avatrombopag (Rx)

Brand and Other Names:Doptelet
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 20mg

Thrombocytopenia

Patients with chronic liver disease

  • Indicated for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a procedure
  • Initiate 10-13 days before the scheduled procedure
  • Patients should undergo their procedure 5-8 days after the last dose
  • Dose based on pre-procedure platelet count
    • Platelet count <40 x109/L: 60 mg PO qDay x 5 days
    • Platelet count 40 to <50 x109/L: 40 mg PO qDay x 5 days

Patients with chronic immune thrombocytopenia

  • Indicated for thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment
  • Use lowest dose needed to achieve and maintain a platelet count ≥50 x109/L to reduce the risk for bleeding
  • Initial dose: 20 mg PO qDay; not to exceed 40 mg PO qDay

Dosage Modifications

Chronic ITP

  • Dose adjustments by platelet count
    • Platelet count <50 x109/L after ≥2 weeks: Increase by 1 dose level; wait 2 wk to assess effects before further adjustment
    • Platelet count 200-400 x109/L: Decrease 1 dose level; wait 2 wk to assess effects before further adjustment
    • Platelet count >400 x109/L: Stop treatment and increase platelet monitoring to twice weekly; may restart by decreasing 1 dose level when platelets <150 x109/L
    • Platelet count <50 x109/L after 4 weeks at 40 mg/day: Discontinue treatment
    • Platelet count >400 x109/L after 2 weeks at 20 mg/week: Discontinue treatment
  • Dose levels for titration
    • Dose level 6: 40 mg qDay
    • Dose level 5: 40 mg 3x/week AND 20 mg on the 4 remaining days each week
    • Dose level 4: 20 mg qDay
    • Dose level 3: 20 mg 3x/week
    • Dose level 2: 20 mg 2x/week OR 40 mg qWeek
    • Dose level 1: 20 mg qWeek
  • Discontinue treatment
    • Platelet count does not increase ≥50 x109/L after 4 weeks at 40 mg qDay (maximum dose)
    • Platelet count is >400 x109/L after 2 weeks at 20 mg qWeek
  • Coadministration of dual CYP2C9 and CYP3A4 inhibitors or inducers
    • Moderate or strong dual inhibitors of CYP2C9 and CYP3A4: Start avatrombopag 20 mg 3x/week
    • Moderate or strong dual inducers of CYP2C9 and CYP3A4: Start avatrombopag 40 mg qDay

Renal impairment

  • Mild-to-moderate (CrCl ≥30 mL/min): No dose adjustment required; minimally excreted by the kidneys
  • Severe (CrCl <30 mL/min) or hemodialysis: Unknown

Hepatic impairment

  • Child-Turcotte-Pugh grades A, B, or C or MELD score 4-23: No clinically meaningful effects on the pharmacokinetics

Dosing Considerations

Do not administer in an attempt to normalize platelet counts

Chronic liver disease

  • Obtain platelet count before initiating therapy and on the day of a procedure

Chronic ITP

  • After initiating, assess platelet count weekly until ≥50 x109/L achieved, and then monthly thereafter
  • Obtain platelet counts weekly for at least 4 weeks following discontinuation

Safety and efficacy not established

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Interactions

Interaction Checker

and avatrombopag

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Chronic liver disease

            • Pyrexia (8-11%)

            Chronic ITP

            • Headache (31%)
            • Fatigue (28%)
            • Contusion (26%)
            • Epistaxis (19%)
            • Upper respiratory tract infection (15%)
            • Arthralgia (13%)
            • Gingival bleeding (13%)
            • Petechiae (11%)

            1-10%

            Chronic liver disease

            • Abdominal pain (6-7%)
            • Nausea (6-7%)
            • Fatigue (3-4%)
            • Peripheral edema (2-4%)

            Chronic ITP

            • Nasopharyngitis (10%)
            • Headache (1.6%)

            <1%

            Chronic liver disease

            • Anemia (0.4%)
            • Pyrexia (0.4%)
            • Myalgia (0.4%)

            Frequency Not Defined

            Chronic liver disease

            • Hyponatremia
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            Warnings

            Contraindications

            None

            Cautions

            Thrombotic/thromboembolic complications

            • Thrombopoietin (TPO) receptor agonists associated with thrombotic and thromboembolic complications in patients with chronic liver disease or chronic ITP
            • Portal vein thrombosis reported with chronic liver disease in patients treated with thrombopoietin (TPO) receptor agonists (ADAPT-1 and ADAPT-2 clinical trials)
            • Consider the potential increased thrombotic risk when administering to patients with known risk factors for thromboembolism, including genetic prothrombotic conditions (eg, factor V Leiden, prothrombin 20210A, antithrombin deficiency, or protein C or S deficiency)
            • Not to be administered to patients with chronic liver disease or chronic immune thrombocytopenia in an attempt to normalize platelet counts; thromboembolic events (arterial or venous) reported
            • Follow dosing guidelines to achieve target platelet counts; monitor patients receiving therapy for signs and symptoms of thromboembolic events and institute treatment promptly

            Drug interaction overview

            • Avatrombopag is a CYP2C9 and CYP3A4 substrate; it inhibits organic anion transporter (OAT) 3 and breast cancer resistance protein (BCRP)
            • Moderate or strong dual CYP2C9 and CYP3A4 inhibitors
              • Coadministration with a moderate or strong dual CYP2C9 and CYP3A4 inhibitor increases avatrombopag AUC, which may increase the risk of avatrombopag toxicities
              • If starting a moderate or strong dual CYP2C9 and CYP3A4 inhibitor during treatment, monitor platelet counts and adjust avatrombopag dose as necessary
            • Moderate or strong dual CYP2C9 and CYP3A4 inducers
              • Coadministration with a moderate or strong dual CYP2C9 and CYP3A4 inducers decreases avatrombopag AUC, which may reduce efficacy of avatrombopag
              • If starting a moderate or strong dual CYP2C9 and CYP3A4 inducer during treatment, monitor platelet counts and adjust avatrombopag dose as necessary
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            Pregnancy

            Pregnancy

            Based on findings from animal reproduction studies, may cause fetal harm when administered to pregnant women

            Animal data

            • In animal reproduction studies, administration resulted in adverse developmental outcomes when administered during organogenesis in rabbits and during organogenesis and the lactation period in rats
            • These findings were observed at exposures based on AUC substantially higher than AUC observed in patients at a dose of 60 mg qDay
            • Advise pregnant women of the potential risk to a fetus

            Lactation

            No data are available regarding the presence of the drug in human milk, the effects on the breastfed child, or the effects on milk production

            In studies, avatrombopag was present in the milk of lactating rats; when a drug is present in animal milk, it is likely the drug will be present in human milk

            Owing to the potential for serious adverse reactions in a breastfed child, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose

            Clinical considerations

            • Interrupt breastfeeding and pump and discard breast milk in lactating women receiving avatrombopag for brief periods (eg, before an invasive procedure) during treatment and for 2 weeks after the last dose in order to minimize exposure to a breastfed child

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Second-generation orally administered thrombopoietin receptor agonist (TPO-RA)

            Stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in an increased production of platelets

            Does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production

            Absorption

            Peak plasma time: 5-6 hr

            Peak plasma concentration: 166 ng/mL

            AUC: 4198 ng·hr/mL

            Systemic exposure variability reduced by 40-60% when administered with food

            Distribution

            Protein bound: >96%

            Vd: 180 L

            Metabolism

            Metabolized primarily by CYP2C9 and CYP3A4

            Elimination

            Half-life: 19 hr

            Clearance: 6.9 L/hr

            Excretion: 88% feces (34% unchanged); 6% urine

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            Administration

            Oral Administration

            Take with food

            Chronic liver disease: Administer for 5 consecutive days; all 5 doses should be completed

            Missed dose

            • In the case of a missed dose, administer next dose as soon as possible
            • Do not take 2 doses at one time to make up for a missed dose; take the next dose at the usual time the next day

            Storage

            Store at room temperature of 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

            Store in original package

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.