Mulpleta

5 WARNINGS AND PRECAUTIONS 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. Monitor platelet counts and for thromboembolic events and institute treatment promptly. ( 5.1 ) 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 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 Shionogi Inc. at 1-800-849-9707 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.

<table width="90%" ID="table1"><caption>Table 1. Adverse Reactions with a Frequency &#x2265;3% in Patients Treated with MULPLETA (Pooled Data (L-PLUS 1, L-PLUS 2, and M0626))</caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="bottom">Adverse Reaction <footnote ID="K714">Includes treatment-emergent adverse reactions occurring at a rate higher than placebo. </footnote></th><th styleCode="Rrule">MULPLETA 3 mg (N=171) % </th><th styleCode="Rrule">Placebo (N=170) % </th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">5</td><td styleCode="Rrule">4</td></tr></tbody></table>