoring.
• Ongoing Studies: Investigational use in chemotherapy-induced thrombocytopenia and post-transplant thrombocytopenia.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C.
• Humidity: Store in a dry place, protect from moisture.
• Light Protection: Keep in original packaging to protect from light.
• Handling Precautions: No special handling or reconstitution required.