Lusutrombopag

1 INDICATIONS AND USAGE MULPLETA is indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. MULPLETA 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 )

2 DOSAGE AND ADMINISTRATION Begin MULPLETA dosing 8-14 days prior to a scheduled procedure. ( 2.1 ) Patients should undergo their procedure 2-8 days after the last dose. ( 2.1 ) Recommended Dosage: 3 mg orally once daily with or without food for 7 days. ( 2.1 ) 2.1 Recommended Dosage Begin MULPLETA dosing 8-14 days prior to a scheduled procedure. Patients should undergo their procedure 2-8 days after the last dose. The recommended dosage of MULPLETA is 3 mg taken orally once daily with or without food for 7 days. In the case of a missed dose of MULPLETA, patients should take the missed dose as soon as possible on the same day and return to the normal schedule the following day. MULPLETA has been investigated only as a single 7-day once daily dosing regimen in clinical trials in patients with chronic liver disease [see Clinical Studies (14) ] . MULPLETA should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts. 2.2 Monitoring Obtain a platelet count prior to initiation of MULPLETA therapy and not more than 2 days before the procedure.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in detail in other sections of the labeling: Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.1) ] The most common adverse reaction (≥3%): headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eddingpharm (U. S.) Inc. at 1-888-465-2125 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. The safety of MULPLETA was evaluated in 3 randomized, double-blind, placebo-controlled trials, L-PLUS 1, L-PLUS 2, and M0626, in which patients with chronic liver disease and thrombocytopenia were treated with MULPLETA (N=171) or placebo (N=170) at a dose of 3 mg daily for up to 7 days prior to a scheduled procedure. The majority of patients were males (59%), and median age was 61 years (range 19-88). The racial and ethnic distribution was White (50%), Asian (47%), Black (<1%), and Other (3%). The most common adverse reactions (those occurring in at least 3%) in the MULPLETA-treated group across the pooled data from the three trials are summarized in table 1. Table 1. Adverse Reactions with a Frequency ≥3% in Patients Treated with MULPLETA (Pooled Data (L-PLUS 1, L-PLUS 2, and M0626)) Adverse Reaction Includes treatment-emergent adverse reactions occurring at a rate higher than placebo. MULPLETA 3 mg (N=171) % Placebo (N=170) % Headache 5 4 The incidence of serious adverse events was 5% (9 of 171 patients) in the MULPLETA group and 7% (12 of 170 patients) in the placebo group. The most common serious adverse reaction reported with MULPLETA was portal vein thrombosis [see Warnings and Precautions (5.1) ] . No adverse reactions resulted in discontinuation of MULPLETA.

12.3 Pharmacokinetics Lusutrombopag demonstrated dose-proportional pharmacokinetics after single doses ranging from 1 mg (0.33 times the lowest approved dosage) to 50 mg (16.7 times the highest recommended dosage). Healthy subjects administered 3 mg of lusutrombopag had a geometric mean (%CV) maximal concentration (C max ) of 111 (20.4) ng/mL and area under the time-concentration curve extrapolated to infinity (AUC 0-inf ) of 2931 (23.4) ng.hr/mL. The pharmacokinetics of lusutrombopag were similar in both healthy subjects and the chronic liver disease population. The accumulation ratios of C max and AUC were approximately 2 with once-daily multiple-dose administration, and steady-state plasma lusutrombopag concentrations were achieved after Day 5. Absorption In patients with chronic liver disease, the time to peak lusutrombopag concentration (T max ) was observed 6 to 8 hours after oral administration. Food Effect Lusutrombopag AUC and C max were not affected when MULPLETA was co-administered with a high-fat meal (a total of approximately 900 calories, with 500, 250, and 150 calories from fat, carbohydrate, and protein, respectively) . Distribution The mean (%CV) lusutrombopag apparent volume of distribution in healthy adult subjects was 39.5 (23.5) L. The plasma protein binding of lusutrombopag is more than 99.9%. Elimination The terminal elimination half-life (t 1/2 ) in healthy adult subjects was approximately 27 hours. The mean (%CV) clearance of lusutrombopag in patients with chronic liver disease is estimated to be 1.1 (36.1) L/hr. Metabolism Lusutrombopag is primarily metabolized by CYP4 enzymes, including CYP4A11. Excretion Fecal excretion accounted for 83% of the administered dose, with 16% of the dose excreted as unchanged lusutrombopag, and urinary excretion accounted for approximately 1%. Specific Populations No clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on age or race/ethnicity. Though lusutrombopag exposure tends to decrease with increasing body weight, differences in exposure are not considered clinically relevant. Patients with Renal Impairment A population pharmacokinetic analysis did not find a clinically meaningful effect of mild (creatinine clearance (CLcr) 60 to less than 90 mL/min) and moderate (CLcr 30 to less than 60 mL/min) renal impairment on the pharmacokinetics of lusutrombopag. Data in patients with severe renal impairment (CLcr less than 30 mL/min) are limited. Patients with Hepatic Impairment No clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on mild to moderate (Child-Pugh class A and B) hepatic impairment. The mean observed lusutrombopag C max and AUC 0-τ decreased by 20% to 30% in patients (N=5) with severe (Child-Pugh class C) hepatic impairment compared to patients with Child-Pugh class A and class B liver disease. However, the ranges for C max and AUC 0-τ overlapped among patients with Child-Pugh class A, B, and C liver disease. Drug Interaction Studies Clinical Studies No clinically significant changes in lusutrombopag exposure were observed when co-administered with cyclosporine (an inhibitor of P-gp and BCRP) or an antacid containing a multivalent cation (calcium carbonate). No clinically significant changes in midazolam (a CYP3A substrate) exposure were observed when co-administered with lusutrombopag. In Vitro Studies CYP Enzymes : lusutrombopag has low potential to inhibit CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5). Lusutrombopag did not induce CYP1A2, CYP2C9, or CYP3A4. UGT Enzymes : lusutrombopag did not induce UGT1A2, UGT1A6, or UGT2B7. Transporter Systems : lusutrombopag is a substrate of P-gp and BCRP. Lusutrombopag has low potential to inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K, and BSEP.