Mulpleo (previously Lusutrombopag Shionogi)

Evrópusambandið - enska - EMA (European Medicines Agency)

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Virkt innihaldsefni:
Lusutrombopag
Fáanlegur frá:
Shionogi B.V.
ATC númer:
B02BX
INN (Alþjóðlegt nafn):
lusutrombopag
Meðferðarhópur:
Antihemorrhagics,
Lækningarsvæði:
Thrombocytopenia
Ábendingar:
Mulpleo is indicated for the treatment of severe thrombocytopenia in adult patients with chronic liver disease undergoing invasive procedures,
Vörulýsing:
Revision: 3
Leyfisstaða:
Authorised
Leyfisnúmer:
EMEA/H/C/004720
Leyfisdagur:
2019-02-18
EMEA númer:
EMEA/H/C/004720

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B. PACKAGE LEAFLET

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

What Mulpleo is and what it is used for

What you need to know before you take Mulpleo

How to take Mulpleo

Possible side effects

How to store Mulpleo

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

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.

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.

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

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

Other sources of information

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

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

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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).

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.

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 C

and AUC

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.

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

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.

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.

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)

(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

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.

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)

(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).

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)

(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 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.

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

- Median (days)

21.1

15.1

17.3

- (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

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.

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

Platelet Count (*10^4/uL)

10.0

Baseline

Day

Treatment Group

Lusutrombopag 3 mg

Placebo

Phase 3 Study M0634

Platelet Count (*10^4/uL)

10.0

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 C

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.

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

thrombocytopenic patients with chronic liver disease (Study M0634)

(ng/mL)

(hr)

0-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 T

, 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 [

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 t

(% coefficient of variation), was 38.3 hours (18.7%) after multiple oral dose of

3 mg lusutrombopag.

Linearity/non-linearity

Both C

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.

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 C

and AUC

0-τ

overlapped among the patients with Child-Pugh class A, B,

and C. C

and AUC

0-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).

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 C

[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.

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

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

Official address

Domenico Scarlattilaan 6

1083 HS Amsterdam

The Netherlands

An agency of the European Union

Address for visits and deliveries

Refer to www.ema.europa.eu/how-to-find-us

Send us a question

Go to www.ema.europa.eu/contact

Telephone

+31 (0)88 781 6000

© European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged.

EMA/553072/2019

EMEA/H/C/004720

Mulpleo

(lusutrombopag)

An overview of Mulpleo and why it is authorised in the EU

What is Mulpleo and what is it used for?

Mulpleo is a medicine used to prevent excessive bleeding in adults with thrombocytopenia due to long-

standing liver disease. Patients with thrombocytopenia have reduced number of platelets (components

in the blood that help it to clot), which can cause excessive bleeding.

The medicine is for use in patients having an invasive procedure (a medical procedure that involves

cutting into or puncturing the skin or inserting instruments into the body).

Mulpleo contains the active substance lusutrombopag.

How is Mulpleo used?

Mulpleo is available as 3 mg tablets. The medicine can only be obtained with a prescription.

Treatment with Mulpleo should start at least 8 days before the procedure and the recommended dose

is 1 tablet daily for 7 days.

For more information about using Mulpleo, see the package leaflet or contact your doctor or

pharmacist.

How does Mulpleo work?

In the body, a hormone called thrombopoietin stimulates the production of platelets by attaching to

receptors (targets) in the bone marrow. The active substance in Mulpleo, lusutrombopag, attaches to

the same receptors as thrombopoietin, helping to increase the platelet count.

What benefits of Mulpleo have been shown in studies?

In two main studies involving adults with low levels of platelets due to long-standing liver disease,

Mulpleo increased platelet count before an invasive procedure and reduced the need for transfusions.

Previously known as Lusutrombopag Shionogi.

Mulpleo0F (lusutrombopag)

EMA/553072/2019

Page 2/2

The first study, involving 96 adults, found that 79% of patients who took Mulpleo did not require a

transfusion of platelets before their procedure, compared with 13% of patients who received placebo

(a dummy treatment). The second study involving 215 adults found that 65% of patients who took

Mulpleo did not require platelet transfusion before their procedure, compared with 29% of patients who

received placebo.

What are the risks associated with Mulpleo?

Unwanted effects that occurred in studies involving patients taking Mulpleo were headache, nausea

(feeling sick), portal vein thrombosis (a blockage in the blood vessel that carries blood from the

intestines to the liver) and rash. Similar effects occurred in patients receiving placebo.

For more information on the side effects and restrictions of Mulpleo, see the package leaflet.

Why is Mulpleo authorised in the EU?

Studies have found that Mulpleo increases platelet count, thereby lowering the risk of excessive

bleeding during or after an invasive procedure and reducing the need for transfusing platelets.

Unwanted effects that occurred in studies are thought to result from patients’ medical condition and

the nature of the invasive procedure for which Mulpleo was used.

The European Medicines Agency decided that Mulpleo’s benefits are greater than its risks and it can be

authorised for use in the EU.

What measures are being taken to ensure the safe and effective use of

Mulpleo?

Recommendations and precautions to be followed by healthcare professionals and patients for the safe

and effective use of Mulpleo have been included in the summary of product characteristics and the

package leaflet.

As for all medicines, data on the use of Mulpleo are continuously monitored. Side effects reported with

Mulpleo are carefully evaluated and any necessary action taken to protect patients.

Other information about Mulpleo

Mulpleo received a marketing authorisation valid throughout the EU on 18 February 2019.

Further information on Mulpleo can be found on the Agency’s website:

ema.europa.eu/medicines/human/EPAR/mulpleo.

This overview was last updated in 10-2019.

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