ADVERSE REACTIONS SECTION.


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)] 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 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 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 dose of mg daily for up to days prior to 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 Frequency >=3% in Patients Treated with MULPLETA (Pooled Data (L-PLUS 1, L-PLUS 2, and M0626))Adverse ReactionIncludes treatment-emergent adverse reactions occurring at rate higher than placebo. MULPLETA mg(N=171)%Placebo(N=170)%Headache54The 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


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 mg/kg/day in females (a dose 49 times and 30 times, respectively, the human exposure (AUC) at the recommended clinical dose of mg/day for 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 mg/day for days). Lusutrombopag was not genotoxic based on an in vitro bacterial reverse mutation (Ames) assay, chromosomal aberration assay with cultured Chinese hamster lung cells, and an in vivo micronucleus assay with mouse bone marrow cells. In 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 mg/day for days).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 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. Platelet ResponseLusutrombopag 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 mg in thrombocytopenic patients with chronic liver disease. With the mg daily dose, the mean (standard deviation) maximum platelet count in patients (N=74) without platelet transfusion was 86.9 (27.2) 109/L, and the median time to reach the maximum platelet count was 12.0 (5 to 35) days.. Cardiac ElectrophysiologyAt dose times the recommended dosage, MULPLETA does not prolong QT interval to any clinically relevant extent. 12.3 Pharmacokinetics. Lusutrombopag demonstrated dose-proportional pharmacokinetics after single doses ranging from mg (0.33 times the lowest approved dosage) to 50 mg (16.7 times the highest recommended dosage). Healthy subjects administered mg of lusutrombopag had 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 with once-daily multiple-dose administration, and steady-state plasma lusutrombopag concentrations were achieved after Day 5. AbsorptionIn patients with chronic liver disease, the time to peak lusutrombopag concentration (Tmax) was observed to hours after oral administration. Food EffectLusutrombopag AUC and Cmax were not affected when MULPLETA was co-administered with high-fat meal (a total of approximately 900 calories, with 500, 250, and 150 calories from fat, carbohydrate, and protein, respectively). DistributionThe 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%. EliminationThe terminal elimination half-life (t1/2) 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. MetabolismLusutrombopag is primarily metabolized by CYP4 enzymes, including CYP4A11.. ExcretionFecal 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 PopulationsNo 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 ImpairmentA population pharmacokinetic analysis did not find 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 ImpairmentNo clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on mild to moderate (Child-Pugh class and B) hepatic impairment.The mean observed lusutrombopag Cmax and AUC0- decreased by 20% to 30% in patients (N=5) with severe (Child-Pugh class C) hepatic impairment compared to patients with Child-Pugh class and class liver disease. However, the ranges for Cmax and AUC0- overlapped among patients with Child-Pugh class A, B, and liver disease. Drug Interaction Studies. Clinical StudiesNo clinically significant changes in lusutrombopag exposure were observed when co-administered with cyclosporine (an inhibitor of P-gp and BCRP) or an antacid containing multivalent cation (calcium carbonate). No clinically significant changes in midazolam (a CYP3A substrate) exposure were observed when co-administered with lusutrombopag. In Vitro StudiesCYP 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 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.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. The efficacy of MULPLETA for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo procedure was evaluated in randomized, double-blind, placebo-controlled trials (L-PLUS (N=97) and L-PLUS (N=215; NCT02389621)). Patients with chronic liver disease who were undergoing an invasive procedure and had platelet count less than 50 109/L were eligible to participate. Patients undergoing laparotomy, thoracotomy, open-heart surgery, craniotomy, or organ resection were excluded. Patients with history of splenectomy, partial splenic embolization, or thrombosis and those with Child-Pugh class liver disease, absence of hepatopetal blood flow, or 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 mg of MULPLETA or placebo once daily for up to 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 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 >=50 109/L, and the time course of platelet counts.In both the L-PLUS and L-PLUS trials, responders were defined as patients who had platelet count of >=50 109/L with an increase of >=20 109/L from baseline. Table 2.L-PLUS Trial: Proportion of Patients Not Requiring Platelet Transfusion Prior to Invasive Procedure and Proportion of RespondersEndpointProportion (n/N)Exact 95% Confidence IntervalTreatment Difference(95% Confidence Interval)p valueMULPLETA(N=49)Placebo (N=48)Not requiring platelet transfusion prior to invasive procedureA platelet transfusion was required if the platelet count was less than 50 109/L. 78% (38/49)(63, 88)13% (6/48)(4.7, 25)64 (49, 79)<0.0001Cochran-Mantel-Haenszel test with baseline platelet count as stratum; value and confidence interval calculated using Wald method. ResponderPlatelet count reached at least 50 109/L and increased at least 20 109/L from baseline. during study76% (37/49)(61, 87)6% (3/48)(1.3, 17)68 (54, 82)<0.0001 Table 3.L-PLUS Trial: Proportion of Patients Not Requiring Platelet Transfusion Prior to Invasive Procedure or Rescue Therapy for Bleeding Through Days After Invasive Procedure and Proportion of RespondersEndpointProportion (n/N)Exact 95% Confidence IntervalTreatment Difference(95% Confidence Interval)p valueMULPLETA(N=108)Placebo (N=107)Not requiring platelet transfusion prior to invasive procedureA platelet transfusion was required if the platelet count was less than 50 109/L. or rescue therapy for bleeding from randomization through days after invasive procedure65% (70/108)(55, 74)29% (31/107)(21, 39)37 (25, 49)<0.0001Cochran-Mantel-Haenszel test with baseline platelet count as stratum; value and confidence interval calculated using Wald method. ResponderPlatelet count reached at least 50 109/L and increased at least 20 109/L from baseline. during study65% (70/108)(55, 74)13% (14/107)(7.3, 21)52 (41, 62)<0.0001 The median (Q1, Q3) duration of platelet count increase to at least 50 109/L was 22 (17, 27) days in MULPLETA-treated patients without platelet transfusion and 1.8 (0.0, 8.3) days in placebo-treated patients with platelet transfusion in L-PLUS and 19 (13, 28) days in MULPLETA-treated patients without platelet transfusion and 0.0 (0.0, 5.0) days in placebo-treated patients with platelet transfusion in L-PLUS 2.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. None.. None. None.

DESCRIPTION SECTION.


11 DESCRIPTION. MULPLETA (lusutrombopag), thrombopoietin (TPO) receptor agonist, contains lusutrombopag as the active ingredient.The chemical name for lusutrombopag is (2 E)-3-2,6-Dichloro-4-[(4-3-[(1 S)-1-(hexyloxy) ethyl]-2-methoxyphenyl-1,3-thiazol-2-yl) carbamoyl]phenyl-2-methylprop-2-enoic acid.The structural formula is:The empirical formula for lusutrombopag is 29H 32Cl 2N 2O 5S and the molecular weight is 591.54.Lusutrombopag is white to slightly yellowish white powder, and is freely soluble in N,N-dimethylformamide, slightly soluble in ethanol (99.5%) and methanol, very slightly soluble in acetonitrile, and practically insoluble in water. Lusutrombopag is slightly soluble in the buffer solution at pH 11 and practically insoluble in buffer solutions with pH ranges of to 9.MULPLETA (lusutrombopag) tablets for oral use contain lusutrombopag mg.Excipients are D-mannitol, microcrystalline cellulose, magnesium oxide, sodium lauryl sulfate, hydroxypropyl cellulose, carboxymethylcellulose calcium, magnesium stearate, hypromellose, triethyl citrate, titanium dioxide, red ferric oxide, and talc.. Chemical Structure.

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. Platelet ResponseLusutrombopag 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 mg in thrombocytopenic patients with chronic liver disease. With the mg daily dose, the mean (standard deviation) maximum platelet count in patients (N=74) without platelet transfusion was 86.9 (27.2) 109/L, and the median time to reach the maximum platelet count was 12.0 (5 to 35) days.. Cardiac ElectrophysiologyAt dose times the recommended dosage, MULPLETA does not prolong QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Lusutrombopag demonstrated dose-proportional pharmacokinetics after single doses ranging from mg (0.33 times the lowest approved dosage) to 50 mg (16.7 times the highest recommended dosage). Healthy subjects administered mg of lusutrombopag had 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 with once-daily multiple-dose administration, and steady-state plasma lusutrombopag concentrations were achieved after Day 5. AbsorptionIn patients with chronic liver disease, the time to peak lusutrombopag concentration (Tmax) was observed to hours after oral administration. Food EffectLusutrombopag AUC and Cmax were not affected when MULPLETA was co-administered with high-fat meal (a total of approximately 900 calories, with 500, 250, and 150 calories from fat, carbohydrate, and protein, respectively). DistributionThe 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%. EliminationThe terminal elimination half-life (t1/2) 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. MetabolismLusutrombopag is primarily metabolized by CYP4 enzymes, including CYP4A11.. ExcretionFecal 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 PopulationsNo 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 ImpairmentA population pharmacokinetic analysis did not find 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 ImpairmentNo clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on mild to moderate (Child-Pugh class and B) hepatic impairment.The mean observed lusutrombopag Cmax and AUC0- decreased by 20% to 30% in patients (N=5) with severe (Child-Pugh class C) hepatic impairment compared to patients with Child-Pugh class and class liver disease. However, the ranges for Cmax and AUC0- overlapped among patients with Child-Pugh class A, B, and liver disease. Drug Interaction Studies. Clinical StudiesNo clinically significant changes in lusutrombopag exposure were observed when co-administered with cyclosporine (an inhibitor of P-gp and BCRP) or an antacid containing multivalent cation (calcium carbonate). No clinically significant changes in midazolam (a CYP3A substrate) exposure were observed when co-administered with lusutrombopag. In Vitro StudiesCYP 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 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.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Begin MULPLETA dosing 8-14 days prior to scheduled procedure. (2.1)Patients should undergo their procedure 2-8 days after the last dose. (2.1) Recommended Dosage: mg orally once daily with or without food for days. (2.1). Begin MULPLETA dosing 8-14 days prior to scheduled procedure. (2.1). Patients should undergo their procedure 2-8 days after the last dose. (2.1) Recommended Dosage: mg orally once daily with or without food for days. (2.1). 2.1 Recommended Dosage. Begin MULPLETA dosing 8-14 days prior to scheduled procedure. Patients should undergo their procedure 2-8 days after the last dose.The recommended dosage of MULPLETA is mg taken orally once daily with or without food for days. In the case of 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 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 platelet count prior to initiation of MULPLETA therapy and not more than days before the procedure.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Tablets: mg lusutrombopag as light red, round, film-coated tablet debossed with the Shionogi trademark ) above the identifier code 551 on one side and with 3 on the other side.. Tablet: mg. 3). Trademark.

GERIATRIC USE SECTION.


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.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. MULPLETA is supplied as mg lusutrombopag tablets in child-resistant blister pack containing tablets NDC 59630-551-07.. Store MULPLETA in the original package at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.


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

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). Prior to treatment, patients should fully understand and be informed of the following risks and considerations for MULPLETA. Risks. Thrombotic/Thromboembolic ComplicationsMULPLETA is 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.. PregnancyAdvise 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)].. LactationAdvise 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)].

LACTATION SECTION.


8.2 Lactation. Risk SummaryThere is no information regarding the presence of lusutrombopag in human milk, the effects on the breastfed child, and the effects on milk production. Lusutrombopag was present in the milk of lactating rats. Due to the potential for serious adverse reactions in breastfed child, breastfeeding is not recommended during treatment with MULPLETA and for at least 28 days after the last dose (see Clinical Considerations). Clinical Considerations. Minimizing ExposureA lactating woman should interrupt breastfeeding and pump and discard breast milk during MULPLETA treatment and for 28 days after the last dose of MULPLETA in order to minimize exposure to breastfed child.

MECHANISM OF ACTION SECTION.


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.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 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 mg/kg/day in females (a dose 49 times and 30 times, respectively, the human exposure (AUC) at the recommended clinical dose of mg/day for 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 mg/day for days). Lusutrombopag was not genotoxic based on an in vitro bacterial reverse mutation (Ames) assay, chromosomal aberration assay with cultured Chinese hamster lung cells, and an in vivo micronucleus assay with mouse bone marrow cells. In 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 mg/day for days).

OVERDOSAGE SECTION.


10 OVERDOSAGE. No antidote for MULPLETA overdose is known. 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. Hemodialysis is not expected to enhance the elimination of MULPLETA because lusutrombopag is highly bound to protein in plasma [see Clinical Pharmacology (12.3)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 3 mg Tablet Blister Card Carton. NDC 59630-551-07 Rx onlyFOR ORAL USE ONLYMulpleta (R) (lusutrombopag) tablets mg per tabletSHIONOGI INC.Lift Here to OpenOne blister card with tablets. PRINCIPAL DISPLAY PANEL 3 mg Tablet Blister Card Carton.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PREGNANCY SECTION.


8.1 Pregnancy. Risk SummaryThere are no available data on MULPLETA in pregnant women to inform the drug-associated risk. In animal reproduction studies, oral administration of lusutrombopag to pregnant rats during organogenesis and the lactation period resulted in adverse developmental outcomes. These findings were observed at exposures based on AUC that were substantially higher than the AUC observed in patients (approximately 89 times) at the recommended clinical dose of mg once daily. Advise pregnant women of the potential risk to fetus (see Data).The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the general population in the United States, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn an embryo-fetal development study in rats, lusutrombopag was orally administered during organogenesis at doses of 4, 12.5, 40, and 80 mg/kg/day. Low body weight and decrease in the number of ossified sternebrae were noted in fetuses at 80 mg/kg/day (approximately 251 times the AUC observed in patients at the recommended clinical dose of mg once daily). Minor skeletal variations (supernumerary ribs) were observed at doses of mg/kg/day (approximately 23 times the AUC observed in patients at the recommended clinical dose of mg once daily). In an embryo-fetal development study in rabbits following oral administration of lusutrombopag at doses up to 1000 mg/kg/day, no effect of lusutrombopag was observed on any parameter of embryo-fetal development.In pre- and postnatal development study in rats at oral doses of 1, 4, 12.5, and 40 mg/kg/day, there were adverse effects of lusutrombopag on postnatal development at 40 mg/kg/day (approximately 230 times the AUC observed in patients at the recommended clinical dose of mg once daily). The effects included prolongation of the gestation period in dams, low viability before weaning, delayed postnatal growth (delayed negative geotaxis, delayed eyelid opening, or low pup body weight), abnormal clinical signs (prominent annular rings on the tail after weaning), low fertility index, low number of corpora lutea or implantations, and increased pre-implantation loss. The incidence of short thoracolumbar supernumerary ribs on postnatal Day of F1 pups was high at doses of 12.5 mg/kg/day or more (approximately 89 times the AUC observed in patients at the recommended clinical dose of mg once daily).

SPL PATIENT PACKAGE INSERT SECTION.


PATIENT INFORMATIONMULPLETA(R) (mul ple tah)(lusutrombopag)TabletsThis Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 4/2020What is MULPLETAMULPLETA is prescription medicine used to treat low platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to have procedure.MULPLETA is not used to make platelet count normal in people with chronic liver disease.It is not known if MULPLETA is safe and effective in children.Before taking MULPLETA, tell your healthcare provider about all of your medical conditions, including if you: have blood clot or have had history of blood clot. have any blood clotting problems, other than thrombocytopenia.are pregnant or plan to become pregnant. MULPLETA may harm your baby. are breastfeeding or plan to breastfeed. It is not known if MULPLETA passes into your breast milk. Do not breastfeed during your treatment with MULPLETA and for at least 28 days after your last dose. Talk to your healthcare provider about the best way to feed your baby during your treatment with MULPLETA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take MULPLETA Take MULPLETA exactly as your healthcare provider tells you to take it.Your healthcare provider will tell you when to start taking MULPLETA.Take MULPLETA time each day for days. MULPLETA may be taken with or without food.If you miss dose of MULPLETA, take the missed dose as soon as possible on the same day and return to your normal schedule the following day.If you take too much MULPLETA, call your healthcare provider or go to the nearest hospital emergency room right away. Your healthcare provider will check your platelet count before you start treatment with MULPLETA and before your procedure. What are the possible side effects of MULPLETAMULPLETA may cause serious side effects, including: Blood clots, including blood clots in the liver, may happen in people with chronic liver disease and who take MULPLETA. You may have an increased risk of blood clots if you have certain blood clotting conditions. The most common side effect of MULPLETA is headache. These are not all of the possible side effects of MULPLETA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store MULPLETAStore MULPLETA at room temperature between 68F and 77F (20C to 25C). MULPLETA comes in child-resistant blister pack. Keep MULPLETA in the packaging that it comes in. Keep MULPLETA and all medicines out of the reach of children.General information about the safe and effective use of MULPLETA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use MULPLETA for condition for which it was not prescribed. Do not give MULPLETA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about MULPLETA that is written for healthcare professionals.What are the ingredients of MULPLETAActive ingredient: lusutrombopag.Inactive ingredients: D-mannitol, microcrystalline cellulose, magnesium oxide, sodium lauryl sulfate, hydroxypropyl cellulose, carboxymethylcellulose calcium, magnesium stearate, hypromellose, triethyl citrate, titanium dioxide, red ferric oxide, and talc. Manufactured for: Shionogi Inc., Florham Park, NJ 07932(C) Shionogi Inc. 2020For more information, go to www.mulpleta.com or call 1-800-849-9707.. have blood clot or have had history of blood clot. have any blood clotting problems, other than thrombocytopenia.. are pregnant or plan to become pregnant. MULPLETA may harm your baby. are breastfeeding or plan to breastfeed. It is not known if MULPLETA passes into your breast milk. Do not breastfeed during your treatment with MULPLETA and for at least 28 days after your last dose. Talk to your healthcare provider about the best way to feed your baby during your treatment with MULPLETA. Take MULPLETA exactly as your healthcare provider tells you to take it.. Your healthcare provider will tell you when to start taking MULPLETA.. Take MULPLETA time each day for days. MULPLETA may be taken with or without food.. If you miss dose of MULPLETA, take the missed dose as soon as possible on the same day and return to your normal schedule the following day.. If you take too much MULPLETA, call your healthcare provider or go to the nearest hospital emergency room right away. Your healthcare provider will check your platelet count before you start treatment with MULPLETA and before your procedure. Store MULPLETA at room temperature between 68F and 77F (20C to 25C). MULPLETA comes in child-resistant blister pack. Keep MULPLETA in the packaging that it comes in.

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2.1 Recommended Dosage. Begin MULPLETA dosing 8-14 days prior to scheduled procedure. Patients should undergo their procedure 2-8 days after the last dose.The recommended dosage of MULPLETA is mg taken orally once daily with or without food for days. In the case of 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 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.

STORAGE AND HANDLING SECTION.


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

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended during treatment. (8.2). Lactation: Breastfeeding is not recommended during treatment. (8.2). 8.1 Pregnancy. Risk SummaryThere are no available data on MULPLETA in pregnant women to inform the drug-associated risk. In animal reproduction studies, oral administration of lusutrombopag to pregnant rats during organogenesis and the lactation period resulted in adverse developmental outcomes. These findings were observed at exposures based on AUC that were substantially higher than the AUC observed in patients (approximately 89 times) at the recommended clinical dose of mg once daily. Advise pregnant women of the potential risk to fetus (see Data).The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the general population in the United States, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn an embryo-fetal development study in rats, lusutrombopag was orally administered during organogenesis at doses of 4, 12.5, 40, and 80 mg/kg/day. Low body weight and decrease in the number of ossified sternebrae were noted in fetuses at 80 mg/kg/day (approximately 251 times the AUC observed in patients at the recommended clinical dose of mg once daily). Minor skeletal variations (supernumerary ribs) were observed at doses of mg/kg/day (approximately 23 times the AUC observed in patients at the recommended clinical dose of mg once daily). In an embryo-fetal development study in rabbits following oral administration of lusutrombopag at doses up to 1000 mg/kg/day, no effect of lusutrombopag was observed on any parameter of embryo-fetal development.In pre- and postnatal development study in rats at oral doses of 1, 4, 12.5, and 40 mg/kg/day, there were adverse effects of lusutrombopag on postnatal development at 40 mg/kg/day (approximately 230 times the AUC observed in patients at the recommended clinical dose of mg once daily). The effects included prolongation of the gestation period in dams, low viability before weaning, delayed postnatal growth (delayed negative geotaxis, delayed eyelid opening, or low pup body weight), abnormal clinical signs (prominent annular rings on the tail after weaning), low fertility index, low number of corpora lutea or implantations, and increased pre-implantation loss. The incidence of short thoracolumbar supernumerary ribs on postnatal Day of F1 pups was high at doses of 12.5 mg/kg/day or more (approximately 89 times the AUC observed in patients at the recommended clinical dose of mg once daily).. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of lusutrombopag in human milk, the effects on the breastfed child, and the effects on milk production. Lusutrombopag was present in the milk of lactating rats. Due to the potential for serious adverse reactions in breastfed child, breastfeeding is not recommended during treatment with MULPLETA and for at least 28 days after the last dose (see Clinical Considerations). Clinical Considerations. Minimizing ExposureA lactating woman should interrupt breastfeeding and pump and discard breast milk during MULPLETA treatment and for 28 days after the last dose of MULPLETA in order to minimize exposure to breastfed child.. 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.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Thrombotic/Thromboembolic Complications: MULPLETA is 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) Thrombotic/Thromboembolic Complications: MULPLETA is 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 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 randomized, double-blind trials and was identified post-procedure in protocol-specified imaging. The thromboses were not associated with 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 Leiden, Prothrombin 20210A, Antithrombin deficiency, or Protein or 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.