Lusutrombopag

Lusutrombopag is a substrate of P-gp and BCRP, but not a substrate of OATP1B1, OATP1B3, and OCT1. In the clinical drug-drug interaction study, co-administration of cyclosporine, a P-gp and BCRP dual inhibitor, increased the C_max and AUC inf values of lusutrombopag by approximately 20% compared with lusutrombopag administration alone. Therefore, a potential interaction with either P-gp or BCRP inhibitors cannot be excluded, but no dose adjustment is necessary at the recommended clinical dosage of 3 mg in adults.

There is limited information on the use of lusutrombopag in patients with severe (Child-Pugh class C) hepatic impairment. Lusutrombopag should only be used in such patients if the expected benefit outweighs the expected risks. Due to the unstable nature of these patients, they should be supported in line with clinical practice by close monitoring for early signs of worsening or new onset hepatic encephalopathy, ascites, and thrombotic or bleeding tendency, through monitoring of liver function tests, tests used for assessing clotting status and through imaging of portal vasculature as needed. In addition, although no dose adjustment is required in these subjects, platelet count should be measured at least once approximately 5 days after the first dose and as necessary thereafter. Appropriate measures such as discontinuation of lusutrombopag should be taken, if the platelet count reaches ≥50,000/μL as a result of a 20,000/μL increase from baseline.

Interferon preparations have been known to reduce platelet counts, therefore, this should be considered when co-administering lusutrombopag with interferon preparations.

The efficacy and safety of lusutrombopag have not been established when administered in patients with a history of splenectomy. Platelet count should be carefully monitored in patients with a history of splenectomy treated with lusutrombopag.

There is limited information on the use of lusutrombopag in patients with body weight <45 Kg. Platelet count should be measured at least once approximately 5 days after the first dose and as necessary thereafter. Appropriate measures such as discontinuation of lusutrombopag should be taken, if the platelet count reaches ≥50,000/μL as a result of a 20,000/μL increase from baseline.

There are no or limited amount of data from the use of lusutrombopag in pregnant women. Animal studies are insufficient with respect to reproductive toxicity.

Lusutrombopag is not recommended during pregnancy and in women of child-bearing potential not using contraception.

It is unknown whether lusutrombopag or its metabolites are excreted in human milk. Studies in animals have shown lusutrombopag is secreted in the milk of lactating rats. Therefore, a risk to the breast-feeding child cannot be excluded. Lusutrombopag should not be administered to breast-feeding women as it was excreted in mammary milk in animals.

Women of childbearing potential/contraception

Lusutrombopag should be used with contraception.

Fertility

Lusutrombopag did not affect male or female fertility in rats at doses up to 176 and 252 times the human clinical exposures in adults based on AUC in males and females, respectively.

Lusutrombopag has no known influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions were headache (4.7%, 8/171 patients in the lusutrombopag group; 3.5%, 6/170 patients in the placebo group), nausea (2.3%, 4/171 patients in the lusutrombopag group; 4.1%, 7/170 patients in the placebo group), portal vein thrombosis (1.2%, 2/171 patients in the lusutrombopag group; 1.2%, 2/170 patients in the placebo group) and rash (1.2%, 2/171 patients in the lusutrombopag group; 0%, 0/170 patients in the placebo group).

List of adverse reactions

Adverse reactions with 3 mg of lusutrombopag once daily for up to 7 days in randomised, double-blind, placebo-controlled trials in thrombocytopenic patients with chronic liver disease undergoing an invasive procedure (M0626, M0631 and M0634; N=171) are listed below by MedDRA System Organ Class.

Adverse reactions:

Nervous system disorders

Common: Headache

Gastrointestinal disorders

Common: Nausea

Hepatobiliary disorders

Common: Portal vein thrombosis

Skin and subcutaneous tissue disorders

Common: Rash

^a Category of frequency: very common (≥1/10), common (≥1/100 to <1/10) , uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000)

Description of selected adverse reactions

Thrombotic/thromboembolic complications

Portal vein thrombosis has been reported in Phase 3 randomised, double-blind, placebo-controlled clinical studies with 3 mg of lusutrombopag once daily for up to 7 days (1.2%, 2/171 patients); the incidence was comparable to that of the placebo group (1.2%, 2/170 patients); one case of cardiac ventricular thrombosis was reported (0.6%, 1/171) in the lusutrombopag group only. In the phase 2b study one patient had portal vein thrombosis reported as a treatment-emergent adverse event (TEAE) in the lusutrombopag 2 mg and 4 mg groups. One patient had mesenteric vein thrombosis reported as a TEAE in the lusutrombopag 4 mg group; two patients had mesenteric vein thrombosis reported as a TEAE in the placebo group.