Avatrombopag

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Doptelet: 20 mg

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: ~180 L

Metabolism

Hepatic; primarily by CYP2C9 and CYP3A4

Excretion

Feces (88%; 34% as unchanged drug); urine (6%)

Onset of Action

Platelet count increase: 3 to 5 days after therapy initiation; Peak effect: after 10 to 13 days.

Time to Peak

5 to 6 hours; delayed up to 2 hours when administered with a high-fat or low-fat meal (compared to fasting).

Duration of Action

Platelet count steadily declines within 7 days of procedure (Terrault 2018); Posttreatment: platelet count gradually returns to baseline values.

Half-Life Elimination

~19 hours

Protein Binding

>96% to human plasma proteins

Use: Labeled Indications

Chronic immune thrombocytopenia: Treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment.

Chronic liver disease-associated thrombocytopenia: Treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Note: Do not use avatrombopag to normalize platelet counts.

Chronic immune thrombocytopenia : Oral: Note: Use the lowest dose necessary to achieve platelets count ≥50,000/mm³ as necessary to reduce the risk of bleeding.

Initial: 20 mg once daily (Jurczak 2018).

Dosage adjustment based on platelet count:

Avatrombopag dose levels for dose titration in chronic immune thrombocytopenia:

Dose level 6: 40 mg once daily.

Dose level 5: 40 mg 3 times per week and 20 mg/day on the other 4 days of the week.

Dose level 4: 20 mg once daily (initial dose for all patients except those taking moderate or strong dual inhibitors or inducers of CYP2C9 and CYP3A4).

Dose level 3: 20 mg 3 times per week.

Dose level 2: 20 mg twice per week or 40 mg once per week.

Dose level 1: 20 mg once weekly.

Avatrombopag dosage adjustment in chronic immune thrombocytopenia (see above for dose levels):

Platelet count <50,000/mm³ after ≥2 weeks of avatrombopag: Increase dose one dose level; wait 2 weeks to reassess for subsequent dosage adjustments.

Platelet count 200,000/mm³ to 400,000/mm³: Decrease dose one dose level; wait 2 weeks to reassess for subsequent dosage adjustments.

Platelet count >400,000/mm³: Withhold avatrombopag and increase platelet monitoring to twice per week; when platelet count is <150,000/mm³, reinitiate avatrombopag with the dose decreased one dose level.

Platelet count <50,000/mm³ after 4 weeks of avatrombopag at 40 mg once daily: Discontinue avatrombopag.

Platelet count >400,000/mm³ after 2 weeks of avatrombopag at 20 mg once weekly: Discontinue avatrombopag.

Avatrombopag discontinuation in chronic immune thrombocytopenia: Discontinue avatrombopag if the platelet count does not increase to ≥50,000/mm³ after 4 weeks of therapy at the maximum dose of 40 mg once daily or if the platelet count is >400,000/mm³ after 2 weeks of therapy at 20 mg once weekly.

Dosage adjustment for concomitant therapy with moderate or strong dual inhibitors of CYP2C9 and CYP3A4 in chronic immune thrombocytopenia: Initial: 20 mg 3 times per week.

Dosage adjustment for concomitant therapy with moderate or strong dual inducers of CYP2C9 and CYP3A4 in chronic immune thrombocytopenia: Initial: 40 mg once daily.

Chronic liver disease-associated thrombocytopenia: Oral: Note: Begin avatrombopag 10 to 13 days prior to the scheduled procedure. Patients should undergo procedure 5 to 8 days after the last avatrombopag dose. Obtain a platelet count prior to therapy administration and on the day of the procedure (to ensure adequate increase in platelet count).

Platelet count 40,000 to <50,000/mm³: 40 mg once daily for 5 consecutive days (Terrault 2018).

Platelet count <40,000/mm³: 60 mg once daily for 5 consecutive days (Terrault 2018).

Dosage adjustment for concomitant therapy with moderate or strong dual inhibitors or inducers of CYP2C9 and CYP3A4 in chronic liver disease-associated thrombocytopenia: No dosage adjustment necessary.

Missed doses: If a dose is missed, administer the next dose as soon as it is remembered. Do not administer 2 doses at the same time to make up for a missed dose; take the next dose at the usual time the next day. Complete all 5 days of dosing if treating chronic liver disease-associated thrombocytopenia.

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer with food.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store tablets in original package.

Drug Interactions

Enzalutamide: May decrease the serum concentration of Avatrombopag. Management: Management of this interaction varies based on avatrombopag indication. Dose adjustments are required for patients using avatrombopag for chronic immune thrombocytopenia. See monograph for details. Consider therapy modification

Fluconazole: May increase the serum concentration of Avatrombopag. Management: Management of this interaction varies based on avatrombopag indication. Dose adjustments are required for patients using avatrombopag for chronic immune thrombocytopenia. See monograph for details. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of Avatrombopag. Management: Management of this interaction varies based on avatrombopag indication. Dose adjustments are required for patients using avatrombopag for chronic immune thrombocytopenia. See monograph for details. Consider therapy modification

RifAMPin: May decrease the serum concentration of Avatrombopag. Management: Management of this interaction varies based on avatrombopag indication. Dose adjustments are required for patients using avatrombopag for chronic immune thrombocytopenia. See monograph for details. Consider therapy modification

Adverse Reactions

Higher incidences reported with longer duration of use.

>10%:

Central nervous system: Headache (7% to 31%), fatigue (3% to 28%)

Gastrointestinal: Gingival hemorrhage (13%)

Hematologic & oncologic: Bruise (26%), petechia (11%)

Neuromuscular & skeletal: Arthralgia (13%)

Respiratory: Epistaxis (19%), upper respiratory tract infection (15%)

Miscellaneous: Fever (11%)

1% to 10%:

Cardiovascular: Arterial thromboembolism (≤7%), venous thromboembolism (≤7%), peripheral edema (3% to 4%)

Gastrointestinal: Abdominal pain (7%), nausea (7%)

Respiratory: Nasopharyngitis (10%)

<1%: Anemia, hyponatremia, myalgia, portal vein thrombosis

Warnings/Precautions

Concerns related to adverse effects:

• Thromboembolism: Thrombotic and thromboembolic complications with thrombopoietin receptor agonist use have occurred. Portal vein thrombosis has occurred (rarely) in patients with chronic liver disease who received avatrombopag. Arterial and venous thrombotic events have occurred in patients with chronic immune thrombocytopenia. Use with caution in patients with known risk factors for thromboembolism (eg, Factor V Leiden, prothrombin 20210A, antithrombin deficiency, protein C or S deficiency). Do not administer to patients in an attempt to normalize platelet counts. Monitor for signs/symptoms of thromboembolism.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Lactose: Dosage form contains lactose monohydrate.

Other warnings/precautions:

• Appropriate use: Do not use to normalize platelet counts in patients with chronic liver disease or chronic immune thrombocytopenia.
• CYP2C9 polymorphisms: CYP2C9*2 and CYP2C9*3 loss-of-function polymorphisms result in reduced CYP2C9 enzymatic activity. In a pooled pharmacogenomic analysis, when compared to subjects wild-type for CYP2C9 (normal metabolizers), subjects heterozygous for CYP2C9 loss-of-function polymorphisms (intermediate metabolizers) experienced ~1.4-fold higher exposure, and subjects homozygous for CYP2C9 loss-of-function polymorphisms (poor metabolizers) had ~2-fold higher exposure.

Monitoring Parameters

Chronic immune thrombocytopenia: Platelet count weekly initially until stabilized at ≥50,000/mm³ then monthly thereafter. Obtain platelet count weekly for ≥4 weeks following discontinuation of therapy.

Chronic liver disease-associated thrombocytopenia: Platelet count prior to therapy initiation and on the day of the scheduled procedure.

All patients: Monitor for signs/symptoms of thromboembolism. Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on findings from animal reproduction studies, in utero exposure to avatrombopag may cause fetal harm.

Patient Education

What is this drug used for?

• It is used to raise platelet counts.

Frequently reported side effects of this drug

• Nausea
• Headache
• Loss of strength and energy
• Common cold symptoms
• Joint pain
• Stuffy nose
• Sore throat

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Swelling of arms or legs
• Fast heartbeat
• Bruising
• Bleeding
• Petechiae
• Abdominal pain
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.