Platelet-stimulating agents
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Mulpleta Prescribing Information

Drug Detail:Mulpleta (Lusutrombopag [ loo-soo-trom-boe-pag ])

Drug Class: Platelet-stimulating agents

Contents
Uses Warnings Before Taking Dosage Side effects Interactions

Highlights of Prescribing Information

These highlights do not include all the information needed to use MULPLETA safely and effectively. See full prescribing information for MULPLETA.

MULPLETA ® (lusutrombopag tablets) for oral use

Initial U.S. Approval: 2018

Indications and Usage for Mulpleta

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

Mulpleta Dosage and Administration

  • Begin MULPLETA dosing 8-14 days prior to a scheduled procedure. (2.1)
  • Patients should undergo their procedure 2-8 days after the last dose. (2.1)
  • Recommended Dosage: 3 mg orally once daily with or without food for 7 days. (2.1)

Dosage Forms and Strengths

Tablet: 3 mg. ( 3)

Contraindications

  • None.

Warnings and Precautions

  • Thrombotic/Thromboembolic Complications: MULPLETA is a thrombopoietin (TPO) receptor agonist, and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. Monitor platelet counts and for thromboembolic events and institute treatment promptly. (5.1)

Adverse Reactions/Side Effects

The most common adverse reaction (≥3%): headache. (6.1)


To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc. at 1-800-849-9707 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Use In Specific Populations

  • Lactation: Breastfeeding is not recommended during treatment. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 4/2020

Related/similar drugs

Doptelet, prednisone, dexamethasone, Decadron, Deltasone, Promacta

Full Prescribing Information

6. Adverse Reactions/Side Effects

The following serious adverse reactions are discussed in detail in other sections of the labeling:

  • Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of MULPLETA was evaluated in 3 randomized, double-blind, placebo-controlled trials, L-PLUS 1, L-PLUS 2, and M0626, in which patients with chronic liver disease and thrombocytopenia were treated with MULPLETA (N=171) or placebo (N=170) at a dose of 3 mg daily for up to 7 days prior to a scheduled procedure.

The majority of patients were males (59%), and median age was 61 years (range 19-88). The racial and ethnic distribution was White (50%), Asian (47%), Black (<1%), and Other (3%).

The most common adverse reactions (those occurring in at least 3%) in the MULPLETA-treated group across the pooled data from the three trials are summarized in table 1.

Table 1. Adverse Reactions with a Frequency ≥3% in Patients Treated with MULPLETA (Pooled Data (L-PLUS 1, L-PLUS 2, and M0626))
Adverse Reaction*MULPLETA 3 mg
(N=171)
%		Placebo
(N=170)
%
*
Includes treatment-emergent adverse reactions occurring at a rate higher than placebo.
Headache54

The incidence of serious adverse events was 5% (9 of 171 patients) in the MULPLETA group and 7% (12 of 170 patients) in the placebo group. The most common serious adverse reaction reported with MULPLETA was portal vein thrombosis [see Warnings and Precautions (5.1)]. No adverse reactions resulted in discontinuation of MULPLETA.

8. Use In Specific Populations

8.1 Pregnancy

Risk Summary

There are no available data on MULPLETA in pregnant women to inform the drug-associated risk. In animal reproduction studies, oral administration of lusutrombopag to pregnant rats during organogenesis and the lactation period resulted in adverse developmental outcomes. These findings were observed at exposures based on AUC that were substantially higher than the AUC observed in patients (approximately 89 times) at the recommended clinical dose of 3 mg once daily. Advise pregnant women of the potential risk to a fetus (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the general population in the United States, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study in rats, lusutrombopag was orally administered during organogenesis at doses of 4, 12.5, 40, and 80 mg/kg/day. Low body weight and a decrease in the number of ossified sternebrae were noted in fetuses at 80 mg/kg/day (approximately 251 times the AUC observed in patients at the recommended clinical dose of 3 mg once daily). Minor skeletal variations (supernumerary ribs) were observed at doses of 4 mg/kg/day (approximately 23 times the AUC observed in patients at the recommended clinical dose of 3 mg once daily).

In an embryo-fetal development study in rabbits following oral administration of lusutrombopag at doses up to 1000 mg/kg/day, no effect of lusutrombopag was observed on any parameter of embryo-fetal development.

In a pre- and postnatal development study in rats at oral doses of 1, 4, 12.5, and 40 mg/kg/day, there were adverse effects of lusutrombopag on postnatal development at 40 mg/kg/day (approximately 230 times the AUC observed in patients at the recommended clinical dose of 3 mg once daily). The effects included prolongation of the gestation period in dams, low viability before weaning, delayed postnatal growth (delayed negative geotaxis, delayed eyelid opening, or low pup body weight), abnormal clinical signs (prominent annular rings on the tail after weaning), low fertility index, a low number of corpora lutea or implantations, and increased pre-implantation loss. The incidence of short thoracolumbar supernumerary ribs on postnatal Day 4 of F1 pups was high at doses of 12.5 mg/kg/day or more (approximately 89 times the AUC observed in patients at the recommended clinical dose of 3 mg once daily).

12. Mulpleta - Clinical Pharmacology

12.3 Pharmacokinetics

Lusutrombopag demonstrated dose-proportional pharmacokinetics after single doses ranging from 1 mg (0.33 times the lowest approved dosage) to 50 mg (16.7 times the highest recommended dosage). Healthy subjects administered 3 mg of lusutrombopag had a geometric mean (%CV) maximal concentration (Cmax) of 111 (20.4) ng/mL and area under the time-concentration curve extrapolated to infinity (AUC0-inf) of 2931 (23.4) ng.hr/mL. The pharmacokinetics of lusutrombopag were similar in both healthy subjects and the chronic liver disease population.

The accumulation ratios of Cmax and AUC were approximately 2 with once-daily multiple-dose administration, and steady-state plasma lusutrombopag concentrations were achieved after Day 5.

Absorption

In patients with chronic liver disease, the time to peak lusutrombopag concentration (Tmax) was observed 6 to 8 hours after oral administration.

Food Effect

Lusutrombopag AUC and Cmax were not affected when MULPLETA was co-administered with a high-fat meal (a total of approximately 900 calories, with 500, 250, and 150 calories from fat, carbohydrate, and protein, respectively).

Distribution

The mean (%CV) lusutrombopag apparent volume of distribution in healthy adult subjects was 39.5 (23.5) L. The plasma protein binding of lusutrombopag is more than 99.9%.

Elimination

The terminal elimination half-life (t1/2) in healthy adult subjects was approximately 27 hours. The mean (%CV) clearance of lusutrombopag in patients with chronic liver disease is estimated to be 1.1 (36.1) L/hr.

Metabolism

Lusutrombopag is primarily metabolized by CYP4 enzymes, including CYP4A11.

Excretion

Fecal excretion accounted for 83% of the administered dose, with 16% of the dose excreted as unchanged lusutrombopag, and urinary excretion accounted for approximately 1%.

Specific Populations

No clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on age or race/ethnicity. Though lusutrombopag exposure tends to decrease with increasing body weight, differences in exposure are not considered clinically relevant.

Patients with Renal Impairment

A population pharmacokinetic analysis did not find a clinically meaningful effect of mild (creatinine clearance (CLcr) 60 to less than 90 mL/min) and moderate (CLcr 30 to less than 60 mL/min) renal impairment on the pharmacokinetics of lusutrombopag. Data in patients with severe renal impairment (CLcr less than 30 mL/min) are limited.

Patients with Hepatic Impairment

No clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on mild to moderate (Child-Pugh class A and B) hepatic impairment.

The mean observed lusutrombopag Cmax and AUC0-τ decreased by 20% to 30% in patients (N=5) with severe (Child-Pugh class C) hepatic impairment compared to patients with Child-Pugh class A and class B liver disease. However, the ranges for Cmax and AUC0-τ overlapped among patients with Child-Pugh class A, B, and C liver disease.

Drug Interaction Studies

Clinical Studies

No clinically significant changes in lusutrombopag exposure were observed when co-administered with cyclosporine (an inhibitor of P-gp and BCRP) or an antacid containing a multivalent cation (calcium carbonate).

No clinically significant changes in midazolam (a CYP3A substrate) exposure were observed when co-administered with lusutrombopag.

In Vitro Studies

CYP Enzymes: lusutrombopag has low potential to inhibit CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5). Lusutrombopag did not induce CYP1A2, CYP2C9, or CYP3A4.

UGT Enzymes: lusutrombopag did not induce UGT1A2, UGT1A6, or UGT2B7.

Transporter Systems: lusutrombopag is a substrate of P-gp and BCRP. Lusutrombopag has low potential to inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K, and BSEP.

14. Clinical Studies

The efficacy of MULPLETA for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure was evaluated in 2 randomized, double-blind, placebo-controlled trials (L-PLUS 1 (N=97) and L-PLUS 2 (N=215; NCT02389621)). Patients with chronic liver disease who were undergoing an invasive procedure and had a platelet count less than 50 × 109/L were eligible to participate. Patients undergoing laparotomy, thoracotomy, open-heart surgery, craniotomy, or organ resection were excluded. Patients with a history of splenectomy, partial splenic embolization, or thrombosis and those with Child-Pugh class C liver disease, absence of hepatopetal blood flow, or a prothrombotic condition other than chronic liver disease were not allowed to participate.

The patient populations were similar between the MULPLETA and placebo arms and consisted of 60% male and 40% female; median age was 60 years (range 19-88). The racial and ethnic distribution was White (55%), Asian (41%), and Other (4%).

Patients were randomized 1:1 to receive 3 mg of MULPLETA or placebo once daily for up to 7 days. Randomization was stratified by liver ablation/coagulation or other procedures and the platelet count at screening/baseline. In L-PLUS 1, 57% of patients underwent procedures other than liver ablation/coagulation and 43% underwent liver ablation/coagulation (RFA/MCT). In L-PLUS 2, 98% of patients underwent procedures other than liver ablation/coagulation and 2% underwent liver ablation/coagulation (RFA/MCT). Procedures other than liver ablation/coagulation (RFA/MCT) included liver-related procedures (transcatheter arterial chemoembolization, liver biopsy, and others), upper and lower gastrointestinal endoscopy-related procedures (endoscopic variceal ligation, endoscopic injection sclerotherapy, polypectomy, and biopsy), and other procedures (dental extraction, diagnostic paracentesis or laparocentesis, septoplasty, embolization of splenic artery aneurysm, bone marrow biopsy, removal of cervical polyp, and inguinal hernia repair (non-laparotomy based)).

In L-PLUS 1, the major efficacy outcome was the proportion of patients who require no platelet transfusion prior to the primary invasive procedure. In L-PLUS 2, the major efficacy outcome was the proportion of patients who require no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding (i.e., platelet preparations, other blood preparations, including red blood cells and plasma, volume expanders) from randomization through 7 days after the primary invasive procedure. In both trials, additional efficacy outcomes included the proportion of patients who require no platelet transfusion during the study, proportion of responders, duration of the increase in platelet count defined as the number of days during which the platelet count was maintained as ≥50 × 109/L, and the time course of platelet counts.

In both the L-PLUS 1 and L-PLUS 2 trials, responders were defined as patients who had a platelet count of ≥50 × 109/L with an increase of ≥20 × 109/L from baseline.

Table 2. L-PLUS 1 Trial: Proportion of Patients Not Requiring Platelet Transfusion Prior to Invasive Procedure and Proportion of Responders
EndpointProportion (n/N)
Exact 95% Confidence Interval		Treatment Difference
(95% Confidence Interval)
p value
MULPLETA
(N=49)		Placebo
(N=48)
*
A platelet transfusion was required if the platelet count was less than 50 × 109/L.
†
Cochran-Mantel-Haenszel test with baseline platelet count as stratum; p value and confidence interval calculated using Wald method.
‡
Platelet count reached at least 50 × 109/L and increased at least 20 × 109/L from baseline.
Not requiring platelet transfusion prior to invasive procedure*78% (38/49)
(63, 88)		13% (6/48)
(4.7, 25)		64 (49, 79)
<0.0001†
Responder‡ during study76% (37/49)
(61, 87)		6% (3/48)
(1.3, 17)		68 (54, 82)
<0.0001†
Table 3. L-PLUS 2 Trial: Proportion of Patients Not Requiring Platelet Transfusion Prior to Invasive Procedure or Rescue Therapy for Bleeding Through 7 Days After Invasive Procedure and Proportion of Responders
EndpointProportion (n/N)
Exact 95% Confidence Interval		Treatment Difference
(95% Confidence Interval)
p value
MULPLETA
(N=108)		Placebo
(N=107)
*
A platelet transfusion was required if the platelet count was less than 50 × 109/L.
†
Cochran-Mantel-Haenszel test with baseline platelet count as stratum; p value and confidence interval calculated using Wald method.
‡
Platelet count reached at least 50 × 109/L and increased at least 20 × 109/L from baseline.
Not requiring platelet transfusion prior to invasive procedure* or rescue therapy for bleeding from randomization through 7 days after invasive procedure65% (70/108)
(55, 74)		29% (31/107)
(21, 39)		37 (25, 49)
<0.0001†
Responder‡ during study65% (70/108)
(55, 74)		13% (14/107)
(7.3, 21)		52 (41, 62)
<0.0001†

The median (Q1, Q3) duration of platelet count increase to at least 50 × 109/L was 22 (17, 27) days in MULPLETA-treated patients without platelet transfusion and 1.8 (0.0, 8.3) days in placebo-treated patients with platelet transfusion in L-PLUS 1 and 19 (13, 28) days in MULPLETA-treated patients without platelet transfusion and 0.0 (0.0, 5.0) days in placebo-treated patients with platelet transfusion in L-PLUS 2.

MULPLETA is a registered trademark of Shionogi & Co., Ltd.

Manufactured for Shionogi Inc., Florham Park, NJ 07932.

PATIENT INFORMATION
MULPLETA® (mul ple' tah)
(lusutrombopag)
Tablets
This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 4/2020
What is MULPLETA?
MULPLETA is a prescription medicine used to treat low platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to have a procedure.
MULPLETA is not used to make platelet count normal in people with chronic liver disease.
It is not known if MULPLETA is safe and effective in children.
Before taking MULPLETA, tell your healthcare provider about all of your medical conditions, including if you:
  • have a blood clot or have had a history of a blood clot.
  • have any blood clotting problems, other than thrombocytopenia.
  • are pregnant or plan to become pregnant. MULPLETA may harm your baby.
  • are breastfeeding or plan to breastfeed. It is not known if MULPLETA passes into your breast milk. Do not breastfeed during your treatment with MULPLETA and for at least 28 days after your last dose. Talk to your healthcare provider about the best way to feed your baby during your treatment with MULPLETA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I take MULPLETA?
  • Take MULPLETA exactly as your healthcare provider tells you to take it.
  • Your healthcare provider will tell you when to start taking MULPLETA.
  • Take MULPLETA 1 time each day for 7 days.
  • MULPLETA may be taken with or without food.
  • If you miss a dose of MULPLETA, take the missed dose as soon as possible on the same day and return to your normal schedule the following day.
  • If you take too much MULPLETA, call your healthcare provider or go to the nearest hospital emergency room right away.
  • Your healthcare provider will check your platelet count before you start treatment with MULPLETA and before your procedure.
What are the possible side effects of MULPLETA?
MULPLETA may cause serious side effects, including:
Blood clots, including blood clots in the liver, may happen in people with chronic liver disease and who take MULPLETA. You may have an increased risk of blood clots if you have certain blood clotting conditions.
The most common side effect of MULPLETA is headache.
These are not all of the possible side effects of MULPLETA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store MULPLETA?
  • Store MULPLETA at room temperature between 68°F and 77°F (20°C to 25°C).
  • MULPLETA comes in a child-resistant blister pack. Keep MULPLETA in the packaging that it comes in.
Keep MULPLETA and all medicines out of the reach of children.
General information about the safe and effective use of MULPLETA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use MULPLETA for a condition for which it was not prescribed. Do not give MULPLETA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about MULPLETA that is written for healthcare professionals.
What are the ingredients of MULPLETA?
Active ingredient: lusutrombopag.
Inactive ingredients: D-mannitol, microcrystalline cellulose, magnesium oxide, sodium lauryl sulfate, hydroxypropyl cellulose, carboxymethylcellulose calcium, magnesium stearate, hypromellose, triethyl citrate, titanium dioxide, red ferric oxide, and talc.
Manufactured for: Shionogi Inc., Florham Park, NJ 07932
© Shionogi Inc. 2020
For more information, go to www.mulpleta.com or call 1-800-849-9707.

PRINCIPAL DISPLAY PANEL - 3 mg Tablet Blister Card Carton - NDC 59630-551-77

NDC 59630-551-77
Rx only

FOR ORAL USE ONLY
Physician Sample
Not For Sale

Mulpleta®
(lusutrombopag) tablets
3 mg per tablet

SHIONOGI INC.

Lift Here to Open

One blister card
with 7 tablets

PRINCIPAL DISPLAY PANEL - 3 mg Tablet Blister Card Carton - NDC 59630-551-77

MULPLETA
lusutrombopag tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:59630-551
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
LUSUTROMBOPAG (UNII: 6LL5JFU42F) (LUSUTROMBOPAG - UNII:6LL5JFU42F) LUSUTROMBOPAG3 mg
Inactive Ingredients
Ingredient NameStrength
MANNITOL (UNII: 3OWL53L36A)
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
MAGNESIUM OXIDE (UNII: 3A3U0GI71G)
SODIUM LAURYL SULFATE (UNII: 368GB5141J)
HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)
CARBOXYMETHYLCELLULOSE CALCIUM (UNII: UTY7PDF93L)
MAGNESIUM STEARATE (UNII: 70097M6I30)
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
FERRIC OXIDE RED (UNII: 1K09F3G675)
TALC (UNII: 7SEV7J4R1U)
Product Characteristics
Colorred (light red) Scoreno score
ShapeROUNDSize7mm
FlavorImprint Code551;3
Contains
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:59630-551-071 in 1 CARTON08/27/2018
17 in 1 DOSE PACK; Type 0: Not a Combination Product
2NDC:59630-551-771 in 1 CARTON08/27/2018
27 in 1 DOSE PACK; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA21092308/27/2018
Labeler - SHIONOGI INC. (098241610)

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