DOPTELET Film-coated tablet Ref.[27846] Active ingredients: Avatrombopag

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 (Factor V Leiden, Prothrombin 20210A, Antithrombin deficiency or Protein C or S deficiency) 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 medications

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 medications 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 bleeding if avatrombopag treatment is discontinued in the presence of anticoagulants or anti-platelet agents. Patients should be closely monitored for a decrease in platelet count and medically managed to avoid bleeding upon discontinuation of treatment with avatrombopag. It is recommended that, if treatment with avatrombopag is discontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or antiplatelet therapy, reversal of anticoagulation, or platelet support.

Increased bone marrow reticulin

Increased bone marrow reticulin is believed to be a result of TPO receptor stimulation, leading to an increased number of megakaryocytes in the bone marrow, which may subsequently release cytokines. Increased reticulin may be suggested by morphological changes in the peripheral blood cells and can be detected through bone marrow biopsy. Therefore, examinations for cellular morphological abnormalities using peripheral blood smear and complete blood count (CBC) prior to and during treatment with avatrombopag are recommended.

If a loss of efficacy and abnormal peripheral blood smear are observed in patients, administration of avatrombopag should be discontinued, a physical examination should be performed, and a bone marrow biopsy with appropriate staining for reticulin should be considered. If available, comparison to a prior bone marrow biopsy should be made. If efficacy is maintained and abnormal peripheral blood smear is observed in patients, the physician should follow appropriate clinical judgment, including consideration of a bone marrow biopsy, and the risk-benefit of avatrombopag and alternative ITP treatment options should be re-assessed.

Progression of existing myelodysplastic syndrome (MDS)

The effectiveness and safety of Doptelet have not been established for the treatment of thrombocytopenia due to MDS. Doptelet should not be used outside of clinical studies for the treatment of thrombocytopenia due to MDS.

There is a theoretical concern that TPO-R agonists may stimulate the progression of existing haematological malignancies such as MDS. TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R is predominantly expressed on the surface of cells of the myeloid lineage. For TPO-R agonists there is a concern that they may stimulate the progression of existing haematopoietic malignancies such as MDS.

The diagnosis of ITP in adults and elderly patients should have been confirmed by the exclusion of other clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must be excluded. Consideration should be given to performing a bone marrow aspirate and biopsy over the course of the disease and treatment, particularly in patients over 60 years of age, for those with systemic symptoms or abnormal signs such as increased peripheral blast cells.

Severe hepatic impairment

There is limited information on the use of avatrombopag in patients with severe (Child-Pugh class C, MELD score >24) hepatic impairment. Avatrombopag should only be used in such patients if the expected benefit outweighs the expected risks (see sections 4.2 and 5.2).

Patients with severe hepatic impairment 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.

Patients with Child-Pugh class C liver disease who take avatrombopag prior to an invasive procedure, should be evaluated on the day of the procedure for an unexpectedly high increase in platelet count.

Use in patients with chronic liver disease undergoing invasive procedures

The objective of treatment with Doptelet is to increase platelet counts. While the benefit-risk profile for procedures that were not specifically included in the clinical studies is likely to be comparable, the efficacy and safety of avatrombopag have not been established in major surgeries like laparotomy, thoracotomy, open-heart surgery, craniotomy or excision of organs.

Retreatment for patients with chronic liver disease undergoing invasive procedures

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

Co-administration with interferon preparations

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

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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 dosage 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).

Chronic immune thrombocytopenia

Increase the recommended starting dosage 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, while receiving avatrombopag, monitor platelet counts and adjust dose as necessary (see Table 2, Table 3 and section 4.2).

Medicinal products for treatment of ITP

Medicinal products used in the treatment of ITP in combination with avatrombopag in clinical trials included corticosteroids, danazol, dapsone, and intravenous immunoglobulin (IVIg). Platelet counts should be monitored when combining avatrombopag with other medicinal products for the treatment of ITP in order to avoid platelet counts outside of the recommended range.

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).

Doptelet has no or negligible influence on the ability to drive and use machines.

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.

Chronic Immune Thrombocytopenia

The safety of avatrombopag 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.

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:

^* Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.

Chronic primary immune thrombocytopenia study population:

Description of selected adverse reactions

Thromboembolic Events

In the ADAPT-1 and ADAPT-2 clinical trials in patients with thrombocytopenia and chronic liver disease, there was 1 treatment-emergent event of portal vein thrombosis in a patient (n=1/430) which was reported 14 days after treatment with Doptelet ended. This adverse reaction was assessed as non-serious.

In the four pooled clinical trials in patients with chronic immune thrombocytopenia, thromboembolic events were observed in 7% (9/128) of patients. The only thromboembolic event which occurred in more than 1 individual patient was cerebrovascular accident, occurring in 1.6% (2/128).

Thrombocytopenia following discontinuation of treatment in patients with chronic immune thrombocytopenia

In the 4 pooled clinical trials in patients with chronic immune thrombocytopenia, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8.6% (11/128) of patients treated with avatrombopag.

Hypersensitivity reactions

Hypersensitivity reactions including pruritus, rash, swelling face, and swollen tongue.

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.