Bleeding disorders:

Indications for: DOPTELET

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.

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.

Adult Dosage:

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 Dosage:

Not established.

DOPTELET 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).

DOPTELET Classification:

Thrombopoietin receptor agonist.

DOPTELET 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.

Adverse Reactions:

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

Metabolism:

Primarily metabolized by cytochrome P450 CYP2C9 and CYP3A4.

Drug 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.

Generic Drug Availability:

NO

How Supplied:

Tabs—10, 15, 30