Lusutrombopag is an oral thrombopoietin (TPO) receptor agonist indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Lusutrombopag is not appropriate for use to normalize platelet counts in patients with chronic liver disease. Clinical trials enrolled patients with chronic liver disease who were undergoing an invasive procedure and had a platelet count less than 50 x 109/L. Lusutrombopag treatment was associated with significantly more patients achieving a platelet count more than 50 x 109/L or a platelet count increase of 20 x 109/L or more from baseline and avoiding a platelet transfusion prior to the invasive procedure. TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease; the potential increased thrombotic risk must be considered when administering lusutrombopag to patients with known risk factors for thromboembolism.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Obtain a platelet count prior to initiation of lusutrombopag therapy and not more than 2 days before the procedure.
-Schedule the procedure 2 to 8 days after the last lusutrombopag dose.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer with or without food.
-In the case of a missed dose, administer as soon as possible on the same day and return to the normal schedule the following day.
Headache was reported in 5% of lusutrombopag-treated patients (vs. 4% placebo) during clinical trials.
Portal vein thrombosis was the most common severe adverse reaction reported in 1% of lusutrombopag-treated patients (vs. 1% placebo). The thromboses were identified post-procedure and were not associated with a marked increase in platelet count.
Consider the potential increased thrombotic risk when administering lusutrombopag to patients with known risk factors for thromboembolism, including genetic thromboembolic disease (i.e., factor V Leiden, prothrombin 20210A, antithrombin deficiency, or protein C or S deficiency). Use lusutrombopag in patients with ongoing or prior thrombosis or absence of hepatopetal blood flow only if the potential benefit to the patient justifies the potential risk. Do not use lusutrombopag in patients with chronic liver disease in an attempt to normalize platelet counts. Thrombopoietin receptor antagonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. Portal vein thrombosis was reported in clinical trials of lusutrombopag.
There are no data on lusutrombopag use during human pregnancy to inform a drug-associated risk. Adverse developmental outcomes (e.g., low body weight, minor skeletal variations, delayed postnatal growth, increased pre-implantation loss) were observed in animal reproduction studies when lusutrombopag was given to pregnant rats during organogenesis and the lactation period at exposures based on AUC that were substantially higher (approximately 89 times) than the AUC observed in patients at the recommended clinical dose. Advise pregnant women of the potential risk to a fetus.
There is no information regarding the presence of lusutrombopag in human milk, the effects on the breast-fed child, and the effects on milk production. Lusutrombopag was present in the milk of lactating rats. Due to the potential for serious adverse reactions in the breast-fed child, breast-feeding is not recommended during lusutrombopag treatment. Advise a breast-feeding woman to interrupt breast-feeding and pump and discard breast milk during lusutrombopag treatment and for 28 days after the last dose in order to minimize exposure to a breast-fed child.
For the treatment of chronic liver disease-associated thrombocytopenia in patients who are scheduled to undergo a procedure:
Oral dosage:
Adults: 3 mg PO once daily for 7 days beginning 8 to 14 days before a scheduled procedure. Schedule the procedure for 2 to 8 days after the last dose.
Maximum Dosage Limits:
-Adults
3 mg/day PO.
-Geriatric
3 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Lusutrombopag products.
Lusutrombopag is a small molecule thrombopoietin (TPO) receptor agonist that interacts with the transmembrane domain of the TPO receptor expressed on megakaryocytes to cause proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells and megakaryocyte maturation. Lusutrombopag upregulates the production of platelets through its agonistic effect on human TPO receptors.
Lusutrombopag is administered orally. Protein binding of lusutrombopag is nearly 100%. The accumulation ratios of Cmax and AUC were approximately 2 with once-daily, multiple-dose administration, and steady-state plasma concentrations were achieved after day 5. The terminal half-life in healthy adults is about 27 hours. The mean clearance in patients with chronic liver disease is estimated to be 1.1 L/hour. Lusutrombopag is primarily metabolized by CYP4 enzymes, including CYP4A11. The majority (83%) of the administered lusutrombopag dose is excreted via feces, with 16% of the dose excreted as unchanged drug; urinary excretion accounts for approximately 1%.
The effect of lusutrombopag on platelet count increase correlates with AUC. With the 3 mg dose, the mean maximum platelet count without platelet transfusion was 86.9 x 109/L, and the median time to reach maximum platelet count was 12 days (range, 5 to 35 days).
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, CYP4A11, P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT3, MATE1, MATE2-K, BSEP
Lusutrombopag is a substrate for CYP4 enzymes, including CYP4A11. It has low potential to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5. Lusutrombopag is also a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and has low potential to inhibit P-gp, BCRP, organic anion transporting peptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 3, multidrug and toxin extrusion proteins (MATE) 1, MATE2-K, and bile salt export pump (BSEP).
-Route-Specific Pharmacokinetics
Oral Route
In patients with chronic liver disease, the time to peak lusutrombopag concentration (Tmax) is 6 to 8 hours after oral administration. AUC and Cmax are not affected when lusutrombopag is administered with a high-fat meal. It may be administered without regard to meals.
-Special Populations
Hepatic Impairment
The pharmacokinetics of lusutrombopag were similar between healthy subjects and patients with mild to moderate (Child-Pugh class A and B) hepatic impairment. The mean lusutrombopag AUC and Cmax decreased by 20% to 30% in patients with severe hepatic disease (Child-Pugh class C) compared to patients with Child-Pugh class A and B liver disease; however, the ranges for AUC and Cmax overlapped among patients, regardless of class of liver disease.
Renal Impairment
There was no clinically meaningful effect from mild (CrCl 60 to less than 90 mL/minute) or moderate (CrCl 30 to less than 60 mL/minute) renal impairment on the pharmacokinetics of lusutrombopag. Data are limited in patients with severe renal impairment (CrCl less than 30 mL/minute).
Geriatric
No clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on age.
Ethnic Differences
No clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on ethnicity.
Obesity
The exposure of lusutrombopag decreases with increasing body weight; however, differences in exposure are not considered clinically relevant.