Below are a few of the more commonly asked questions regarding Mulpleo. If you have a question that is not answered below, or would like more information on Mulpleo, then you can request a call, email or virtual meeting using our simple form found here.
Chronic liver disease and thrombocytopenia
Identifying patients and dosing
Mode of action
Efficacy and study design
Safety
Show all
How common is thrombocytopenia in patients with chronic liver disease (CLD)?
Thrombocytopenia (a platelet count of <150x109/L) is a common haematological complication in patients with CLD1, with 64–78% of adult patients with cirrhosis having thrombocytopenia, and 1% of adult patients with advanced fibrosis or cirrhosis having severe thrombocytopenia (a platelet count of <50x109/L).1–5
What effect does thrombocytopenia have on this patient group and their ongoing care?
As part of their ongoing care, adult patients with CLD will often require numerous medical procedures throughout their diagnosis and therapy, some of which are invasive procedures.6 Severe thrombocytopenia significantly increases the risk of bleeding events during these invasive procedures when compared to mild to moderate thrombocytopenia.6 Not only is this an issue for the patient and their safety, but it also comes with a significant disease burden and associated costs.6–8
A study which investigated this burden found that compared to patients with CLD and a platelet count >100x109/L, patients with CLD and a platelet count ≤100x109/L experience:7
2.5x more liver disease-related ambulatory visits (p<0.01)
Nearly 4x greater likelihood of liver disease-related emergency hospital visits (p<0.01)
13x greater likelihood of having to have liver disease-related inpatient hospital stays (p<0.01)
References
Peck-Radosavljevic M. Liver Int. 2017;37(6):778–793.
Bashour FN, Teran JC, Mullen KD. Am J Gastroenterol. 2000;95(10):2936–2939.
Giannini EG. Aliment Pharmacol Ther. 2006;23(8):1055–1065.
de Gottardi A, Thévenot T, Spahr L, et al. Clin Gasterenterol Hepatol. 2009;7(8):906–909.
Hermos JA, Altincatal A, Weber HC, et al. Dig Dis Sci. 2013;58(2):562–573.
Afdhal N, McHutchison J, Brown R, et al. J Hepatol. 2008;48(6):1000–1007.
Poordad F, Theodore D, Sullivan J, et al. J Med Econ. 2012;15(1):112–124.
Brown Jr RS. Aliment Pharmacol Ther. 2007;26(Suppl. 1):41–48.
Which patient group is Mulpleo indicated for?
Mulpleo is indicated for the treatment of severe thrombocytopenia in adult patients with CLD who need to undergo invasive procedures.1
What is the dosing schedule for Mulpleo?
Mulpleo has a simple once-daily dosing regimen, with a single 3mg oral tablet, once-daily for 7 days, with or without food. After waiting for 2 days, Mulpleo offers an extended procedural window compared to platelet transfusion from day 9 onwards. Platelet count should be measured prior to a procedure.1
What happens if a patient misses a dose?
Patients should be advised that if they miss a dose, to take the missed dose as soon as possible on the same day and return to their normal dosing schedule the following day. They should also be advised not to take a double dose to make up for a forgotten tablet.1
Are there any special populations that should be accounted for when prescribing Mulpleo?
There are no dosage adjustments required in the following populations:1
For patients with severe hepatic impairment, platelet count should be measured at least once approximately 5 days after the first dose, and as necessary thereafter.1
Does Shionogi offer any materials to help with educating patients about their condition and their treatment?
Shionogi has designed the following materials to aid with adherence, safety monitoring and answering questions that a patient may have during their treatment with Mulpleo:
For further details about the resources listed above and to download or access any of them, please visit the Resources page.
Which patients is Mulpleo contraindicated in?
Mulpleo is contraindicated in patients who are hypersensitive to the active substance (lusutrombopag) or to any of the following excipients:1
How can I order Mulpleo?
Mulpleo is available to order through Alcura (part of the Alliance Healthcare Group). The PIP code for the product is 414 0745.
Hospitals can order by emailing or faxing their hospital purchase orders to the Alcura Specialist Wholesale team using the following contact details:
References
Mulpleo (lusutrombopag) Summary of Product Characteristics.
What is the mode of action of Mulpleo?
Mulpleo is a thrombopoietin (TPO) receptor agonist. Mulpleo acts on the haematopoietic stem cells and on the transmembrane domain of human TPO receptors expressed in megakaryocytes. This stimulates megakaryocyte proliferation and differentiation via a signal transduction pathway similar to endogenous TPO, leading to thrombocytopoiesis and increased platelet count in patients.1 For more information, visit the Mode of Action page of the website.
References
Mulpleo (lusutrombopag) Summary of Product Characteristics.
What are the details of the clinical trial programme developed for Mulpleo’s EMA marketing authorisation application?
The efficacy and safety of Mulpleo were evaluated in two randomised, double-blind, placebo-controlled studies: L-PLUS 1 and L-PLUS 2. Studies included 312 subjects with CLD (Child-Pugh class A and B) and platelet levels <50x109/L, undergoing scheduled invasive procedures in Japan (L-PLUS 1) and globally (L-PLUS 2).1,2
L-PLUS 1 primary endpoint: Proportion of patients who required no platelet transfusion prior to the primary invasive procedure.1
L-PLUS 2 primary endpoint: Proportion of patients 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 procedure.1
For more information, visit the Efficacy page of the website.
What were the efficacy results in patients receiving Mulpleo vs. placebo during the two Phase III clinical trials?
Studies included 312 subjects with CLD (Child-Pugh class A and B) and platelet levels <50x109/L, undergoing scheduled invasive procedures in Japan (L-PLUS 1) and globally (L-PLUS 2).1,2 Patients were randomised 1:1 to receive 3mg/day Mulpleo or placebo oral tablets.1 Mulpleo was administered orally for up to 7 days, and administration of Mulpleo was stopped if the platelet count was ≥50x109/L together with an increase of ≥20x109/L from baseline. Please note that the recommended Mulpleo dosage is 3mg once-daily for 7 days.1
Benefit was assessed in terms of the pooled primary endpoints of:1
Mulpleo demonstrated a significant reduction in the number of patients that needed a platelet transfusion prior to the primary invasive procedure and rescue therapy for bleeding vs. placebo (68.2% vs. 23.9% respectively, p<0.0001) across all clinical trials.1
For the pooled proportion of responder secondary endpoint detailed above, significantly more patients treated with Mulpleo achieved a platelet count of ≥50x109/L vs. placebo (68.2% vs. 11.0% respectively, p<0.0001).
In the clinical trials, what did rescue therapy entail?
Rescue therapy was defined as platelet preparations, other blood preparations (including red blood cells and plasma) and volume expanders.3
How long does Mulpleo’s effect last for?
Across two Phase III clinical trials with Mulpleo, platelet counts remained at ≥50x109/L for a median of 20.9 days in patients treated with Mulpleo not requiring a platelet transfusion, vs. 0.3 days in patients with placebo and receiving a platelet transfusion.2,4
References
Mulpleo (lusutrombopag) Summary of Product Characteristics.
Brown RS, Imawar M, Izumi N, et al. JHEP Rep. 2021;3(2):100228.
Peck-Radosavljevic M, Simon K, Iacobellis A, et al. Hepatol. 2019;70(4):1336–1348.
Brown RS, Imawari M, Izumi N, et al. Lusutrombopag Is a Safe and Efficacious Treatment Option for Thrombocytopenia in Subjects With Chronic Liver Disease Undergoing Invasive Procedures: A Pooled Analysis of Two Phase 3 Trials. Poster presented at AASLD 2018(2) (P#2016).
In the two Phase III trials (L-PLUS 1 and L-PLUS 2), what were the most common adverse events?
Mulpleo is generally well-tolerated, with rates of adverse events that are comparable to placebo* observed in clinical studies, and no known drug-drug interactions.1,2** The most common adverse reactions (≥1/100 to <1/10 patients) vs. placebo were headache 4.7% (8/171) vs. 3.5% (6/170), nausea 2.3% (4/171) vs. 4.1% (7/170), portal vein thrombosis 1.2% (2/171) vs. 1.2% (2/170) and rash 1.2% (2/171) vs. 0% (0/170).1 A summary of the safety profile can be found on the Safety page of the website.
*This may not represent the overall safety profile of Mulpleo.1
**Potential interaction with P-gp or BCRP inhibitors cannot be excluded, but no dose adjustment is necessary at the recommended clinical dosage.1
Do you have any real-world data?
Mulpleo has been approved in Japan since September 2015 and marketed in Japan since December 2015. After more than 2 years of in-market use, no additional safety concerns were identified in approximately 4,000 patients.3*
This study also demonstrated an adverse event profile consistent with clinical trials, which is generally well-tolerated.3**
For more information, visit the Safety page of the website.
*The number of packets shipped by Shionogi as of April 30, 2018.
**All spontaneous reported adverse events by HCPs and consumers for lusutrombopag were retrieved from the Shionogi Global Safety database.
What are the rates of thrombotic and thromboembolic adverse events for Mulpleo vs. placebo?
Thrombotic and thromboembolic adverse events occurred in comparable proportions of patients receiving Mulpleo vs. placebo in two Phase III trials.4
| Study | L-PLUS 1 | |
|---|---|---|
|
Adverse event |
PVT† (Female) |
MVT†† (Male) |
|---|---|---|
|
Treatment group |
Mulpleo (n=48) |
Placebo (n=48) |
|
Day of onset |
14 |
20 |
|
Duration (days) |
72 |
23 |
|
Onset in relation to first invasive procedure (days) |
After (5) |
After (8) |
|
Maximum platelet count (x109/L) |
79 |
60 |
|
Severity |
Severe |
Moderarte |
|
Seriousness |
Serious |
Not serious |
|
Treatment-related |
Yes |
No |
|
Outcome |
Resolved |
Not resolved |
†PVT, Portal vein thrombosis
††MVT, Mesenteric venous thrombosis
| Study | L-PLUS 2 | |
|---|---|---|
|
Adverse event |
PVT† (Male) |
CVT§ (Male) |
PVT† (Male) |
PVT† (Female) |
|---|---|---|---|---|
|
Treatment group |
Mulpleo (n=107) |
Mulpleo (n=107) |
Placebo (n=107) |
Placebo (n=107) |
|
Day of onset |
14 |
14 |
12 |
14 |
|
Duration (days) |
27 |
114 |
N/A |
28 |
|
Onset in relation to first invasive procedure (days) |
After (6) |
After (4) |
After (4) |
After (5) |
|
Maximum platelet count (x109/L) |
62 |
119 |
53 |
167 |
|
Severity |
Moderate |
Mild |
Moderate |
Mild |
|
Seriousness |
Serious |
Serious |
Not serious |
Not serious |
|
Treatment-related |
No |
Yes |
No |
Yes |
|
Outcome |
Resolved |
Resolved |
Resolving |
Resolved with sequelae |
**PVT, Portal vein thrombosis
§CVT, Cardiac venous thrombosis
It is also useful to note that patients taking Mulpleo had a lower incidence of bleeding-related adverse events vs. placebo, with a study by Afdhal et al. demonstrating a 44.8% relative risk reduction of bleeding related adverse events (absolute risk reduction=0.07).4
References
Mulpleo (lusutrombopag) Summary of Product Characteristics.
Katsube T, Inoue Y, Fukuhara T, et al. Eur J Clin Pharmacol. 2020;76:1659–1665.
Izumi N, Shrestha P, Sasaki R, et al. Data on file (R-1767).
Afdhal N, Brown RS, Izumi N, et al. Lusutrombopag Is a Safe Treatment Option for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing an Invasive Procedure: Pooled Safety Analysis From Three Studies. Poster presented at EASL 2019 (#SAT-002).
How common is thrombocytopenia in patients with chronic liver disease (CLD)?
Thrombocytopenia (a platelet count of <150x109/L) is a common haematological complication in patients with CLD1, with 64–78% of adult patients with cirrhosis having thrombocytopenia, and 1% of adult patients with advanced fibrosis or cirrhosis having severe thrombocytopenia (a platelet count of <50x109/L).1–5
What effect does thrombocytopenia have on this patient group and their ongoing care?
As part of their ongoing care, adult patients with CLD will often require numerous medical procedures throughout their diagnosis and therapy, some of which are invasive procedures.6 Severe thrombocytopenia significantly increases the risk of bleeding events during these invasive procedures when compared to mild to moderate thrombocytopenia.6 Not only is this an issue for the patient and their safety, but it also comes with a significant disease burden and associated costs.6–8
A study which investigated this burden found that compared to patients with CLD and a platelet count >100x109/L, patients with CLD and a platelet count ≤100x109/L experience:7
Which patient group is Mulpleo indicated for?
Mulpleo is indicated for the treatment of severe thrombocytopenia in adult patients with CLD who need to undergo invasive procedures.9
What is the dosing schedule for Mulpleo?
Mulpleo has a simple once-daily dosing regimen, with a single 3mg oral tablet, once-daily for 7 days, with or without food. After waiting for 2 days, Mulpleo offers an extended procedural window compared to platelet transfusion from day 9 onwards. Platelet count should be measured prior to a procedure.9
What happens if a patient misses a dose?
Patients should be advised that if they miss a dose, to take the missed dose as soon as possible on the same day and return to their normal dosing schedule the following day. They should also be advised not to take a double dose to make up for a forgotten tablet.9
Are there any special populations that should be accounted for when prescribing Mulpleo?
There are no dosage adjustments required in the following populations:9
For patients with hepatic impairment, platelet count should be measured at least once approximately 5 days after the first dose, and as necessary thereafter.9
Does Shionogi offer any materials to help with educating patients about their condition and their treatment?
Shionogi has designed the following materials to aid with adherence, safety monitoring and answering questions that a patient may have during their treatment with Mulpleo:
For further details about the resources listed above and to download or access any of them, please visit the Resources page.
Which patients is Mulpleo contraindicated in?
Mulpleo is contraindicated in patients who are hypersensitive to the active substance (lusutrombopag) or to any of the following excipients:9
How can I order Mulpleo?
Mulpleo is available to order through Alcura (part of the Alliance Healthcare Group). The PIP code for the product is 414 0745.
Hospitals can order by emailing or faxing their hospital purchase orders to the Alcura Specialist Wholesale team using the following contact details:
What is the mode of action of Mulpleo?
Mulpleo is a thrombopoietin (TPO) receptor agonist. Mulpleo acts on the haematopoietic stem cells and on the transmembrane domain of human TPO receptors expressed in megakaryocytes. This stimulates megakaryocyte proliferation and differentiation via a signal transduction pathway similar to endogenous TPO, leading to thrombocytopoiesis and increased platelet count in patients.1 For more information, visit the Mode of Action page of the website.
What are the details of the clinical trial programme developed for Mulpleo’s EMA marketing authorisation application?
The efficacy and safety of Mulpleo were evaluated in two randomised, double-blind, placebo-controlled studies: L-PLUS 1 and L-PLUS 2. Studies included 312 subjects with CLD (Child-Pugh class A and B) and platelet levels <50x109/L, undergoing scheduled invasive procedures in Japan (L-PLUS 1) and globally (L-PLUS 2).9,10
L-PLUS 1 primary endpoint: Proportion of patients who required no platelet transfusion prior to the primary invasive procedure.9
L-PLUS 2 primary endpoint: Proportion of patients 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 procedure.9
For more information, visit the Efficacy page of the website.
What were the efficacy results in patients receiving Mulpleo vs. placebo during the two Phase III clinical trials?
Studies included 312 subjects with CLD (Child-Pugh class A and B) and platelet levels <50x109/L, undergoing scheduled invasive procedures in Japan (L-PLUS 1) and globally (L-PLUS 2).9,10 Patients were randomised 1:1 to receive 3mg/day Mulpleo or placebo oral tablets.1 Mulpleo was administered orally for up to 7 days, and administration of Mulpleo was stopped on day 5 to day 7 if the platelet count was ≥50x109/L together with an increase of ≥20x109/L from baseline. Please note that the recommended Mulpleo dosage is 3mg once daily for 7 days.9
Benefit was assessed in terms of the pooled primary endpoints of:9
Mulpleo demonstrated a significant reduction in the number of patients that needed a platelet transfusion prior to the primary invasive procedure and rescue therapy for bleeding vs. placebo (68.2% vs. 23.9% respectively, p<0.0001) across all clinical trials.9
For the pooled proportion of responder secondary endpoint detailed above, significantly more patients treated with Mulpleo achieved a platelet count of ≥50x109/L vs. placebo (68.2% vs. 11.0% respectively, p<0.0001).
In the clinical trials, what did rescue therapy entail?
Rescue therapy was defined as platelet preparations, other blood preparations (including red blood cells and plasma) and volume expanders.11
How long does Mulpleo’s effect last for?
Across two Phase III clinical trials with Mulpleo, platelet counts remained at ≥50x109/L for a median of 20.9 days in patients treated with Mulpleo not requiring a platelet transfusion, vs. 0.3 days in patients with placebo and receiving a platelet transfusion.10,12
In the two Phase III trials (L-PLUS 1 and L-PLUS 2), what were the most common adverse events?
Mulpleo is generally well-tolerated, with rates of adverse events that are comparable to placebo* observed in clinical studies, and no known drug-drug interactions.9,13** The most common adverse reactions (≥1/100 to <1/10 patients) vs. placebo were headache 4.7% (8/171) vs. 3.5% (6/170), nausea 2.3% (4/171) vs. 4.1% (7/170), portal vein thrombosis 1.2% (2/171) vs. 1.2% (2/170) and rash 1.2% (2/171) vs. 0% (0/170).9 A summary of the safety profile can be found on the Safety page of the website.
*This may not represent the overall safety profile of Mulpleo.9
**Potential interaction with P-gp or BCRP inhibitors cannot be excluded, but no dose adjustment is necessary at the recommended clinical dosage.9
Do you have any real-world data?
Mulpleo has been approved in Japan since September 2015 and marketed in Japan since December 2015. After more than 2 years of in-market use, no additional safety concerns were identified in approximately 4,000 patients.14*
This study also demonstrated an adverse event profile consistent with clinical trials, which is generally well-tolerated.14**
For more information, visit the Safety page of the website.
*The number of packets shipped by Shionogi as of April 30, 2018.
**All spontaneous reported adverse events by HCPs and consumers for lusutrombopag were retrieved from the Shionogi Global Safety database.
What are the rates of thrombotic and thromboembolic adverse events for Mulpleo vs. placebo?
Thrombotic and thromboembolic adverse events occurred in comparable proportions of patients receiving Mulpleo vs. placebo in two Phase III trials.15
| Study | L-PLUS 1 | |
|---|---|---|
|
Adverse event |
PVT† (Female) |
MVT†† (Male) |
|---|---|---|
|
Treatment group |
Mulpleo (n=48) |
Placebo (n=48) |
|
Day of onset |
14 |
20 |
|
Duration (days) |
72 |
23 |
|
Onset in relation to first invasive procedure (days) |
After (5) |
After (8) |
|
Maximum platelet count (x109/L) |
79 |
60 |
|
Severity |
Severe |
Moderarte |
|
Seriousness |
Serious |
Not serious |
|
Treatment-related |
Yes |
No |
|
Outcome |
Resolved |
Not resolved |
†PVT, Portal vein thrombosis
††MVT, Mesenteric venous thrombosis
| Study | L-PLUS 2 | |
|---|---|---|
|
Adverse event |
PVT† (Male) |
CVT§ (Male) |
PVT† (Male) |
PVT† (Female) |
|---|---|---|---|---|
|
Treatment group |
Mulpleo (n=107) |
Mulpleo (n=107) |
Placebo (n=107) |
Placebo (n=107) |
|
Day of onset |
14 |
14 |
12 |
14 |
|
Duration (days) |
27 |
114 |
N/A |
28 |
|
Onset in relation to first invasive procedure (days) |
After (6) |
After (4) |
After (4) |
After (5) |
|
Maximum platelet count (x109/L) |
62 |
119 |
53 |
167 |
|
Severity |
Moderate |
Mild |
Moderate |
Mild |
|
Seriousness |
Serious |
Serious |
Not serious |
Not serious |
|
Treatment-related |
No |
Yes |
No |
Yes |
|
Outcome |
Resolved |
Resolved |
Resolving |
Resolved with sequelae |
†PVT, Portal vein thrombosis
§CVT, Cardiac venous thrombosis
It is also useful to note that patients taking Mulpleo had a lower incidence of bleeding-related adverse events vs. placebo, with a study by Afdhal et al. demonstrating a 44.8% relative risk reduction of bleeding related adverse events (absolute risk reduction=0.07).15
References
Peck-Radosavljevic M. Liver Int. 1 2017;37(6):778–793.
Bashour FN, Teran JC, Mullen KD. Am J Gastroenterol. 2000;95(10):2936–2939.
Giannini EG. Aliment Pharmacol Ther. 2006;23(8):1055–1065.
de Gottardi A, Thévenot T, Spahr L, et al. Clin Gasterenterol Hepatol. 2009;7(8):906–909.
Hermos JA, Altincatal A, Weber HC, et al. Dig Dis Sci. 2013;58(2):562–573.
Afdhal N, McHutchison J, Brown R, et al. J Hepatol. 2008;48(6):1000–1007.
Poordad F, Theodore D, Sullivan J, et al. J Med Econ. 2012;15(1):112–124.
Brown Jr RS. Aliment Pharmacol Ther. 2007;26(Suppl. 1):41–48.
Mulpleo (lusutrombopag) Summary of Product Characteristics.
Brown RS, Imawar M, Izumi N, et al. JHEP Rep. 2021;3(2):100228
Peck-Radosavljevic M, Simon K, Iacobellis A, et al. Hepatol. 2019;70(4):1336–1348.
Brown RS, Imawari M, Izumi N, et al. Lusutrombopag Is a Safe and Efficacious Treatment Option for Thrombocytopenia in Subjects With Chronic Liver Disease Undergoing Invasive Procedures: A Pooled Analysis of Two Phase 3 Trials. Poster presented at AASLD 2018(2) (P#2016).
Katsube T, Inoue Y, Fukuhara T, et al. Eur J Clin Pharmacol. 2020;76:1659–1665.
Izumi N, Shrestha P, Sasaki R, et al. Data on file (R-1767).
Afdhal N, Brown RS, Izumi N, et al. Lusutrombopag Is a Safe Treatment Option for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing an Invasive Procedure: Pooled Safety Analysis From Three Studies. Poster presented at EASL 2019 (#SAT-002).
PP-UK-LUS-0323. Date of preparation: May 2023.
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Disable Analytics Cookies Return to sitePP-UK-LUS-0315. Date of preparation: January 2023.