Doptelet · 4.3 Contraindications · 1

HOS-098593 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile Chronic liver disease The safety of avatrombopag was evaluated in two randomised, double-blind, placebo-controlled trials, ADAPT-1 and ADAPT-2, in which 430 patients with chronic liver disease and thrombocytopenia received either avatrombopag (n = 274) or placebo (n = 156), and had 1 post-dose safety assessment. 9 Chronic immune thrombocytopenia The safety of avatrombopag in adult patients was evaluated in three controlled trials and one uncontrolled trial which enrolled 161 patients with chronic immune thrombocytopenia. The pooled safety data from these four trials includes 128 patients who were exposed to avatrombopag for a median duration of 29 weeks. The safety of avatrombopag in paediatric patients ≥ 1 to < 18 years of age with persistent or chronic thrombocytopenia was evaluated in a randomized, placebo-controlled trial with a 12-week double- blind Core Phase followed by an optional open-label Extension Phase in which patients could receive avatrombopag for up to 2 years. The safety data from the Core Phase includes 54 patients who were exposed to avatrombopag for a median duration of 12 weeks. The overall safety profile in paediatric patients treated with avatrombopag is comparable to that in adult patients. Tabulated list of adverse reactions Adverse reactions are classified by Preferred Term and System Organ Class, and by frequency. Frequencies are defined as: 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); very rare (< 1/10 000); not known (cannot be estimated from the available data). Chronic liver disease study population System organ class Common Uncommon Not known (MedDRA terminology*) Blood and lymphatic system Anaemia disorders Immune system disorders Hypersensitivity Portal vein Vascular disorders thrombosis Musculoskeletal & connective Bone pain tissue disorders Myalgia General disorders and Fatigue Pyrexia administration site conditions * Medical Dictionary for Regulatory Activities (MedDRA) ver

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HOS-098589 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-098588 · has-indication-information · PDF-Seite 2

Doptelet is indicated for the treatment of severe thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure. Doptelet is indicated for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments (e.g., corticosteroids, immunoglobulins).

HOS-098591 · has-interaction-information · PDF-Seite 8

P-gp inhibitors Concomitant use of avatrombopag with P-gp inhibitors resulted in alterations in exposure that were not clinically significant. No dose adjustment is recommended (see section 5.2). CYP3A4/5 and CYP2C9 inhibitors Concomitant use of avatrombopag with moderate or strong CYP3A4/5 and CYP2C9 dual inhibitors (e.g., fluconazole) increases avatrombopag exposure. Concomitant use of avatrombopag with moderate or strong CYP2C9 inhibitors is expected to increase avatrombopag exposure. Chronic liver disease The increase in avatrombopag exposure is not expected to have a clinically important effect on platelet counts due to the 5-day treatment duration, and no dose adjustment is recommended. However, these patients should be evaluated on the day of the procedure for an unexpectedly high increase in platelet count (see section 4.2 and 5.2). Chronic immune thrombocytopenia Reduce the starting dose of avatrombopag when used concomitantly with a moderate or strong dual inhibitor of CYP2C9 and CYP3A4/5 (see Table 4 and section 4.2). Reduction of the starting dose should also be considered for patients receiving a moderate or strong CYP2C9 inhibitor. In patients starting moderate or strong dual inhibitors of CYP2C9 and CYP3A4/5, or moderate or strong inhibitors of CYP2C9, while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary (see Table 2, Table 3 and section 4.2). CYP3A4/5 and CYP2C9 inducers Concomitant use of moderate or strong CYP3A4/5 and CYP2C9 dual inducers (e.g., rifampicin, enzalutamide) reduces avatrombopag exposure, and may result in a decreased effect on platelet counts. Concomitant use of avatrombopag with moderate or strong CYP2C9 inducers is expected to reduce avatrombopag exposure. Chronic liver disease The decrease in avatrombopag exposure is not expected to have a clinically important effect on platelet counts due to the 5-day treatment duration. No dose adjustment is recommended (see section 5.2). 8 Chronic immune thrombocytopenia Increase the recommended starting dose of Doptelet when used concomitantly with a moderate or strong dual inducer of CYP2C9 and CYP3A4/5 (see Table 4 and section 4.2). An increase in the starting dose should also be considered for patients receiving a moderate or strong CYP2C9 inducer. In patients starting moderate or strong dual inducers of CYP2C9 and CYP3A4/5, or moderate or strong inducers of CYP2C9, whil

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HOS-098592 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are no or limited amount of data from the use of avatrombopag in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Doptelet is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding There are no data on the presence of avatrombopag in human milk, the effects on the breastfed child, or the effects on milk production. It is unknown whether avatrombopag or its metabolites are excreted in human milk. Avatrombopag was present in the milk of lactating rats, see section 5.3. A risk to the breast-feeding child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Doptelet therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility The effect of avatrombopag on human fertility has not been established, and a risk cannot be ruled out. In animal studies, avatrombopag had no effect on male and female fertility or early embryogenesis in rats (see section 5.3).

HOS-098590 · has-warning-information · PDF-Seite 6

Thrombotic/thromboembolic events Patients with chronic liver disease are known to be at increased risk for thromboembolic events. Portal vein thrombosis has been reported at an increased frequency in patients with chronic liver disease who had platelet counts > 200 × 109/L receiving a thrombopoietin receptor agonist (see section 4.8). In patients with chronic immune thrombocytopenia, thromboembolic events (arterial or venous) occurred in 7% (9/128) of patients receiving avatrombopag (see section 4.8). Doptelet was not studied in patients with prior thromboembolic events. Consider the potential increased thrombotic risk when administering Doptelet to patients with known risk factors for thromboembolism, including but not limited to genetic prothrombotic conditions (e.g. Factor V Leiden, Prothrombin 20210A, Antithrombin deficiency or Protein C or S deficiency), acquired risk factors (e.g. antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking. Doptelet should not be administered to patients with chronic liver disease or chronic immune thrombocytopenia in an attempt to normalise platelet counts. QTc prolongation with concomitant medicinal products At exposures similar to that achieved at the 40 mg and 60 mg dose, Doptelet did not prolong the QT interval to any clinically relevant extent. Mean QTc prolongation effects > 20 ms are not anticipated with the highest recommended therapeutic dosing regimen based on analysis of data from the pooled clinical trials in patients with chronic liver disease. However, caution must be exercised when Doptelet is co-administered with moderate or strong dual CYP3A4/5 and CYP2C9 inhibitors, or with moderate or strong CYP2C9 inhibitors, as these medicinal products can increase avatrombopag exposures. Caution must also be exercised in patients with loss-of-function polymorphisms of CYP2C9, as these can increase avatrombopag exposure. Reoccurrence of thrombocytopenia and bleeding after cessation of treatment in patients with chronic immune thrombocytopenia Thrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment with avatrombopag. Following discontinuation of avatrombopag, platelet counts return to baseline levels within 2 weeks in the majority of patients, which increases the bleeding risk and in some cases may lead to bleeding. There is an increased risk of b

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