Avatrombopag

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.

The recommended starting doses of avatrombopag in patients with chronic immune thrombocytopenia receiving concomitant medications are summarised in Table 4.

Table 4. Avatrombopag recommended starting dose for patients with primary chronic immune thrombocytopenia based on concomitant medications:

Concomitant use of avatrombopag with moderate or strong CYP3A4/5 and CYP2C9 dual inhibitors (e.g., fluconazole) increases avatrombopag exposure.

The recommended starting doses of avatrombopag in patients with chronic immune thrombocytopenia receiving concomitant medications are summarised in Table 4.

Table 4. Avatrombopag recommended starting dose for patients with primary chronic immune thrombocytopenia based on concomitant medications:

Concomitant use of avatrombopag with moderate or strong CYP2C9 inhibitors is expected to increase avatrombopag exposure.

Concomitant use of avatrombopag with moderate or strong CYP2C9 inducers is expected to reduce avatrombopag exposure.

Concomitant use of avatrombopag with P-gp inhibitors resulted in alterations in exposure that were not clinically significant. No dose adjustment is recommended.

Due to limited information available, the safety and efficacy of avatrombopag in patients with severe hepatic impairment (Child-Pugh class C, MELD score >24) have not been established. No dosage adjustment is expected for these patients. Avatrombopag therapy should only be initiated in patients with severe hepatic impairment if the expected benefit outweighs the expected risks.

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

The effectiveness and safety of avatrombopag have not been established for the treatment of thrombocytopenia due to MDS. Avatrombopag 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.

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.

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. In patients with chronic immune thrombocytopenia, thromboembolic events (arterial or venous) occurred in 7% (9/128) of patients receiving avatrombopag.

Avatrombopag was not studied in patients with prior thromboembolic events. Consider the potential increased thrombotic risk when administering avatrombopag 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. Avatrombopag should not be administered to patients with chronic liver disease or chronic immune thrombocytopenia in an attempt to normalise platelet counts.

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. Avatrombopag is not recommended during pregnancy and in women of childbearing potential not using contraception.

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. 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 avatrombopag 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.

Avatrombopag 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 avatrombopag 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.