Mulpleta Lusutrombopag 3 mg Tablet, Film Coated, 7-count — NDC 59630-551-07 (Billing 59630-0551-07)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Lusutrombopag is an orally bioavailable, small molecule TPO receptor agonist that interacts with the transmembrane domain of human TPO receptors expressed on megakaryocytes to induce the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells and megakaryocyte maturation.

12.2Pharmacodynamics Platelet Response Lusutrombopag upregulates the production of platelets through its agonistic effect on human TPO receptors. The effect of lusutrombopag on platelet count increase was correlated with the AUC across the studied dose range of 0.25 mg to 4 mg in thrombocytopenic patients with chronic liver disease. With the 3 mg daily dose, the mean (standard deviation) maximum platelet count in patients (N=74) without platelet transfusion was 86.9 (27.2) × 10 9 /L, and the median time to reach the maximum platelet count was 12.0 (5 to 35) days.

Cardiac Electrophysiology At a dose 8 times the recommended dosage, MULPLETA does not prolong QT interval to any clinically relevant extent.

12.3Pharmacokinetics 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… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Lusutrombopag is an orally bioavailable, small molecule TPO receptor agonist that interacts with the transmembrane domain of human TPO receptors expressed on megakaryocytes to induce the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells and megakaryocyte maturation.

12.3Pharmacokinetics 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.

12.2Pharmacodynamics Platelet Response Lusutrombopag upregulates the production of platelets through its agonistic effect on human TPO receptors. The effect of lusutrombopag on platelet count increase was correlated with the AUC across the studied dose range of 0.25 mg to 4 mg in thrombocytopenic patients with chronic liver disease. With the 3 mg daily dose, the mean (standard deviation) maximum platelet count in patients (N=74) without platelet transfusion was 86.9 (27.2) × 10 9 /L, and the median time to reach the maximum platelet count was 12.0 (5 to 35) days.

Cardiac Electrophysiology At a dose 8 times the recommended dosage, MULPLETA does not prolong QT interval to any clinically relevant extent.

14 CLINICAL STUDIES The efficacy of MULPLETA for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure was evaluated in 2 randomized, double-blind, placebo-controlled trials (L-PLUS 1 (N=97) and L-PLUS 2 (N=215; NCT02389621)). Patients with chronic liver disease who were undergoing an invasive procedure and had a platelet count less than 50 × 10 9 /L were eligible to participate. Patients undergoing laparotomy, thoracotomy, open-heart surgery, craniotomy, or organ resection were excluded.

Patients with a history of splenectomy, partial splenic embolization, or thrombosis and those with Child-Pugh class C liver disease, absence of hepatopetal blood flow, or a prothrombotic condition other than chronic liver disease were not allowed to participate. The patient populations were similar between the MULPLETA and placebo arms and consisted of 60% male and 40% female; median age was 60 years (range 19-88). The racial and ethnic distribution was White (55%), Asian (41%), and Other (4%).

Patients were randomized 1:1 to receive 3 mg of MULPLETA or placebo once daily for up to 7 days. Randomization was stratified by liver ablation/coagulation or other procedures and the platelet count at screening/baseline. In L-PLUS 1, 57% of patients underwent procedures other than liver ablation/coagulation and 43% underwent liver ablation/coagulation (RFA/MCT).

In L-PLUS 2, 98% of patients underwent procedures other than liver ablation/coagulation and 2% underwent liver ablation/coagulation (RFA/MCT). Procedures other than liver ablation/coagulation (RFA/MCT) included liver-related procedures (transcatheter arterial chemoembolization, liver biopsy, and others), upper and lower gastrointestinal endoscopy-related procedures (endoscopic variceal ligation, endoscopic injection sclerotherapy, polypectomy, and biopsy), and other procedures (dental extraction, diagnostic paracentesis or laparocentesis, septoplasty, embolization of splenic artery aneurysm, bone marrow biopsy, removal of cervical polyp, and inguinal hernia repair (non-laparotomy based)).

In L-PLUS 1, the major efficacy outcome was the proportion of patients who require no platelet transfusion prior to the primary invasive procedure. In L-PLUS 2, the major efficacy outcome was the proportion of patients who require no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding (i.e., platelet preparations, other blood preparations, including red blood cells and plasma, volume expanders) from randomization through 7 days after the primary invasive procedure. In both trials, additional efficacy outcomes included the proportion of patients who require no platelet transfusion during the study, proportion of responders, duration of the increase in platelet count defined as the number of days during which the platelet count was maintained as ≥50 × 10 9 /L, and the time course of platelet counts.

In both the L-PLUS 1 and L-PLUS 2 trials, responders were defined as patients who had a platelet count of ≥50 × 10 9 /L with an increase of ≥20 × 10 9 /L from baseline. Table 2. L-PLUS 1 Trial: Proportion of Patients Not Requiring Platelet Transfusion Prior to Invasive Procedure and Proportion of Responders Endpoint Proportion (n/N) Exact 95% Confidence Interval Treatment Difference (95% Confidence Interval) p value MULPLETA (N=49) Placebo (N=48) Not requiring platelet transfusion prior to invasive procedure A platelet transfusion was required if the platelet count was less than 50 × 10 9 /L.

78% (38/49) (63, 88) 13% (6/48) (4.7, 25) 64 (49, 79) <0.0001 Cochran-Mantel-Haenszel test with baseline platelet count as stratum; p value and confidence interval calculated using Wald method. Responder Platelet count reached at least 50 × 10 9 /L and increased at least 20 × 10 9 /L from baseline. during study 76% (37/49) (61, 87) 6% (3/48) (1.3, 17) 68 (54, 82) <0.0001 Table 3. L-PLUS 2 Trial: Proportion of Patients Not Req… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In 2-year studies, lusutrombopag was not carcinogenic to rats at oral doses up to 20 mg/kg/day in males and 2 mg/kg/day in females (a dose 49 times and 30 times, respectively, the human exposure (AUC) at the recommended clinical dose of 3 mg/day for 7 days) and to mice at oral doses up to 20 mg/kg/day in males and females (a dose approximately 45 times the human exposure (AUC) at the recommended clinical dose of 3 mg/day for 7 days). Lusutrombopag was not genotoxic based on an in vitro bacterial reverse mutation (Ames) assay, a chromosomal aberration assay with cultured Chinese hamster lung cells, and an in vivo micronucleus assay with mouse bone marrow cells.

In a fertility and early embryonic development study, lusutrombopag did not affect fertility in male and female rats at oral doses up to 100 mg/kg/day (a dose in males and females approximately 176 and 252 times, respectively, the human exposure (AUC) at the recommended clinical dose of 3 mg/day for 7 days).