Lusutrombopag (Monograph)

Brand name: Mulpleta
Drug class: Hematopoietic Agents
Chemical name: (E)-3-[2,6-dichloro-4-[[4-[3-[(1S)-1-hexoxyethyl]-2-methoxyphenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]-2-methylprop-2-enoic acid
Molecular formula: C₂₉H₃₂Cl₂N₂O₅S
CAS number: 1110766-97-6

Medically reviewed by Drugs.com on Oct 24, 2022. Written by ASHP.

Introduction

Small-molecule thrombopoietin receptor agonist (TPO-RA).

Uses for Lusutrombopag

Thrombocytopenia in Chronic Liver Disease

Treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.

Do not use to normalize platelet counts.

Lusutrombopag Dosage and Administration

General

Patient Monitoring

Obtain a platelet count prior to initiation of therapy and not more than 2 days before the procedure.

Administration

Oral Administration

Administer orally once daily for 7 days, starting 8–14 days prior to the scheduled procedure; patients should undergo their procedure 2–8 days after the last dose of the drug.

Administer without regard to food.

Dosage

Adults

Chronic Liver Disease

Patients with Thrombocytopenia Scheduled to Undergo a Procedure

Oral

3 mg once daily for 7 days.

If a dose is missed, administer it as soon as it is remembered on the same day. Administer the next dose at the regularly scheduled time the following day.

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with chronic liver disease.

Renal Impairment

Manufacturer makes no specific dosage recommendations.

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

Cautions for Lusutrombopag

Contraindications

None.

Warnings/Precautions

Thrombotic/Thromboembolic Complications

Thrombopoietin receptor agonists (TPO-RAs), including lusutrombopag, have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease.

Consider the potential increased risk in patients with known risk factors for thromboembolism, including genetic prothrombotic conditions (e.g., factor V Leiden, prothrombin 20210A, antithrombin deficiency, protein C or S deficiency).

Use in patients with ongoing or prior thrombosis or absence of hepatopetal blood flow only if the potential benefit outweighs the potential risk.

Specific Populations

Pregnancy

No adequate data in humans; in animal studies, adverse developmental outcomes observed at dose exposures substantially higher than those achieved with the recommended human dosage.

Apprise pregnant women of fetal risk.

Lactation

Distributed into milk in rats; not known whether the drug is distributed into human milk. Effects on milk production or the breast-fed infant also not known.

Advise women not to breast-feed during therapy and for at least 28 days after the last dose. Manufacturer recommends interruption of breast-feeding and discarding the affected milk during treatment and for 28 days after the last dose.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. No clinically important differences in response observed.

Hepatic Impairment

Pharmacokinetics not substantially altered in patients with mild to moderate hepatic impairment (Child-Pugh class A or B). In patients with severe hepatic impairment (Child-Pugh class C), peak plasma concentrations and systemic exposure decreased by 20–30% compared with patients with mild to moderate hepatic impairment.

Renal Impairment

Pharmacokinetics not substantially altered in patients with mild or moderate renal impairment (Cl_cr≥30 mL/minute).

Pharmacokinetics not established in patients with severe renal impairment (Cl_cr<30 mL/minute).

Common Adverse Effects

Headache.

Drug Interactions

Metabolized by CYP isoenzymes, including CYP4A11. In vitro, low potential to inhibit CYP isoenzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4/5). Does not induce CYP1A2, CYP2C9, or CYP3A4, or uridine diphosphate-glucuronosyltransferase (UGT) enzymes UGT1A3, UGT1A6, or UGT2B7 in vitro.

In vitro, substrate of p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Low potential to inhibit P-gp, BCRP, organic anion transporting polypeptide (OATP) 1B or 1B3, organic cation transporter (OCT) 1 or 2, organic anion transporter (OAT) 1 or 3, multidrug and toxin extrusion transporter (MATE) 1 or 2K, or bile salt export pump (BSEP).

Antacids or Mineral Supplements Containing Multivalent Cations

Clinically important effects on lusutrombopag exposure not expected.

Specific Drugs

Drug	Interaction
Calcium carbonate	No clinically important effects on lusutrombopag exposure
Cyclosporine	No clinically important effects on lusutrombopag exposure
Midazolam	No clinically important effects on midazolam exposure

Lusutrombopag Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics are dose-proportional over single-doses of 1–50 mg. Following multiple-dose administration, steady state concentrations are reached after 5 days with a systemic accumulation ratio of approximately 2.

Following oral administration, peak plasma lusutrombopag concentrations occur within 6–8 hours.

Onset

Mean time to peak platelet count: 12 days.

Food

High-fat meal has no effect on lusutrombopag pharmacokinetics.

Special Populations

Mild to moderate hepatic impairment (Child-Pugh class A or B): Pharmacokinetics not substantially altered.

Severe hepatic impairment (Child-Pugh class C): Peak plasma concentrations and systemic exposure decreased by 20–30% compared with patients with mild to moderate hepatic impairment.

Mild or moderate renal impairment (Cl_cr≥30 mL/minute): Pharmacokinetics not substantially altered.

Distribution

Plasma Protein Binding

>99%.

Elimination

Metabolism

Metabolized by CYP isoenzymes, including CYP4A11.

Elimination Route

Excreted in feces (83%) and urine (1%). Unchanged drug excreted in feces accounts for 14% of the dose.

Hemodialysis not expected to affect elimination.

Half-life

Approximately 27 hours.

Stability

Storage

Oral

Tablets

Store at 20–25°C (excursions permitted between 15–30°C). Store in original package.

Actions

Interacts with the transmembrane domain of the thrombopoietin (TPO) receptor and stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in increased production of platelets.
Increases platelet count in an exposure-dependent manner.
Mean time to peak platelet count 12 days; mean maximum platelet count (without platelet transfusion) was 86,900/mm³ in patients receiving dosage of 3 mg daily.

Advice to Patients

Instruct patients to read the manufacturer’s patient information.
Advise patients of the risk of thrombotic or thromboembolic complications.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise patients that the drug should be used during pregnancy only if the potential benefits justify the risks to the fetus.
Importance of advising women to avoid breast-feeding while receiving the drug and for 28 days after the last dose.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.