Avatrombopag

1 INDICATIONS AND USAGE DOPTELET is a thrombopoietin receptor agonist indicated for the treatment of: Thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. ( 1.1 ) Thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment. ( 1.2 ) Thrombocytopenia in pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia who have had an insufficient response to a previous treatment ( 1.3 ) 1.1 Treatment of Thrombocytopenia in Patients with Chronic Liver Disease (CLD) DOPTELET is indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. 1.2 Treatment of Thrombocytopenia in Adult Patients with Chronic Immune Thrombocytopenia (ITP) DOPTELET is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment. 1.3 Treatment of Thrombocytopenia in Pediatric Patients 1 Year and Older with Persistent or Chronic Immune Thrombocytopenia (ITP) DOPTELET is indicated for the treatment of thrombocytopenia in pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia who have had an insufficient response to a previous treatment.

12.1 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 production of platelets. Avatrombopag does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production.

2 DOSAGE AND ADMINISTRATION DOPTELET tablets and DOPTELET SPRINKLE are not substitutable on a mg-to-mg basis. DOPTELET SPRINKLE capsules should be opened, and the contents (oral granules) mixed with a soft food or liquid. Administer immediately after mixing. Do not swallow the capsules whole. Administer DOPTELET tablets and DOPTELET SPRINKLE with food. ( 2.1 , 2.3 , 2.5 ) Chronic Liver Disease : Dose DOPTELET tablets based upon platelet count prior to procedure, orally for 5 days beginning 10 days to 13 days before procedure. For platelet count less than 40×10 9 /L, the dose is 60 mg (3 tablets) orally once daily; for platelet count 40 to less than 50×10 9 /L the dose is 40 mg (2 tablets) orally once daily. ( 2.2 ) Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients 6 Years and Older with Persistent or Chronic Immune Thrombocytopenia : Initiate DOPTELET tablets at 20 mg (1 tablet) orally once daily. Adjust the dose or frequency of dosing to maintain platelet count greater than or equal to 50×10 9 /L. Do not exceed 40 mg (2 tablets) per day. Pediatric Patients 1 Year to Less than 6 Years with Persistent or Chronic Immune Thrombocytopenia : Initiate DOPTELET SPRINKLE oral granules at 10 mg (content of 1 capsule) orally once daily. Adjust the dose or frequency of dosing to maintain platelet count greater than or equal to 50×10 9 /L. Do not exceed 20 mg (content of 2 capsules) per day. 2.1 Important Use and Administration Instructions Select the recommended product (DOPTELET tablets or DOPTELET SPRINKLE) based on the indication and patient’s age. Administer DOPTELET tablets and DOPTELET SPRINKLE with food. DOPTELET tablets and DOPTELET SPRINKLE are not substitutable on a mg-to-mg basis. The mixture prepared from the granules in DOPTELET SPRINKLE capsules is more bioavailable than DOPTELET tablets [see Clinical Pharmacology ( 12.3 )] . There is no experience from clinical trials in switching between dosing with the granules and the tablet. If the formulation is switched, monitor platelet counts weekly until stable platelet counts are obtained and adjust dosing as needed before resuming monthly monitoring. 2.2 Recommended Dosage of DOPTELET Tablets for Patients with Chronic Liver Disease Begin DOPTELET tablets dosing 10 days to 13 days prior to the scheduled procedure. The recommended daily dose of DOPTELET is based on the patient’s platelet count prior to the scheduled procedure (see Table 1 ). Patients should undergo their procedure 5 days to 8 days after the last dose of DOPTELET. DOPTELET tablets should be taken orally once daily for 5 consecutive days with food. All 5 days of dosing should be completed. Table 1 : Recommended DOPTELET Tablets Dosage and Duration in Patients with Chronic Liver Disease Scheduled to Undergo a Procedure Platelet Count Recommended DOPTELET Dosage Duration Less than 40×10 9 /L 60 mg (3 tablets) orally once daily 5 days 40×10 9 /L to less than 50×10 9 /L 40 mg (2 tablets) orally once daily 5 days DOPTELET tablets have been investigated only as a single 5-day once daily dosing regimen in clinical trials in patients with chronic liver disease [ see Clinical Studies ( 14.1 ) ] . DOPTELET should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts. Monitoring : Obtain a platelet count prior to administration of DOPTELET therapy and on the day of a procedure to ensure an adequate increase in platelet count. 2.3 Recommended Dosage of DOPTELET Tablets for Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients 6 Years and Older with Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of DOPTELET needed to achieve and maintain a platelet count greater than or equal to 50×10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based on platelet count response. Do not use DOPTELET to normalize platelet counts. Initial Dosage : Begin DOPTELET tablets at an initial dosage of 20 mg (1 tablet)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in detail in other sections of the labeling: Thrombotic/Thromboembolic Complications [ see Warnings and Precautions ( 5.1 ) ] In adult patients with chronic liver disease, the most common adverse reactions (≥3%) were pyrexia, abdominal pain, nausea, headache, fatigue, and edema peripheral. ( 6.1 ) In adult patients with chronic immune thrombocytopenia, the most common adverse reactions (≥10%) were headache, fatigue, contusion, epistaxis, upper respiratory tract infection, arthralgia, gingival bleeding, petechiae and nasopharyngitis. ( 6.1 ) In pediatric patients with persistent or chronic immune thrombocytopenia, the most common adverse reactions (≥10%) were viral infection, nasopharyngitis, cough, pyrexia, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sobi, Inc. at 1-866-773-5274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients with Chronic Liver Disease The safety of DOPTELET was evaluated in two international, identically designed, randomized, double-blind, placebo-controlled trials, ADAPT-1 and ADAPT-2, in which 430 patients with chronic liver disease and thrombocytopenia received either DOPTELET (n=274) or placebo (n=156) daily for 5 days prior to a scheduled procedure, and had 1 post-dose safety assessment. Patients were divided into two groups based on their mean platelet count at baseline: Low Baseline Platelet Count Cohort (less than 40×10 9 /L) who received DOPTELET 60 mg once daily for 5 days High Baseline Platelet Count Cohort (40 to less than 50×10 9 /L) who received DOPTELET 40 mg once daily for 5 days The majority of patients were males (65%) and median subject age was 58 years (ranging from 19-86 years of age). The racial and ethnic distribution was White (60%), Asian (33%), Black (3%) and Other (3%). The most common adverse reactions (those occurring in ≥3% of patients) in the DOPTELET-treated groups (60 mg or 40 mg) across the pooled data from the two trials are summarized in Table 8. Table 8 : Adverse Reactions with a Frequency ≥3% in Patients with C hronic L iver D isease Treated with DOPTELET – Pooled Data ADAPT-1 and ADAPT-2 Adverse Reactions Low Baseline Platelet Count Cohort (˂40 × 10 9 /L) High Baseline Platelet Count Cohort (≥40 to ˂50 × 10 9 /L) Combined Baseline Platelet Count Cohort s (˂ 5 0 × 10 9 /L) DOPTELET 60 mg (N=159) % Placebo (N=91) % DOPTELET 40 mg (N=115) % Placebo (N=65) % Total DOPTELET (N=274) % Total Placebo (N=156) % Pyrexia 11 9 8 9 10 9 Abdominal Pain 6 7 7 6 7 6 Nausea 6 8 7 6 7 7 Headache 4 8 7 5 6 6 Fatigue 4 4 3 2 4 3 Edema Peripheral 3 2 4 2 3 2 For the Low Baseline Platelet Count Cohort, the incidence of serious adverse reactions was 7% (11/159) in the 60 mg DOPTELET treatment group. For the High Baseline Platelet Count Cohort, the incidence of serious adverse reactions was 8% (9/115) in the 40 mg DOPTELET treatment group. The most common serious adverse reaction reported with DOPTELET was hyponatremia. Two DOPTELET-treated patients (0.7%) developed hyponatremia. Adverse reactions resulting in discontinuation of DOPTELET were anemia, pyrexia, and myalgia; each was reported in a single (0.4%) patient in the DOPTELET (60 mg) treatment group. Adult Patients with Chronic Immune Thrombocytopenia The safety of DOPTELET was evaluated in four clinical trials in adult patients with chronic immune thrombocytopenia: two Phase 3 trials (one randomized, double-blind, placebo-controlled trial, and one randomized, double-blind, active-controlled trial) and two Phase 2 trials (one randomized, double-blind, placebo-controlled, dose-ranging, trial, and one open-label extens

5 WARNINGS AND PRECAUTIONS Thrombotic/Thromboembolic Complications: DOPTELET is a thrombopoietin (TPO) receptor agonist and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease or immune thrombocytopenia. Monitor platelet counts. Monitor for signs and symptoms of thromboembolic events and institute treatment promptly. ( 5.1 ) 5.1 Thrombotic/Thromboembolic Complications DOPTELET is a thrombopoietin (TPO) receptor agonist and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease or immune thrombocytopenia. In patients with chronic liver disease, thromboembolic events (portal vein thrombosis) occurred in 0.4% (1/274) of patients receiving DOPTELET. In adult patients with chronic immune thrombocytopenia, thromboembolic events (arterial or venous) occurred in 7% (9/128) of patients receiving DOPTELET. Consider the potential increased thrombotic risk when administering DOPTELET to patients with known risk factors for thromboembolism, including genetic prothrombotic conditions (e.g., Factor V Leiden, Prothrombin 20210A, Antithrombin deficiency or Protein C or S deficiency) and acquired risk factors (e.g., antiphospholipid syndrome). DOPTELET should not be administered to patients with chronic liver disease or immune thrombocytopenia in an attempt to normalize platelet counts. Monitor platelet counts and follow the dosing guidelines to achieve target platelet counts [see Dosage and Administration ( 2.3 and 2.5 )] . Monitor patients receiving DOPTELET for signs and symptoms of thromboembolic events and institute treatment promptly.

4 CONTRAINDICATIONS None. None. ( 4 )

10 OVERDOSAGE In the event of overdose, platelet count may increase excessively and result in thrombotic or thromboembolic complications. Closely monitor the patient and platelet count. Treat thrombotic complications in accordance with standard of care. No antidote for DOPTELET overdose is known. Hemodialysis is not expected to enhance the elimination of DOPTELET because avatrombopag is only approximately 6% renally excreted and is highly bound to plasma proteins. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.