Doptelet

— THERAPEUTIC DISORDERS TREATED —
  • Bleeding disorders
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Doptelet Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Avatrombopag 20mg; tabs.

    Pharmacological Class

    Thrombopoietin receptor agonist.

    How Supplied

    Tabs—10, 15, 30

    How Supplied

    20mg yellow tablet debossed with “AVA” one one side and “20” on the other side.

    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 the original package.

    Manufacturer

    Sobi, Inc.

    Generic Availability

    NO

    Doptelet Indications

    Indications

    Thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a procedure. Thrombocytopenia in adults with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment.

    Doptelet Dosage and Administration

    Prior to Treatment Evaluations

    Obtain platelet count prior to administration and on the day of a procedure to ensure an adequate increase in platelet count.

    Adult

    Chronic liver disease: start treatment 10–13 days prior to a procedure. Should undergo procedure within 5–8 days after last dose. Take with food. Platelet count (<40x109/L): 60mg once daily for 5 days; (40–<50x109/L): 40mg once daily for 5 days. Chronic immune thrombocytopenia: initially 20mg once daily; adjust dose based on platelet count response (see full labeling); max 40mg/day. Discontinue if platelet count <50x109/L after 4 weeks of 40mg/day or >400x109/L after 2 weeks of 20mg once weekly. If concomitant moderate or strong CYP2C9/CYP3A4 dual inhibitors: 20mg three times weekly; moderate or strong CYP2C9/CYP3A4 dual inducers: 40mg once daily.

    Children

    Not established.

    Other Modifications

    The CYP2C9*2 and CYP2C9*3 loss-of-function polymorphisms result in reduced CYP2C9 enzymatic activity.

    Pharmacogenomic analysis

    Heterozygous for CYP2C9 loss-of function polymorphisms (n=24): Approximately 1.4-fold higher exposure

    Homozygous for CYP2C9 loss-of-function polymorphisms (n=2): Approximately 2-fold higher exposure

    Doptelet Contraindications

    Not Applicable

    Doptelet Boxed Warnings

    Not Applicable

    Doptelet Warnings/Precautions

    Warnings/Precautions

    Chronic liver disease: obtain platelet count prior to treatment and on day of procedure. Chronic immune thrombocytopenia: after therapy initiation, obtain platelet count weekly until ≥50x109/L achieved, then monthly thereafter; and weekly for at least 4 weeks after discontinuation. Increased thrombotic risk with known risk factors (eg, Factor V Leiden, Prothrombin 20210A, Antithrombin deficiency, Protein C or S deficiency); monitor. Do not use to normalize platelet counts. Pregnancy. Nursing mothers: not recommended (during and for ≥2 weeks after the last dose).

    Pregnancy Considerations

    Doptelet may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus.

    Nursing Mother Considerations

    There is no information regarding the presence of avatrombopag in human milk, the effects on the breastfed child, or the effects on milk production. The drug has been shown to be present in animal milk. Breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose.

    To minimize exposure, lactating women receiving Doptelet for brief periods, such as before an invasive procedure, should interrupt breastfeeding and pump and discard breastmilk during treatment and for 2 weeks after the last dose.

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established.

    Geriatric Considerations

    Clinical studies of Doptelet did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

    Other Considerations for Specific Populations

    The CYP2C9*2 and CYP2C9*3 loss-of-function polymorphisms result in reduced CYP2C9 enzymatic activity.

    Pharmacogenomic analysis

    Heterozygous for CYP2C9 loss-of function polymorphisms (n=24): Approximately 1.4-fold higher exposure

    Homozygous for CYP2C9 loss-of-function polymorphisms (n=2): Approximately 2-fold higher exposure

    Doptelet Pharmacokinetics

    Absorption

    Median time to maximal concentration (Tmax) occurred at 5 to 6 hours post-dose.

    Distribution

    Avatrombopag is greater than 96% bound to human plasma proteins.

    Metabolism

    Primarily metabolized by cytochrome P450 CYP2C9 and CYP3A4.

    Elimination

    Mean plasma elimination half-life of avatrombopag is ~19 hours.

    Fecal excretion accounted for 88% of the administered dose. Only 6% of the administered dose was found in urine.

    Doptelet Interactions

    Interactions

    See Adult dose. Potentiated by moderate or strong CYP2C9/CYP3A4 dual inhibitors; reduce or adjust dose and monitor. Antagonized by moderate or strong CYP2C9/CYP3A4 dual inducers; increase or adjust dose and monitor.

    Doptelet Adverse Reactions

    Adverse Reactions

    Pyrexia, abdominal pain, nausea, headache, fatigue, peripheral edema, contusion, epistaxis, upper RTI, arthralgia, gingival bleeding, petechiae, nasopharyngitis; thrombotic/thromboembolic complications.

    Doptelet Clinical Trials

    Clinical Trials

    Chronic Immune Thrombocytopenia

    The approval was based on data from a phase 3, double blind, placebo-controlled trial evaluating the efficacy of Doptelet in adult patients (N=49) with chronic immune thrombocytopenia who previously received 1 or more prior chronic immune thrombocytopenia therapies (ie, corticosteroids, immunoglobulins, azathioprine, danazol, cyclophosphamide and/or rituximab). The primary outcome measure was the cumulative number of weeks in which the platelet count was ≥50 x109/L during the 6-month treatment period in the absence of rescue therapy.

    Results showed that patients treated with Doptelet had a longer duration of platelet counts ≥50 x109/L in the absence of rescue therapy compared with those who received placebo (median 12.4 [0, 25] vs [0, 2] weeks, respectively, P <.0001). In addition, a larger proportion of patients in the Doptelet arm had platelet counts ≥50 x109/L at day 8 compared with placebo (21/32; 66% vs 0/17; 0.0%, respectively; P <.0001).

     

    Chronic Liver Disease

    The approval was based on results from the ADAPT-1 (N=231) and ADAPT-2 trials (N=204), 2 identically-designed multicenter, randomized, double-blind, placebo-controlled studies. Study results showed that patients in the Doptelet treatment groups had a greater proportion of responders (defined as patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure) than the corresponding placebo treatment groups.

    ADAPT-1

    • Low baseline platelet count cohort (60mg dose): 66% vs 23%; P <.0001
    • High baseline platelet count cohort (40mg dose): 88% vs 38%; P <.0001 

    ADAPT-2

    • Low baseline platelet cohort (60mg dose): 69% vs 35%; P =.0006
    • High baseline platelet cohort (40mg dose): 88% vs 33%; P <.0001

    Both trials demonstrated a higher proportion of patients who achieved the target platelet count of ≥50×109/L on the day of procedure (secondary endpoint; Doptelet vs placebo):

    ADAPT-1

    • Low baseline platelet count cohort: 69% vs 4%; P <.0001
    • High baseline platelet count cohort: 88% vs 21%; P <.0001 

    ADAPT-2

    • Low baseline platelet cohort: 67% vs 7%; P <.0001
    • High baseline platelet cohort: 93% vs 39%; P <.0001

    Both trials demonstrated a greater mean change in platelet counts from baseline to the day of the procedure (secondary endpoint; Doptelet vs placebo):

    ADAPT-1

    • Low baseline platelet count cohort: 32x109/L vs 0.8x109/L; P <.0001
    • High baseline platelet count cohort: 37.1x109 /L vs 1.0x109/L; P <.0001

    ADAPT-2

    • Low baseline platelet cohort: 31.3x109/L vs 3.0x109/L; P <.0001
    • High baseline platelet cohort: 44.9x109 /L vs 5.9×109 /L; P <.0001

    A measured increase in platelet counts was observed in both Doptelet treatment groups over time beginning on day 4 post dose, that peaked on day 10-13, decreased 7 days post-procedure, and then returned to near baseline values by day 35.

    Doptelet Note

    Not Applicable

    Doptelet Patient Counseling

    Patient Counseling

    Thrombotic/thromboembolic complications have been reported (see Warnings/Precautions).

    May be affected by other drugs and may require a dose adjustment when coadministered with other drugs; report use of any other prescription or nonprescription medications or dietary supplements.

    Pregnant women: Potential risk to a fetus. 

    Females of reproductive potential: Inform prescriber of a known or suspected pregnancy. 

    Lactating women: Do not breastfeed during treatment and for at least 2 weeks after the final dose.

    Cost Savings Program

    Doptelet Copay Program

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