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Lusutrombopag Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Lusutrombopag is a thrombopoietin (TPO) receptor agonist, contains lusutrombopag as the active ingredient. The chemical name for lusutrombopag is (2E)-3-{2,6-Dichloro-4-[(4-{3-[(1S)-1-(hexyloxy) ethyl]-2-methoxyphenyl}-1,3-thiazol-2-yl) carbamoyl]phenyl}-2-methylprop-2-enoic acid. The structural formula is:

Empirical formula: C29H32Cl2N2O5S - Molecular weight: 591.54 g/mol

Lusutrombopag is a white to slightly yellowish white powder, and is freely soluble in N,N-dimethylformamide, slightly soluble in ethanol (99.5%) and methanol, very slightly soluble in acetonitrile, and practically insoluble in water. Lusutrombopag is slightly soluble in the buffer solution at pH 11 and practically insoluble in buffer solutions with pH ranges of 1 to 9.

Lusutrombopag tablets for oral use contain lusutrombopag 3 mg.

Excipients are 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.

2. INDICATIONS AND USAGE

Lusutrombopag is indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosage

Begin lusutrombopag dosing 8-14 days prior to a scheduled procedure.

Patients should undergo their procedure 2-8 days after the last dose.

The recommended dosage of lusutrombopag is 3 mg taken orally once daily with or without food for 7 days. In the case of a missed dose of lusutrombopag, patients should take the missed dose as soon as possible on the same day and return to the normal schedule the following day.

Lusutrombopag has been investigated only as a single 7-day once daily dosing regimen in clinical trials in patients with chronic liver disease [see Clinical Studies]. Lusutrombopag should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts.

3.2 Monitoring

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

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Thrombotic/Thromboembolic Complications

Lusutrombopag is a thrombopoietin (TPO) receptor agonist, and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. Portal vein thrombosis has been reported in patients with chronic liver disease treated with TPO receptor agonists. Portal vein thrombosis was reported in 1% (2 of 171) of lusutrombopag‐treated patients and 1% (2 of 170) of placebo‐treated patients in 3 randomized, double‐blind trials and was identified post‐procedure in protocol‐specified imaging. The thromboses 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 pro‐thrombotic conditions (Factor V Leiden, Prothrombin 20210A, Antithrombin deficiency, or Protein C or S deficiency). In patients with ongoing or prior thrombosis or absence of hepatopetal blood flow, lusutrombopag should only be used if the potential benefit to the patient justifies the potential risk.

Lusutrombopag should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts.

6. ADVERSE REACTIONS

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 lusutrombopag 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 lusutrombopag (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 lusutrombopag‐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 Lusutrombopag (Pooled Data (L‐PLUS 1, L‐PLUS 2, and M0626))

*Includes treatment‐emergent adverse reactions occurring at a rate higher than placebo.

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

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

There are no available data on lusutrombopag 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).

8.2 Lactation

Risk Summary

There is no information regarding the presence of lusutrombopag in human milk, the effects on the breastfed 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 a breastfed child, breastfeeding is not recommended during treatment with lusutrombopag and for at least 28 days after the last dose (see Clinical Considerations).

Clinical Considerations

Minimizing Exposure

A lactating woman should interrupt breastfeeding and pump and discard breast milk during lusutrombopag treatment and for 28 days after the last dose of lusutrombopag in order to minimize exposure to a breastfed child.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of lusutrombopag did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

9. OVERDOSAGE

No antidote for lusutrombopag overdose is known.

In the event of overdose, platelet count may increase excessively and result in thrombotic or thromboembolic complications. Closely monitor the patient and platelet count. Treat thrombotic complications in accordance with standard of care.

Hemodialysis is not expected to enhance the elimination of lusutrombopag because lusutrombopag is highly bound to protein in plasma [see Clinical Pharmacology].

10. MECHANISM OF ACTION

Lusutrombopag is an orally bioavailable, small molecule TPO receptor agonist that interacts with the transmembrane domain of human TPO receptors expressed on megakaryocytes to induce the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells and megakaryocyte maturation.

11. PHARMACODYNAMICS

Platelet Response

Lusutrombopag upregulates the production of platelets through its agonistic effect on human TPO receptors.

The effect of lusutrombopag on platelet count increase was correlated with the AUC across the studied dose range of 0.25 mg to 4 mg in thrombocytopenic patients with chronic liver disease. With the 3 mg daily dose, the mean (standard deviation) maximum platelet count in patients (N=74) without platelet transfusion was 86.9 (27.2) × 109/L, and the median time to reach the maximum platelet count was 12.0 (5 to 35) days.

Cardiac Electrophysiology

At a dose 8 times the recommended dosage, lusutrombopag does not prolong QT interval to any clinically relevant extent.

12. 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 lusutrombopag 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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

MULPLETA is supplied as 3 mg lusutrombopag tablets in a child‐resistant blister pack containing 7 tablets - NDC 59630-551-07.

Tablets: 3 mg lusutrombopag as a light red, round, film‐coated tablet debossed with the Shionogi trademark logo () above the identifier code “551” on one side and with a “3” on the other side.

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Rx only

Rev 07/18