BRIEF SUMMARY

LUSTROBOPAG-(July 2018)

Indn-    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.

Comp-    Tablet 3mg

ADR-  The most common adverse reaction): headache.

CI-  None.

WARNINGS -                                                                                                                        Thrombotic/Thromboembolic Complications: it  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.

Pat Inform-

Prior to treatment, patients should fully understand and be informed of the following risks and considerations for the product. Risks Thrombotic/Thromboembolic Complications

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  26

ADVERSE REACTIONS

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

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.

 PATIENT COUNSELING INFORMATION

 Advise the patient to read the FDA-approved patient labeling (Patient Information).

Prior to treatment, patients should fully understand and be informed of the following risks and considerations for MULPLETA.

Risks 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. Portal vein thrombosis has been reported in patients with chronic liver disease treated with TPO receptor agonists.

Pregnancy-                                                                                                                Advise women of reproductive potential who become pregnant or are planning to become pregnant that MULPLETA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Lactation-                                                                                                                   Advise women not to breastfeed during treatment with MULPLETA and for 28 days after the last dose of MULPLETA.                                                                                           

 Advise women to pump and discard breast milk during this period.

 MULPLETA is a registered trademark of Shionogi & Co., Ltd.                                         Manufactured for Shionogi Inc., Florham Park, NJ 07932.                                            Manufactured by Quotient Sciences ? Philadelphia, LLC, Boothwyn, PA 19061.

CLINICAL PHARMACOLOGY

1. 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.

2. 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, MULPLETA does not prolong QT interval to any clinically relevant extent.

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-t 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-t 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.

USE IN SPECIFIC POPULATIONS -         

 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

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.

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 MULPLETA and for at least 28 days after the last dose.

Minimizing Exposure

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

3. Pediatric Use-                                                                                                                 Safety and effectiveness in pediatric patients have not been established.

4. Geriatric Use-                                                                                                                   Clinical studies of MULPLETA 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.         

OVERDOSAGE-

 No antidote for MULPLETA 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 MULPLETA because lusutrombopag is highly bound to protein in plasma