Mulpleo

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Mulpleo 3 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each film-coated tablet contains 3 mg of lusutrombopag. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 

 

Light red, 7.0 mm round film-coated tablets debossed with the Shionogi trademark above the identifier 

code “551” on one side and debossed on the other side with the strength “3”. 
 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Mulpleo is indicated for the treatment of severe thrombocytopenia in adult patients with chronic liver 

disease undergoing invasive procedures (see section 5.1). 

 

4.2 Posology and method of administration 

 

Posology 

 

The recommended dose is 3 mg lusutrombopag once daily for 7 days. 

 

The procedure should be performed from day 9 after the start of lusutrombopag treatment. Platelet 

count should be measured prior to the procedure. 

 

Missed dose 

If a dose is missed it should be taken as soon as possible. A double dose should not be taken to make 

up for a missed dose.  

 

Duration of treatment 

Mulpleo should not be taken for more than 7 days. 

 

Special populations 

 

Elderly patients 

No dosage adjustment is necessary in patients 65 years of age or older (see section 5.2). 

 

Renal impairment 

No dosage adjustment is necessary in patients with renal impairment (see section 5.2). 

 



3 

Hepatic impairment 

Due to limited information available, the safety and efficacy of Mulpleo in patients with severe hepatic 

impairment (Child-Pugh class C) have not been established (see sections 4.4 and 5.1). No dosage 

adjustment is expected for these patients. Lusutrombopag therapy should only be initiated in patients 

with severe hepatic impairment if the expected benefit outweighs the expected risks (see sections 4.4 

and 5.2). No dosage adjustment is necessary for patients with mild (Child-Pugh class A) to moderate 

(Child-Pugh class B) hepatic impairment.  

 

Paediatric population 

The safety and efficacy of lusutrombopag in children and adolescents (< 18 years of age) have not 

been established. No data are available. 

 

Method of administration  

 

Mulpleo is for oral use. The film-coated tablet is to be taken once daily with liquid, swallowed whole 

and should not be chewed, divided, or crushed. It can be taken with or without food. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

Thrombotic/thromboembolic complications 

 

Patients with chronic liver disease have a risk of portal vein thrombosis and mesenteric vein 

thrombosis. The risk may be increased due to an invasive procedure. Thromboembolic and thrombotic 

complications are known to occur with thrombopoetin (TPO) receptor agonists based upon mechanism 

of action associated with increases in platelets. Caution should be exercised with respect to 

thromboembolic events after invasive procedures as well as post-treatment regardless of platelet 

counts. In patients with thrombosis or thromboembolism, with a history of thrombosis or 

thromboembolism, with absence of hepatopetal blood flow in the main trunk of the portal vein, or 

patients with congenital coagulopathy the risk for thrombosis or thromboembolism may increase. 

These patients should be clinically monitored when treated with lusutrombopag.  

 

Severe hepatic impairment 

 

There is limited information on the use of lusutrombopag in patients with severe (Child-Pugh class C) 

hepatic impairment (see section 5.1). Lusutrombopag should only be used in such patients if the 

expected benefit outweighs the expected risks  (see sections 4.2 and 5.2). 

Due to the unstable nature of these patients, they should be supported in line with clinical practice by 

close monitoring for early signs of worsening or new onset hepatic encephalopathy, ascites, and 

thrombotic or bleeding tendency, through monitoring of liver function tests, tests used for assessing 

clotting status and through imaging of portal vasculature as needed. In addition, although no dose 

adjustment is required in these subjects, platelet count should be measured at least once approximately 

5 days after the first dose and as necessary thereafter. Appropriate measures such as discontinuation of 

lusutrombopag should be taken, if the platelet count reaches ≥50,000/µL as a result of a 20,000/µL 
increase from baseline. 

 

Use in patients with chronic liver disease undergoing invasive procedures 

 

Lusutrombopag should be used when risk for bleeding is considered to be high according to clinical 

laboratory test values such as platelet counts and of the coagulation-fibrinolysis system, clinical 

symptoms and type of invasive procedure. The efficacy and safety of lusutrombopag have not been 

established when administered before laparotomy, thoracotomy, open-heart surgery, craniotomy or 

excision of organs. 

 



4 

Retreatment 

 

There is limited information on the use of lusutrombopag in patients previously exposed to 

lusutrombopag. 

 

Use in patients with a history of splenectomy  

 

The efficacy and safety of lusutrombopag have not been established when administered in patients 

with a history of splenectomy. Platelet count should be carefully monitored in patients with a history 

of splenectomy treated with lusutrombopag. 

 

Co-administration with interferon preparations 

 

Interferon preparations have been known to reduce platelet counts, therefore, this should be considered 

when co-administering lusutrombopag with interferon preparations. 

 

Patients with body weight <45 Kg 

 

There is limited information on the use of lusutrombopag in patients with body weight <45 Kg. 

Platelet count should be measured at least once approximately 5 days after the first dose and as 

necessary thereafter. Appropriate measures such as discontinuation of lusutrombopag should be taken, 

if the platelet count reaches ≥50,000/µL as a result of a 20,000/µL increase from baseline. 
 

4.5 Interaction with other medicinal products and other forms of interaction 

 

P-gp and BCRP inhibitors 

 

Lusutrombopag is a substrate of P-gp and BCRP, but not a substrate of OATP1B1, OATP1B3, and 

OCT1. In the clinical drug-drug interaction study, co-administration of cyclosporine, a P-gp and 

BCRP dual inhibitor, increased the Cmax and AUCinf values of lusutrombopag by approximately 20% 

compared with lusutrombopag administration alone. Therefore, a potential interaction with either P-gp 

or BCRP inhibitors cannot be excluded, but no dose adjustment is necessary at the recommended 

clinical dosage of 3 mg in adults. 

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential/contraception 

 

Mulpleo should be used with contraception (see sub-section Pregnancy and section 5.3). 

 

Pregnancy 

 

There are no or limited amount of data from the use of lusutrombopag in pregnant women. Animal 

studies are insufficient with respect to reproductive toxicity (see section 5.3). 

 

Lusutrombopag is not recommended during pregnancy and in women of child-bearing potential not 

using contraception.  

 

 

Breast-feeding 

 

It is unknown whether lusutrombopag or its metabolites are excreted in human milk. Studies in 

animals have shown lusutrombopag is secreted in the milk of lactating rats (see section 5.3). 

Therefore, a risk to the breast-feeding child cannot be excluded. Mulpleo should not be administered 

to breast-feeding women as it was excreted in mammary milk in animals. 

 



5 

Fertility 

 

Lusutrombopag did not affect male or female fertility in rats at doses up to 176 and 252 times the 

human clinical exposures in adults based on AUC in males and females, respectively (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

Lusutrombopag has no known influence on the ability to drive and use machines. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

The most common adverse reactions were headache (4.7%, 8/171 patients in the lusutrombopag 

group; 3.5%, 6/170 patients in the placebo group), nausea (2.3%, 4/171 patients in the lusutrombopag 

group; 4.1%, 7/170 patients in the placebo group), portal vein thrombosis (1.2%, 2/171 patients in the 

lusutrombopag group; 1.2%, 2/170 patients in the placebo group) and rash (1.2%, 2/171 patients in the 

lusutrombopag group; 0%, 0/170 patients in the placebo group). 

 

Tabulated list of adverse reactions 

 

Adverse reactions with 3 mg of lusutrombopag once daily for up to 7 days in randomised, double-

blind, placebo-controlled trials in thrombocytopenic patients with chronic liver disease undergoing an 

invasive procedure (M0626, M0631 and M0634; N=171) are listed in Table 1 by MedDRA System 

Organ Class. 

 

Table 1 Adverse reactions  

System Organ Class Adverse reaction - Common 

Nervous system disorders Headache 

Gastrointestinal disorders Nausea 

Hepatobiliary disorders Portal vein thrombosis 

Skin and subcutaneous tissue disorders Rash 

a
 Category of frequency: very common (≥1/10), common (≥1/100 to <1/10)  , uncommon (≥1/1,000 to <1/100), 

rare (≥1/10,000 to <1/1,000) , and very rare (<1/10,000) 
 

Description of selected adverse reactions 

 

Thrombotic/thromboembolic complications 

Portal vein thrombosis has been reported in Phase 3 randomised, double-blind, placebo-controlled 

clinical studies with 3 mg of lusutrombopag once daily for up to 7 days (1.2%, 2/171 patients); the 

incidence was comparable to that of the placebo group (1.2%, 2/170 patients); one case of cardiac 

ventricular thrombosis was reported (0.6%, 1/171) in the lusutrombopag group only. In the phase 2b 

study one patient had portal vein thrombosis reported as a treatment-emergent adverse event (TEAE) 

in the lusutrombopag 2 mg and 4 mg groups. One patient had mesenteric vein thrombosis reported as a 

TEAE in the lusutrombopag 4 mg group; two patients had mesenteric vein thrombosis reported as a 

TEAE in the placebo group (see section 4.4). 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


6 

4.9 Overdose 

 

Overdose may induce an excessive increase of platelet counts, and it may subsequently provoke a 

medically susceptible state to cause thrombosis and thromboembolism. There is no specific antidote 

for lusutrombopag overdose. Platelet counts should be measured frequently and the condition of 

patients should be observed closely. Since the protein-binding rate in serum of lusutrombopag is high, 

haemodialysis is not thought to be effective. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics, ATC code: B02BX07 

 

Mechanism of action 

 

Lusutrombopag is an orally active TPO receptor agonist. Lusutrombopag acts on the haematopoietic 

stem cells and on the transmembrane domain of human TPO receptors expressed in megakaryocytes, 

to stimulate the megakaryocyte to proliferate and differentiate via the similar signal transduction 

pathway for up-regulating production used by endogenous TPO, thus leading to thrombocytopoiesis.  

 

Clinical efficacy and safety 

 

Two Phase 3, randomised, double-blind, placebo-controlled studies were conducted to evaluate 

lusutrombopag versus placebo in thrombocytopenic (platelet count < 50,000/µL) subjects with chronic 

liver disease (Child-Pugh class A and B), undergoing elective invasive procedures (excluding 

laparotomy, thoracotomy, craniotomy, open-heart surgery, organ resection, or partial organ resection) 

in Japan (M0631 (L-PLUS 1)) and multiple countries (M0634 (L-PLUS 2)). Subjects were randomised 

to either of 3 mg of lusutrombopag or placebo in a 1:1 ratio. Randomisation was stratified by platelet 

count at screening/baseline and primary invasive procedure. Study drug was administered orally for up 

to 7 days. On Day 5 to Day 7, the platelet count was measured before administration of study drug. 

Administration of study drug was stopped if the platelet count was ≥ 50,000/µL together with an 
increase of ≥ 20,000/µL from baseline. 
 

Invasive procedure was performed between Days 9 and 14. 

 

In Study M0631, 96 subjects received lusutrombopag or placebo once daily: 48 subjects in the 

lusutrombopag group and 48 subjects in the placebo group. Eight lusutrombopag-treated subjects and 

2 placebo-treated subjects received less than 7 days of treatment as they met the criterion for a 

responder prior to Day 7. Among the 48 subjects in the lusutrombopag group, 40 subjects received 

lusutrombopag for 7 days, 4 subjects for 6 days, 1 subject for 5 days, and 3 subjects for 4 days. Among 

the 48 subjects in the placebo group, 46 were treated for 7 days and 2 were treated for 4 days. 

 

In Study M0634, 215 subjects were randomised in the study: 108 in the lusutrombopag 3 mg group 

and 107 in the placebo group. One subject in the lusutrombopag group withdrew from the study prior 

to administration of study drug. In the lusutrombopag group, 73/107 subjects (68.2%) received the 

study drug for 7 days. Of the remaining subjects in the lusutrombopag group, 15, 8, and 11 subjects 

received study drug for 4, 5, and 6 days, respectively. In the placebo group, 94/107 subjects (87.9%) 

received the study drug for 7 days. Of the remaining subjects in the placebo group, 5, 4, and 4 subjects 

received study drug for 4, 5, and 6 days, respectively. 

 

The primary endpoint in Study M0631 was the proportion of subjects who required no platelet 

transfusion (i.e. achieved platelet count >50,000/µL) before the primary invasive procedure. The 

primary endpoint in Study M0634 was the proportion of subjects who required no platelet transfusion 

(i.e. achieved platelet count >50,000/µL) before the primary invasive procedure and no rescue therapy 

for bleeding from randomisation through 7 days after the primary invasive procedure. 



7 

 

In order to allow an overall comparison of the results across Studies M0631 and M0634, as presented 

in Table 2 to Table 5, data from study M0631 was reanalysed according to the primary endpoint for 

study M0634. The proportion of subjects who required no platelet transfusion prior to the primary 

invasive procedure and no rescue therapy for bleeding from randomisation through 7 days after the 

primary invasive procedure was statistically significantly greater in the lusutrombopag group 

compared with placebo group for the individual study and pooled analyses (Table 2). 

 

Table 2 Proportion of subjects who required no platelet transfusion and no rescue therapy 

 

Study M0631 Study M0634 Overall 

LUSU 3 mg 

N = 49 

Placebo 

N =48 

LUSU 3 mg 

N = 108 

Placebo 

N = 107 

LUSU 3 mg 

N = 157 

Placebo 

N = 155 

Proportion of subjects [a] 75.5% 12.5% 64.8% 29.0% 68.2% 23.9% 

(number of subjects) (37) (6) (70) (31) (107) (37) 

Comparison with placebo 

[b]: Difference of 

proportion (95% CI) 

61.8 

(46.4, 77.2) 
 

36.6 

(24.6, 48.5) 
 

44.4 

(34.9, 54.0) 
 

P value  < 0.0001  < 0.0001  < 0.0001  

LUSU = lusutrombopag 

[a] Proportion of subjects who required no platelet transfusion prior to the primary invasive procedure and no 

rescue therapy (including platelet transfusion) for bleeding from randomisation through 7 days after the primary 

invasive procedure. In addition to subjects who received platelet transfusion, subjects who did not receive an 

invasive procedure regardless of the reason were considered as receiving platelet transfusion. 

[b] Cochran-Mantel-Haenszel test with baseline platelet count as stratum. In the analysis for pooled data, 

study was added as a stratum. The p value and confidence interval were calculated using the Wald method. 

 

The key secondary endpoints in Studies M0631 and M0634 were 

 

Proportion of subjects who required no platelet transfusion during the study (Day 1 through Day 35) 

The proportion of subjects who required no platelet transfusion during the study was significantly 

greater in the lusutrombopag groups in the individual studies and the pooled (Studies M0631 and 

M0634) lusutrombopag group compared with placebo (Table 3).  

 

Table 3 Proportion of Subjects who required no platelet transfusion during the study (Day 1 

through Day 35) 

 

Study M0631 Study M0634 Overall 

LUSU 3 mg 

N = 49 

Placebo 

N =48 

LUSU 3 mg 

N = 108 

Placebo 

N = 107 

LUSU 3 mg 

N = 157 

Placebo 

N = 155 

Proportion of subjects [a] 77.6% 12.5% 63.0% 29. 0% 67.5% 23.9% 

(number of subjects) (38) (6) (68) (31) (106) (37) 

Comparison with placebo 

[b]: Difference of 

proportion (95% CI) 

63.8 

(48.7, 78.9) 
 

34.7 

(22.6, 46.8) 
 

43.8 

(34.2, 53.4) 
 

P value  < 0.0001  < 0.0001  < 0.0001  

[a] Proportion of subjects who required no platelet transfusion during the study (i.e., from Day 1 through 

Day 35). In addition to subjects who received platelet transfusion, subjects who did not receive an invasive 

procedure regardless of the reason were considered as receiving platelet transfusion. 

[b] Cochran-Mantel-Haenszel test with baseline platelet count as stratum. In the analysis for pooled data, study 

was added as a stratum. The p value and confidence interval were calculated using the Wald method. 

 

Proportion of responders 

The proportion of subjects who met the responder criterion (defined as platelet count increase to 

≥ 50,000/μL with an increase of ≥ 20,000/μL from baseline) during the study was significantly greater 
in the lusutrombopag groups in the individual studies and the pooled (Studies M0631 and M0634) 

lusutrombopag group compared with placebo (Table 4). 

 



8 

Table 4 Proportion of responders  

 

Study M0631 Study M0634 Overall 

LUSU 3 mg 

N = 49 

Placebo 

N =48 

LUSU 3 mg 

N = 108 

Placebo 

N = 107 

LUSU 3 mg 

N = 157 

Placebo 

N = 155 

Proportion of subjects [a] 75.5% 6.3% 64.8% 13.1% 68.2% 11.0% 

(number of subjects) (37) (3) (70) (14) (107) (17) 

Comparison with placebo 

[b]: Difference of 

proportion (95% CI) 

68.4 

(54.4, 82.3) 
 

51.7 

(41.1, 62.4) 
 

56.9 

(48.4, 65.4) 
 

P value  < 0.0001  < 0.0001  < 0.0001  

[a] A responder was defined as a subject who achieved a platelet count of ≥ 50,000/μL with an increase of 
≥ 20,000/μL from baseline. A subject was considered a nonresponder if the subject met the responder criterion 
only after platelet transfusion. 

[b] Cochran-Mantel-Haenszel test with baseline platelet count as stratum. In the analysis for pooled data, 

study was added as a stratum. The p value and confidence interval were calculated using the Wald method. 

 

Duration of the increase in platelet count to ≥ 50,000/μL 
The duration of the increase in platelet count to ≥ 50,000/µL in Studies M0631 and M0634 and the 
pooled (Studies M0631 and M0634) lusutrombopag group was significantly greater than compared 

with placebo (Table 5). 

 

Table 5 Duration of the increase in platelet count to ≥ 50,000/µL  

 

Study M0631 Study M0634 Overall 

LUSU 3 mg 

N = 49 

Placebo 

N = 48 

LUSU 3 mg 

N = 108 

Placebo 

N = 107 

LUSU 3 mg 

N = 157 

Placebo 

N = 155 

Total       

- n 48 48 107 107 155 155 

- Median (days)  21.1 3.4 15.1 1.0 17.3 1.8 

- (Q1, Q3) (13.7, 25.5) (0.0, 11.3) (6.6, 23.9) (0.0, 9.2) (9.7, 24.4) (0.0, 9.5) 

- P value [a] 0.0197  0.0002  <0.0001  

LUSU = lusutrombopag; Q1 = 25th percentile; Q3 = 75th percentile 

[a] P-value was calculated by the van Elteren test with platelet transfusion status as stratum. In the analysis 

for pooled data, study was added as a stratum. 

 

Time course of platelet count 

The mean (range) maximum platelet count in subjects without platelet transfusion in the 

lusutrombopag group in Studies M0631 and M0634 was 90,200 (59,000 to 145,000)/µL and 86,900 

(25,000 to 219,000)/µL, respectively; and the median (range) time to reach the maximum platelet 

count was 14.0 (6 to 28) days and 12.0 (5 to 35) days, respectively, and platelet count is expected to 

decrease thereafter.  

The time course of platelet counts in lusutrombopag-treated subjects without platelet transfusion and 

placebo-treated subjects with platelet transfusion in Studies M0631 and M0634 is presented in 

Figure 1. 

 



9 

Figure 1 Time course profiles of platelet count in the Phase 3 studies in thrombocytopenic 

patients with chronic liver disease (lusutrombopag-treated subjects without platelet 

transfusion and placebo-treated subjects with platelet transfusion) 

Phase 3 Study M0631 

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Baseline   

  Day 

   

   Treatment Group  Lusutrombopag 3 mg  
Placebo  

   

 

 

Phase 3 Study M0634 

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Baseline   

  Day 

   

   Treatment Group  Lusutrombopag 3 mg  
Placebo  

   

 

Patients with severe hepatic impairment 

In Study M0634, 3 subjects with Child-Pugh class C liver disease were erroneously enrolled (all in the 

lusutrombopag group). All 3 received 7 days of treatment with lusutrombopag. This limited data 

suggested no abnormal pattern of platelet count rise in this subpopulation. 

 

Paediatric population 

 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Mulpleo in all subsets of the paediatric population for thrombocytopenia secondary to liver disease 

(see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

 

Lusutrombopag is absorbed with a peak concentration occurring 6 to 8 hours after oral administration. 

The accumulation ratios of the Cmax and the AUC are approximately 2 at once-daily multiple doses and 

the steady-state of the plasma concentration of lusutrombopag appear to be achieved after Day 5. The 

pharmacokinetics of lusutrombopag was similar in both healthy subjects and the chronic liver disease 

population. The pharmacokinetic parameters in patients with chronic liver disease are shown in 

Table 6. 

 



10 

Table 6  Pharmacokinetic parameters of lusutrombopag after 3 mg dose once daily in 

thrombocytopenic patients with chronic liver disease (Study M0634) 

Cmax (ng/mL) Tmax (hr) AUC0-τ (ng·hr/mL) CL/F (L/hr) 

157 (34.7) 5.95 (2.03, 7.85) 2737 (36.1) 1.10 (36.1) 

n = 9.  

Geometric mean (%CV) other than for Tmax, which is median (range). 

 

Food interaction 

Neither food (including high-fat and high-calorie diet) nor co-administration with calcium has a 

clinically meaningful effect on the pharmacokinetics of lusutrombopag. 

 

Distribution 

 

Human plasma protein binding ratio is ≥ 99.9%. The mean (% coefficient of variation) apparent 
volume of distribution during the terminal phase of lusutrombopag in healthy adult subjects (n = 16) 

was 39.5 L (23.5%).  

 

In rats, results indicated that lusutrombopag and its metabolites transfer to fetus via placenta. 

 

Biotransformation  

 

Lusutrombopag is a substrate of P-gp and BCRP, but is not a substrate of OATP1B1, OATP1B3 or 

OCT1. In the human mass balance study using [
14

C]-lusutrombopag, unchanged lusutrombopag (97% 

of radioactivity in plasma) was the major circulating component, and the metabolites, such as 

deshexyl, β-oxidated carboxylic acid, taurine conjugate of β-oxidated carboxylic acid, and acyl-
glucuronide, were detected with less than 2.6% of radioactivity in plasma. In faeces, the components 

of radioactivity were unchanged lusutrombopag (16% of administered radioactivity) and β-oxidation-
related metabolites (35% of administered radioactivity), suggesting that lusutrombopag is metabolised 

by ω-oxidation first, and subsequently metabolised by β-oxidation of O-hexyl side chain. In vitro 
studies revealed that CYP4 enzymes including CYP4A11 and partially CYP3A4 enzyme contributed 

to ω-oxidation to form 6-hydroxylated lusutrombopag. Drug interactions via inhibition and induction 
of any CYP4A enzymes have not been reported in clinical use. Therefore, inducers and inhibitors of 

CYP4A enzymes including CYP4A11 are unlikely to affect the pharmacokinetics of lusutrombopag.  

Lusutrombopag has low potential to inhibit CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 

and 3A4/5), and to induce both CYP enzymes (CYP1A2, 2C9, and 3A4) and UGT enzymes (UGT1A2, 

1A6, and 2B7). Lusutrombopag has also low potential to inhibit P-gp, BCRP, OATP1B1, OATP1B3, 

OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K, and BSEP. Lusutrombopag is not considered to 

affect the pharmacokinetics of co-administered medicinal products that are substrates of these 

enzymes or transporters. 

 

Elimination 

 

Lusutrombopag was excreted mainly via faecal route in humans (approximately 83% into faeces and 

1% into urine). 

Geometric mean of t1/2 (% coefficient of variation), was 38.3 hours (18.7%) after multiple oral dose of 

3 mg lusutrombopag.  

 

Linearity/non-linearity  

 

Both Cmax and AUC for lusutrombopag increase dose-proportionally over dose range of multiple oral 

dose of 0.25 to 4 mg once daily in patients with chronic liver disease. 

 



11 

Pharmacokinetics in subpopulations  

 

Age, gender and race 

A population pharmacokinetic analysis using plasma lusutrombopag concentrations from clinical 

studies with lusutrombopag did not identify a clinically meaningful effect of age, gender or race on the 

pharmacokinetics of lusutrombopag. 

 

Paediatric population 

No pharmacokinetic data have been obtained in children. 

 

Renal impairment 

Lusutrombopag is rarely excreted into urine (approximately 1%). A population pharmacokinetic 

analysis using plasma lusutrombopag concentrations from clinical studies with lusutrombopag did not 

identify a clinically meaningful effect of renal function on the pharmacokinetics of lusutrombopag. 

 

Hepatic impairment 

Mild and moderate hepatic impairment (mild, Child-Pugh class A; moderate, Child-Pugh class B) is 

expected to have little effect on the pharmacokinetics of lusutrombopag. The differences in 

pharmacokinetics of a single 0.75 mg dose of lusutrombopag were relatively small in both subjects 

with mild hepatic impairment and subjects with moderate hepatic impairment, compared with the 

healthy matched control group. Ratios of AUC relative to the healthy matched control group were 1.05 

in subjects with mild hepatic impairment and 1.20 in subjects with moderate hepatic impairment. 

 

The ranges of observed Cmax and AUC0-τ overlapped among the patients with Child-Pugh class A, B, 

and C. Cmax and AUC0-τ of all patients with Child-Pugh class C did not exceed the maximum values 

from Child-Pugh class A and class B. Due to the limited information available, lusutrombopag should 

not be used in Child-Pugh class C patients unless the expected benefit outweighs the expected risks.  

 

5.3 Preclinical safety data 

 

Lusutrombopag does not stimulate platelet production in the species used for toxicological testing 

because of unique human TPO receptor specificity. Thus, the data from the toxicology program in 

these animals do not present potential adverse effects related to exaggerated pharmacology in humans. 

 

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the 

maximum human exposure indicating little relevance to clinical use. 

 

In rats, lusutrombopag and its metabolites are excreted in milk, and the concentrations in milk 

decreased as with those in plasma. 

 

Repeated toxicity 

 

The principal toxicity findings associated with lusutrombopag administration included prolongation of 

PT and APTT (rats), increased activities of plasma ALT and AST (rats and dogs), adrenal toxicity 

(rats and dogs), skin and forestomach lesions (rats) and renal toxicity (rats). 

 

High dose (10 mg/kg/day) and long-term treatment (8 weeks) of lusutrombopag has a potential risk of 

fibrosis in the bone marrow via human TPO receptor based on the results of study in TPOR-Ki/Shi 

mice with chimeric human transmembrane domain TPO receptor knocked-in to the mouse TPO 

receptor.  

 

Carcinogenesis 

 

Lusutrombopag was not carcinogenic to mice at doses up to 20 mg/kg/day in males and females (a 

dose at least 45 times the human clinical exposures in adults based on AUC), or rats at doses up to 

20 mg/kg/day in males and 2 mg/kg/day in females (a dose 49 and 30 times, respectively, the human 

clinical exposures in adults based on AUC). 



12 

 

Mutagenesis 

 

Lusutrombopag was not genotoxic when tested in a bacterial reverse mutation test, a chromosomal 

aberration test with cultured Chinese hamster lung cells, or an in vivo micronucleus test with mouse 

bone marrow cells. 

 

Fertility 

 

Lusutrombopag did not affect male and female fertility and early embryo development in rats at doses 

up to 100 mg/kg/day (176 and 252 times respectively, the human clinical exposures in adults based on 

AUC). 

 

Embryo-foetal development 

 

Lusutrombopag showed no teratogenicity in rats and rabbits at up to 80 mg/kg/day and 

1000 mg/kg/day respectively. No effects on foetal viability embryo-foetal development were noted in 

rabbits at doses up to 1000 mg/kg/day (161 times the human clinical exposures in adults based on 

AUC). In rats, there were adverse effects of lusutrombopag on foetal intrauterine growth and skeletal 

morphology as follows: a suppression of foetal intrauterine growth (low foetal body weight and a 

decrease in the number of ossified sternebrae) at 80 mg/kg/day, and an high incidence of short cervical 

supernumerary ribs at 40 mg/kg/day or more, and an high incidence of short thoracolumbar 

supernumerary rib at 4 mg/kg/day or more. A suppression of foetal intrauterine growth as well as 

cervical ribs occurred at doses (40 mg/kg/day or more), showing maternal toxicity. Meanwhile, the 

short thoracolumbar supernumerary ribs were observed at doses without maternal toxicity. The 

changes were also noted in F1 pups on postnatal day (PND) 4 at 12.5 mg/kg/day or more in the pre- 

and postnatal development study; however, F1 mature animals showed no full and short 

thoracolumbar supernumerary rib. On the basis of the results, the no observed adverse effect level 

(NOAEL) was estimated to be near 4 mg/kg/day in the embryo-foetal development study in rats 

(23 times the human clinical exposures in adults based on AUC). 

 

Pre- and post-natal development 

 

In the pre- and postnatal development study in rats at doses up to 40 mg/kg/day, there were adverse 

effects of lusutrombopag on postnatal development at 40 mg/kg/day as follow: prolongation of 

gestation period in dams, low viability before weaning, delayed postnatal growth such as delayed 

negative geotaxis or delayed eyelid opening, low pup body weight, low female fertility index, a 

tendency to low number of corpora lutea or implantations, and a tendency to increased pre-

implantation loss rate and an abnormal clinical sign such as prominent annular rings on tail after 

weaning. There were no effects on pregnancy, parturition, lactation in F0 dams and postnatal 

development in F1 pups at doses up to 12.5 mg/kg/day (89 times the human clinical exposures in 

adults based on AUC). 

 

Phototoxicity 

 

Lusutrombopag has no phototoxic potential in the skin phototoxicity study in hairless mice at doses up 

to 500 mg/kg (96.3 µg/mL) (613 times the human clinical exposures in adults based on Cmax 

[0.157 µg/mL]). 

 

Environmental Risk Assessment (ERA) 

 

Environmental risk assessment studies have shown that lusutrombopag has the potential to be very 

persistent, very bioaccumulative and toxic to the environment. 

 

 



13 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core 

 

Mannitol 

Microcrystalline cellulose 

Magnesium oxide 

Sodium lauryl sulfate  

Hydroxypropylcellulose 

Carmellose calcium 

Magnesium stearate 

 

Film-coating 

 

Hypromellose 

Titanium dioxide 

Triethyl citrate 

Talc 

Red ferric oxide (E172) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

3 years. 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special temperature storage conditions. 

Store in the original package in order to protect from moisture. 

 

6.5 Nature and contents of container  

 

OPA/Aluminium foil/PVC film blister with push through aluminium lidding foil, packed in a 

cardboard box. Each box contains 7 film-coated tablets. 

 

6.6 Special precautions for disposal  

 

This medicinal product may pose a risk to the environment (see section 5.3). 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements.  

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Shionogi B.V. 

Kingsfordweg 151,  

1043GR Amsterdam 

The Netherlands 

 



14 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/18/1348 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

02/2019 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

 



15 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 

 



16 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) responsible for batch release 

 

MPF B.V. (Manufacturing Packaging Farmaca) 

Appelhof 13 

8465RX Oudehaske 

NETHERLANDS 

 

Shionogi B.V. 

Kingsfordweg 151,  

1043GR Amsterdam 

The Netherlands 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription. 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

The marketing authorisation holder shall submit the first periodic safety update report for this 

product within 6 months following authorisation.  

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the  

agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed  subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached.  



17 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



18 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



19 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Mulpleo 3 mg film-coated tablets 

lusutrombopag 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 3 mg lusutrombopag 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

7 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

 

 



20 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Shionogi B.V. 

Kingsfordweg 151,  

1043GR Amsterdam 

The Netherlands 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/18/1348 

 

 

13. BATCH NUMBER 

 

BN 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Mulpleo 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 

2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN:  

NN:  



21 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Mulpleo 3 mg film-coated tablets 

lusutrombopag 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Shionogi 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

BN 

 

 

5. OTHER 

 

 



22 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



23 

Package leaflet: Information for the patient 

 

Mulpleo 3 mg film-coated tablets 

lusutrombopag 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again.  

- If you have any further questions, ask your doctor, pharmacist, or nurse. 

- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Mulpleo is and what it is used for  

2. What you need to know before you take Mulpleo 

3. How to take Mulpleo  

4. Possible side effects  

5. How to store Mulpleo 

6. Contents of the pack and other information 

 

1. What Mulpleo is and what it is used for 

 

Mulpleo contains the active substance lusutrombopag, which belongs to a group of medicines called 

thrombopoietin receptor agonists. The medicine helps to increase the number of platelets in your 

blood. Platelets are blood components that help the blood to clot and so prevent bleeding. 

 

Mulpleo is used to reduce the risk of bleeding during surgery and other procedures (including 

tooth extractions and endoscopy). It is given to adults who have low numbers of platelets because of 

chronic liver disease. 

 

 

2. What you need to know before you take Mulpleo  

 

Do not take Mulpleo: 

- if you are allergic to lusutrombopag or any of the other ingredients of this medicine (listed in 

section 6 under ‘What Mulpleo contains’).  
➤ Check with your doctor if this applies to you before you take Mulpleo 

 

Warnings and precautions 

Talk to your doctor: 

- if you are at risk of blood clots in your veins or arteries, or if you previously have had blood 

clots 

- if you have severe liver disease 

- if your spleen has been removed 

- if you are having interferon treatment. 

➤ Talk to your doctor before taking Mulpleo, if any of these applies. 
 

Signs of a blood clot: look out for any of the signs below: 

 swelling, pain, heat, redness, or tenderness in your leg 



24 

 sudden shortness of breath, especially with sharp pain in the chest or rapid breathing 
 pain in the abdomen (tummy), swollen abdomen, blood in your stools.  
 ➤ Get medical help immediately if you notice any of these. 
 

Children and adolescents 

Do not give this medicine to children or adolescents under the age of 18 years, because the medicine 

has not been studied in children and adolescents. 

 

Other medicines and Mulpleo 

Tell your doctor if you are taking, have recently taken or might take any other medicines. 

 

Pregnancy and breast-feeding  

Do not take Mulpleo if you are pregnant unless your doctor specifically recommends it. The effect of 

Mulpleo during pregnancy is not known. 

- Tell your doctor if you are pregnant, think you may be pregnant, or are planning to have 

a baby. 

- Use reliable methods of contraception while you are taking Mulpleo. 

- If you do become pregnant during treatment with Mulpleo, tell your doctor 

immediately. 

  

Do not breast-feed during treatment with Mulpleo, as it is not known if the medicine passes into 

milk.  

→ If you are already breast-feeding, talk to your doctor immediately. 
 

Driving and using machines 

Mulpleo has no known effects on your ability to drive or to use machines. 

 

Mulpleo contains sodium 

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 

 

3. How to take Mulpleo 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

Recommended dose: take one tablet once a day, at the same time each day, for seven days only. Take 

the tablet with a liquid and swallow it whole. Do not chew, break, or crush the tablet. You can take it 

with food or between meals.  

 

Your treatment will start at least 8 days before your surgery or procedure. Do not change the dose or 

schedule for taking Mulpleo unless your doctor or pharmacist tells you to. 

 

 

If you have severe liver disease, tell your doctor before taking Mulpleo. 

 

If you take more than you should 

If you have taken more Mulpleo than you should, talk to your doctor or go to the hospital. If possible, 

show them the pack, or this leaflet. You may be monitored for side effects associated with excessive 

platelets such as blood clots (see section 2, ‘Warnings and precautions’, and section 4, ‘Possible side 
effects’). 
 

If you forget to take a tablet 

If you miss a tablet of Mulpleo, take it as soon as you remember on the same day. 

Do not take a double dose to make up for a forgotten tablet. 

 



25 

If you stop taking Mulpleo 

Do not stop taking Mulpleo without talking to your doctor and do not take Mulpleo for more than 

7 days. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

 

Higher risk of blood clots  

Certain people may have a higher risk of blood clots, including people with liver disease, and 

medicines like Mulpleo could make this problem worse.  

 

Signs of a blood clot: look out for any of the signs below: 

 swelling, pain, heat, redness, or tenderness in your leg  
 sudden shortness of breath, especially with sharp pain in the chest or rapid breathing  
 pain in the abdomen (tummy), swollen abdomen, blood in your stools.  
➤ Get medical help immediately if you notice any of these. 
 

Common side effects  

(may affect up to 1 in 10 people) 

 Headache 
 Nausea 
 Blood clot in the liver (portal vein thrombosis) 
 Rash. 
 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. 

 

By reporting side effects you can help provide more information on the safety of this medicine. 

 

 

5. How to store Mulpleo 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the carton and blisters after EXP. The 

expiry date refers to the last day of that month. 

 

Store in the original package in order to protect from moisture. 

 

This medicine does not require any special temperature storage conditions. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


26 

6. Contents of the pack and other information 

 

What Mulpleo contains  

- The active substance is lusutrombopag. Each film-coated tablet contains 3 mg lusutrombopag. 

- The other ingredients are:  

- Tablet core: mannitol, microcrystalline cellulose, magnesium oxide, sodium lauryl sulfate, 

hydroxypropylcellulose, carmellose calcium and magnesium stearate 

- Film coating: hypromellose, titanium dioxide, triethyl citrate, talc and red-ferric oxide (E172) 

 

What Mulpleo looks like and contents of the pack 

 

Mulpleo 3 mg film-coated tablets are light red, 7 mm, round, film-coated tablets debossed with the 

Shionogi trademark above the identifier code “551” on one side and debossed with the strength “3” on 
the other side. 

 

Mulpleo is supplied in aluminium blisters in a carton containing 7 film-coated tablets. 

 

Marketing Authorisation Holder  

Shionogi B.V. 

Kingsfordweg 151,  

1043GR Amsterdam 

The Netherlands 

 

Manufacturer  

Manufacturing Packaging Farmaca (MPF) B.V. 

Appelhof 13 

Oudehaske 

8465RX 

The Netherlands 

 

Shionogi B.V. 

Kingsfordweg 151,  

1043GR Amsterdam 

The Netherlands 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

AT, BE, BG, CY, CZ, DK, EE, IE, EL, FI, FR, HR, HU, IE, IS, LT, 

LU, LV, MT, NL, NO, PL, PT, RO, SE, SI, SK  

Shionogi B.V. Tel/Tel./Teл./Tlf/Tél/Puh/Sími/Τηλ:  
+31 (0) 207038327 

contact@shionogi.eu 

 

DE 

Shionogi GmbH 

Tel: +49 (0)89 2109 3049 

kontakt@shionogi.eu 

 

ES 

Shionogi SLU 

Tel: +34 911 239 258 

contacta@shionogi.eu 

 

IT 

Shionogi Srl 

Tel: +39 06 94 805 118 

contattaci@shionogi.eu 

 

UK  

Shionogi B.V. 

Tel: +44 (0)20 3053 4190  

contact@shionogi.eu 

 

 

 

This leaflet was last revised in  



27 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu.  

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET