Oral Thrombocytopenia associated with chronic liver disease
Adult: In patients who are scheduled to undergo an invasive procedure: Dose is individualised based on the platelet count of the patient. Baseline platelet count: <40 x 109/L: 60 mg once daily; ≥40-<50 x 109/L: 40 mg once daily. Max treatment duration: 5 days. Initiate treatment 10-13 days before the scheduled procedure; the procedure must be carried out 5-8 days after the last dose.
Oral Chronic immune thrombocytopenia
Adult: In patients who are refractory to other therapy (e.g. corticosteroids, immunoglobulins): Initially, 20 mg once daily. Dose adjustments, dosing interruption, or discontinuation may be required according to platelet count response. Max: 40 mg daily. Use the lowest dose needed to achieve and maintain a platelet count of ≥50 x 109/L as needed to reduce bleeding risk. Refer to detailed product guideline for further information.
Special Patient Group
Chronic immune thrombocytopenia:
Patients taking moderate or strong inhibitors of both CYP2C9 and CYP3A4, or of CYP2C9 alone: Initially, 20 mg 3 times weekly.
Patients taking moderate or strong inducers of both CYP2C9 and CYP3A4, or of CYP2C9 alone: Initially, 40 mg once daily.
Pharmacogenomics:
Avatrombopag is mainly metabolised by CYP2C9 and CYP3A4 isoenzymes. Individuals with CYP2C9*2 and CYP2C9*3 loss-of-function polymorphisms may have increased avatrombopag exposure leading to increased risk of clinically relevant QTc prolongation.
Administration
Should be taken with food.
Special Precautions
Patient with known risk factors for thromboembolism (e.g. Factor V Leiden, prothrombin 20210A, antithrombin deficiency, protein C or S deficiency, prolonged periods of immobilisation, malignancies, contraceptive and hormone replacement therapy, surgery or trauma, obesity, smoking). Patient taking moderate or strong inducers or inhibitors of both CYP2C9 and CYP3A4, or of CYP2C9 alone. Not intended for use to normalise platelet counts. Severe hepatic impairment. Pregnancy and lactation. Individuals with CYP2C9*2 and CYP2C9*3 alleles.
Adverse Reactions
Significant: Thrombotic and thromboembolic complications (e.g. arterial and venous thromboembolic events, portal vein thrombosis), increased bone marrow reticulin; reoccurrence of thrombocytopenia (upon discontinuation). Blood and lymphatic system disorders: Anaemia, splenomegaly. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, upper abdominal pain, flatulence. General disorders and administration site conditions: Fatigue, asthenia, fever. Investigations: Increased platelet count, blood glucose, triglycerides, lactate dehydrogenase, ALT, gastrin; decreased blood glucose; transient decrease in platelet counts (after discontinuation). Metabolism and nutrition disorders: Hyperlipidaemia, decreased appetite. Musculoskeletal and connective tissue disorders: Arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity. Nervous system disorders: Dizziness, headache, migraine, head discomfort, paraesthesia. Respiratory, thoracic and mediastinal disorders: Dyspnoea, epistaxis. Skin and subcutaneous tissue disorders: Rash, acne, pruritus, petechiae. Vascular disorders: Hypertension.
Monitoring Parameters
Monitor for signs and symptoms of thromboembolism; patient adherence. For chronic liver disease-associated thrombocytopenia: Obtain platelet count before starting therapy and on the day of the scheduled procedure. For chronic immune thrombocytopenia: Monitor platelet count weekly after initiation until stabilised at ≥50 x 109/L, then monthly thereafter; and weekly for at least 4 weeks after discontinuation of treatment.
Drug Interactions
Increased exposure with moderate or strong dual inhibitors of CYP3A4 and CYP2C9 (e.g. fluconazole) and moderate or strong CYP2C9 inhibitors. Decreased exposure and efficacy with moderate or strong dual inducers of CYP3A4 and CYP2C9 (e.g. rifampicin, enzalutamide) and moderate or strong CYP2C9 inducers. Risk of bleeding may be increased when avatrombopag is discontinued in presence of anticoagulants or antiplatelet agents.
Food Interaction
Delayed time to peak plasma concentration when given with high-fat or low-fat meal.
Action
Description: Mechanism of Action: Avatrombopag is an active, small molecule thrombopoietin receptor agonist which promotes proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, thus increasing platelet production. It does not compete with thrombopoietin for binding to the receptor; it has an additive effect with thrombopoietin on the production of platelets. Onset: Platelet count increase: 3-5 days (peak effect: 10-13 days). Pharmacokinetics: Absorption: Absorbed from the gastrointestinal tract. High-fat and low-fat meal delays peak plasma concentration. Time to peak plasma concentration: 5-6 hours. Distribution: Volume of distribution: Approx 180 L. Plasma protein binding: >96%. Metabolism: Metabolised in the liver via oxidative metabolism mainly by CYP2C9 and CYP3A4. Excretion: Via urine (approx 6%); faeces (88%; 34% as unchanged drug). Elimination half-life: Approx 19 hours.
Chemical Structure
Avatrombopag Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 9852519, Avatrombopag. https://pubchem.ncbi.nlm.nih.gov/compound/Avatrombopag. Accessed May 26, 2022.
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