Version May 2024
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 (Ref).
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: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 (Ref).
Platelet count <40,000/mm3: 60 mg once daily for 5 consecutive days (Ref).
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, mild to moderate renal impairment had no clinically meaningful effects on avatrombopag pharmacokinetics.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, hemodialysis is not expected to enhance avatrombopag elimination.
Mild, moderate, or severe hepatic impairment (Child Pugh classes A, B, or C or MELD score 4 to 23): There are no dosage adjustments provided in the manufacturer's labeling; however, hepatic impairment had no clinically meaningful effects on avatrombopag pharmacokinetics.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Higher incidences reported with longer duration of use.
>10%:
Gastrointestinal: Gingival hemorrhage (13%)
Hematologic & oncologic: Bruise (26%), petechia (11%)
Nervous system: Fatigue (3% to 28%), headache (7% to 31%)
Neuromuscular & skeletal: Arthralgia (13%)
Respiratory: Epistaxis (19%), upper respiratory tract infection (15%)
Miscellaneous: Fever (11%)
1% to 10%:
Cardiovascular: Arterial thromboembolism (≤7%), peripheral edema (3% to 4%), venous thromboembolism
Gastrointestinal: Abdominal pain (7%), nausea (7%)
Respiratory: Nasopharyngitis (10%)
<1%:
Cardiovascular: Portal vein thrombosis
Endocrine & metabolic: Hyponatremia
Neuromuscular & skeletal: Myalgia
Postmarking: Hypersensitivity: Hypersensitivity reaction (including choking sensation, facial swelling, pharyngeal edema, and swollen tongue)
There are no contraindications listed in the manufacturer's labeling.
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.
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Doptelet: 20 mg
No
Tablets (Doptelet Oral)
20 mg (per each): $493.93
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Oral: Administer with food.
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.
Avatrombopag may be confused with eltrombopag, lusutrombopag
Substrate of CYP2C9 (minor), CYP3A4 (minor), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Adagrasib: May increase the serum concentration of Avatrombopag. Management: For chronic immune thrombocytopenia, reduce initial avatrombopag dose to 20 mg 3 times per week. No dosage reduction needed for patients with chronic liver disease-associated thrombocytopenia using avatrombopag prior to a procedure. Risk D: Consider therapy modification
Enzalutamide: May decrease the serum concentration of Avatrombopag. Management: For chronic immune thrombocytopenia, increase initial avatrombopag dose to 40 mg daily. No dosage adjustment needed for patients with chronic liver disease-associated thrombocytopenia using altrombopag prior to a procedure. Risk D: Consider therapy modification
Fluconazole: May increase the serum concentration of Avatrombopag. Management: For chronic immune thrombocytopenia, reduce initial avatrombopag dose to 20 mg 3 times per week. No dosage reduction needed for patients with chronic liver disease-associated thrombocytopenia using altrombopag prior to a procedure. Risk D: Consider therapy modification
MiFEPRIStone: May increase the serum concentration of Avatrombopag. Management: For chronic immune thrombocytopenia, reduce initial avatrombopag dose to 20 mg 3 times per week. No dosage reduction needed for patients with chronic liver disease-associated thrombocytopenia using altrombopag prior to a procedure. Risk D: Consider therapy modification
RifAMPin: May decrease the serum concentration of Avatrombopag. Management: For chronic immune thrombocytopenia, increase initial avatrombopag dose to 40 mg daily. No dosage adjustment needed for patients with chronic liver disease-associated thrombocytopenia using altrombopag prior to a procedure. Risk D: Consider therapy modification
Based on findings from animal reproduction studies, in utero exposure to avatrombopag may cause fetal harm.
Thrombopoietin (TPO) receptor agonists are not currently recommended to treat immune thrombocytopenia during pregnancy except in very serious cases. If a TPO receptor agonist is needed, an agent other than avatrombopag is preferred (Provan 2019).
It is not known if avatrombopag is present in breast milk. Due to the potential for serious adverse events in the breastfed infant, the manufacturer does not recommend breastfeeding during chronic therapy or for ≥2 weeks after the last avatrombopag dose. If receiving avatrombopag for brief periods (eg, prior to an invasive procedure), lactating females should pump and discard breast milk during treatment and for ≥2 weeks after the last avatrombopag dose.
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.
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.
Onset: Platelet count increase: 3 to 5 days after therapy initiation; Peak effect: after 10 to 13 days.
Duration: Platelet count steadily declines within 7 days of procedure (Terrault 2018); Posttreatment: platelet count gradually returns to baseline values.
Distribution: Vd: ~180 L.
Protein binding: >96% to human plasma proteins.
Metabolism: Hepatic; primarily by CYP2C9 and CYP3A4.
Half-life elimination: ~19 hours.
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).
Excretion: Feces (88%; 34% as unchanged drug); urine (6%).
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