MULPLEO Film-coated tablet Ref.[7587] Active ingredients: Lusutrombopag

Thrombotic/thromboembolic complications

Patients with chronic liver disease have a risk of portal vein thrombosis and mesenteric vein thrombosis. The risk may be increased due to an invasive procedure. Thromboembolic and thrombotic complications are known to occur with thrombopoetin (TPO) receptor agonists based upon mechanism of action associated with increases in platelets. Caution should be exercised with respect to thromboembolic events after invasive procedures as well as post-treatment regardless of platelet counts. In patients with thrombosis or thromboembolism, with a history of thrombosis or thromboembolism, with absence of hepatopetal blood flow in the main trunk of the portal vein, or patients with congenital coagulopathy the risk for thrombosis or thromboembolism may increase. These patients should be clinically monitored when treated with lusutrombopag.

Severe hepatic impairment

There is limited information on the use of lusutrombopag in patients with severe (Child-Pugh class C) hepatic impairment (see section 5.1). Lusutrombopag should only be used in such patients if the expected benefit outweighs the expected risks (see sections 4.2 and 5.2). 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.

Use in patients with chronic liver disease undergoing invasive procedures

Lusutrombopag should be used when risk for bleeding is considered to be high according to clinical laboratory test values such as platelet counts and of the coagulation-fibrinolysis system, clinical symptoms and type of invasive procedure. The efficacy and safety of lusutrombopag have not been established when administered before laparotomy, thoracotomy, open-heart surgery, craniotomy or excision of organs.

Retreatment

There is limited information on the use of lusutrombopag in patients previously exposed to lusutrombopag.

Use in patients with a history of splenectomy

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.

Co-administration with interferon preparations

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

Patients with body weight <45 Kg

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.

P-gp and BCRP inhibitors

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.

Women of childbearing potential/contraception

Mulpleo should be used with contraception (see sub-section Pregnancy and section 5.3).

Pregnancy

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 (see section 5.3).

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

Breast-feeding

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 (see section 5.3). Therefore, a risk to the breast-feeding child cannot be excluded. Mulpleo should not be administered to breast-feeding women as it was excreted in mammary milk in animals.

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 (see section 5.3).

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).

Tabulated 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 in Table 1 by MedDRA System Organ Class.

Table 1. 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 (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.