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.

5.1 Thrombotic/Thromboembolic Complications

MULPLETA is a thrombopoietin (TPO) receptor agonist, and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. Portal vein thrombosis has been reported in patients with chronic liver disease treated with TPO receptor agonists. Portal vein thrombosis was reported in 1% (2 of 171) of MULPLETA-treated patients and 1% (2 of 170) of placebo-treated patients in 3 randomized, double-blind trials and was identified post-procedure in protocol-specified imaging. The thromboses were not associated with a marked increase in platelet count.

Consider the potential increased thrombotic risk when administering MULPLETA to patients with known risk factors for thromboembolism, including genetic pro-thrombotic conditions (Factor V Leiden, Prothrombin 20210A, Antithrombin deficiency, or Protein C or S deficiency). In patients with ongoing or prior thrombosis or absence of hepatopetal blood flow, MULPLETA should only be used if the potential benefit to the patient justifies the potential risk.

MULPLETA should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts.

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.

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of MULPLETA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

12.1 Mechanism 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.

12.2 Pharmacodynamics

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 (Cmax) of 111 (20.4) ng/mL and area under the time-concentration curve extrapolated to infinity (AUC0-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 Cmax and AUC were approximately 2 with once-daily multiple-dose administration, and steady-state plasma lusutrombopag concentrations were achieved after Day 5.

13.1 Carcinogenesis, 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).

Store MULPLETA in the original package at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

Risks

Pregnancy

Advise women of reproductive potential who become pregnant or are planning to become pregnant that MULPLETA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed during treatment with MULPLETA and for 28 days after the last dose of MULPLETA. Advise women to pump and discard breast milk during this period [see Use in Specific Populations (8.2)].