4.1. Therapeutic indications

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).

4.2. Posology and method of administration

Posology

Treatment should be initiated by and remain under the supervision of a physician who is experienced in the treatment of haematological diseases. Doptelet should be taken at the same time of day (e.g., in the morning or evening) with food, including when taking the dose less frequently than once daily.

Chronic liver disease

Obtain a platelet count prior to the administration of Doptelet therapy and on the day of a procedure to ensure an adequate increase in platelet count, and no unexpectedly high increase in platelet count in the patient populations specified in sections 4.4 and 4.5.

The recommended daily dose of avatrombopag is based on the patient's platelet count (see Table 1). Dosing should begin 10 to 13 days prior to the planned procedure. The patient should undergo their procedure 5 to 8 days after the last dose of avatrombopag.

Table 1: Daily dose recommendation for avatrombopag

Platelet count (× 109/L)

Once‑daily dose

Duration of dosing

< 40

60 mg (Three 20 mg tablets)

5 days

≥ 40 to < 50

40 mg (Two 20 mg tablets)

5 days

Duration of treatment

Due to limited information, avatrombopag should not be taken for more than 5 days.

Missed doses

If a dose is missed, it should be taken as soon as it is remembered. Two doses should not be taken at one time to make up for a missed dose. The next dose should be taken at the usual time the next day.

Chronic immune thrombocytopenia

Use the lowest dose of Doptelet needed to achieve and maintain a platelet count ≥ 50 × 109/L as necessary to reduce the risk for bleeding. Do not use avatrombopag to normalise platelet counts. In clinical trials, platelet counts generally increased within 1 week after starting avatrombopag and decreased within 1 to 2 weeks after discontinuation.

Initial dose regimen

The recommended starting dose of Doptelet is 20 mg (1 tablet) once daily with food.

Monitoring and dose adjustment

After initiating therapy, assess platelet counts at least once weekly until a stable platelet count ≥ 50 × 109/L and ≤ 150 × 109/L has been achieved. Twice weekly platelet count monitoring should be conducted during the first weeks of therapy in patients receiving avatrombopag only once or twice weekly. Twice weekly monitoring should also be conducted after dose adjustments during the treatment.

Due to the potential risk of platelet counts above 400 × 109/L within the first weeks of treatment patients should be carefully monitored for any signs or symptoms of thrombocytosis. After a stable platelet count has been achieved, obtain platelet counts at least monthly. After discontinuation of avatrombopag, platelet counts should be obtained weekly for at least 4 weeks.

Dose adjustments (see Table 2 and Table 3) are based on the platelet count response. Do not exceed a daily dose of 40 mg (2 tablets).

Table 2: Avatrombopag dose adjustments for patients with primary chronic immune thrombocytopenia

Platelet count (× 109/L)

Dose adjustment or action

< 50 after at least 2 weeks of avatrombopag treatment

• Increase One Dose Level per Table 3.

• Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments.

> 150 and ≤ 250

• Decrease One Dose Level per Table 3.

• Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments.

> 250

• Stop avatrombopag.

• Increase platelet monitoring to twice weekly.

• When platelet count is less than 100 × 109/L, decrease One Dose Level per Table 3 and reinitiate therapy.

< 50 after 4 weeks of avatrombopag 40 mg once daily

• Discontinue avatrombopag.

> 250 after 2 weeks of avatrombopag 20 mg weekly

• Discontinue avatrombopag.

Table 3: Avatrombopag dose levels for titration in patients with primary chronic immune thrombocytopenia

Dose≠

Dose Level

40 mg once daily

6

40 mg three times a week AND 20 mg on the four remaining days of each week

5

20 mg once daily*

4

20 mg three times a week

3

20 mg twice a week OR 40 mg once weekly

2

20 mg once weekly

1

*Initial dose regimen for all patients except those taking moderate or strong dual inducers or moderate or strong dual inhibitors of CYP2C9 and CYP3A4/5, or of CYP2C9 alone.

≠ Patients taking avatrombopag less frequently than once daily should take the medicinal product in a consistent manner from week to week.

Dose Level 3: Three non‑consecutive days a week, e.g. Monday, Wednesday and Friday

Dose Level 2: Two non‑consecutive days a week, e.g. Monday and Friday

Dose Level 1: The same day each week, e.g. Monday

In the case of a missed dose, patients should take the missed dose of avatrombopag as soon as they remember. Patients should not take two doses at one time to make up for a missed dose, and should take the next dose per the current regimen.

Avatrombopag can be administered in addition to other ITP medicinal products. Platelet counts should be monitored when combining avatrombopag with other medicinal products for the treatment of primary ITP in order to avoid platelet counts outside of the recommended range, and to determine whether the dose of either medicinal product should be reduced.

Discontinuation

Discontinue avatrombopag if the platelet count does not increase to ≥ 50 × 109/L after 4 weeks of dosing at the maximum dose of 40 mg once daily. Discontinue Doptelet if the platelet count is greater than 250 × 109/L after 2 weeks of dosing at 20 mg once weekly.

Recommended dose with concomitant moderate or strong dual inducers or inhibitors of CYP2C9 and CYP3A4/5, or of CYP2C9 alone, in patients with chronic immune thrombocytopenia

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

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

Concomitant medicinal products

Recommended starting dose

Moderate or strong dual inhibitors of CYP2C9 and CYP3A4/5, or of CYP2C9 alone (e.g., fluconazole)

20 mg (1 tablet) three times a week

Moderate or strong dual inducers of CYP2C9 and CYP3A4/5, or of CYP2C9 alone (e.g., rifampicin, enzalutamide)

40 mg (2 tablets) once daily

Special populations

Elderly

No dose adjustment is required for patients aged 65 years and older (see section 5.2).

Renal impairment

Avatrombopag is not renally excreted, therefore no dose adjustment is required in patients with mild or moderate renal impairment. Avatrombopag has not been studied in patients with severe renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild (Child‑Pugh class A) to moderate (Child‑Pugh class B) hepatic impairment.

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 (see section 4.4). No dose 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 (see sections 4.4 and 5.2).

Coexisting medical conditions

Due to limited or no information available, the safety and efficacy of avatrombopag in adult patients with chronic ITP and human immunodeficiency virus [HIV], hepatitis C virus [HCV] or subjects with known systemic lupus erythematosus, acute hepatitis, active chronic hepatitis, cirrhosis, lymphoproliferative disease, myeloproliferative disorders, leukemia, myelodysplasia (MDS), concurrent malignant disease, and significant cardiovascular disease (e.g. Grade III/IV congestive heart failure, atrial fibrillation, status post coronary artery bypass or stent placement) have not been established.

Paediatric population

The safety and efficacy of avatrombopag in children aged less than 18 years have not been established. No data are available.

CYP2C9 loss-of-function polymorphisms

Avatrombopag exposure may increase in patients with CYP2C9*2 and CYP2C9*3 loss-of-function polymorphisms. Healthy subjects (n=2) who were homozygous for these mutations (poor metabolizers) had approximately 2-fold higher exposure compared to subjects with wild-type CYP2C9.

Method of administration

Doptelet is for oral use, and the tablets should be taken with food (see section 5.2).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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. 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 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 trials 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.

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 trials 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.

4.5. Interaction with other medicinal products and other forms of interaction

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).

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, 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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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

System organ class

(MedDRA terminology*)

Common

Uncommon

Not known

Blood and lymphatic system disorders

Anaemia

Immune system disorders

Hypersensitivity

Vascular disorders

Portal vein thrombosis

Musculoskeletal & connective tissue disorders

Bone pain

Myalgia

General disorders and administration site conditions

Fatigue

Pyrexia

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

Chronic primary immune thrombocytopenia study population

System organ class

MedDRA terminology

Frequency

Adverse reaction

Infections and infestations

Uncommon

Furuncle, Thrombophlebitis septic, Upper respiratory tract infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon

Myelofibrosis

Blood and lymphatic system disorders

Common

Thrombocytopenia, Anaemia, Splenomegaly

Uncommon

Leukocytosis

Immune system disorders

Not known

Hypersensitivity

Metabolism and nutrition disorders

Common

Hyperlipidaemia, Decreased appetite

Uncommon

Dehydration, Hypertriglyceridaemia, Increased appetite, Iron deficiency

Psychiatric disorders

Uncommon

Mood swings

Nervous system disorders

Very common

Headache

Common

Dizziness, Head discomfort, Migraine, Paraesthesia

Uncommon

Cerebrovascular accident, Cognitive disorder, Dysgeusia, Hypoaesthesia, Sensory disturbance, Transient ischaemia attack

Eye disorders

Uncommon

Abnormal sensation in eye, Eye irritation, Eye pruritus, Eye swelling, Lacrimation increased, Ocular discomfort, Photophobia, Retinal artery occlusion, Vision blurred, Visual impairment

Ear and labyrinth disorders

Uncommon

Ear pain, Hyperacusis

Cardiac disorders

Uncommon

Myocardial infarction

Vascular disorders

Common

Hypertension

Uncommon

Deep vein thrombosis, Jugular vein thrombosis, Vasoconstriction

Respiratory, thoracic and mediastinal disorders

Common

Epistaxis, Dyspnoea

Uncommon

Haemoptysis, Nasal congestion, Pulmonary embolism

Gastrointestinal disorders

Common

Nausea, Diarrhoea, Vomiting, Abdominal pain upper, Flatulence

Uncommon

Abdominal discomfort, Abdominal distension, Abdominal pain lower, Anorectal varices, Constipation, Eructation, Gastrooesophageal reflux disease, Glossodynia, Haemorrhoids, Paraesthesia oral, Swollen tongue, Tongue disorder

Hepatobiliary disorders

Uncommon

Portal vein thrombosis

Skin and subcutaneous tissue disorders

Common

Rash, Acne, Petechiae, Pruritis

Uncommon

Alopecia, Dry skin, Ecchymosis, Hyperhidrosis, Pigmentation disorder, Rash pruritic, Skin haemorrhage, Skin irritation

Musculoskeletal and connective tissue disorders

Common

Arthralgia, Back pain, Pain in extremity, Myalgia, Musculoskeletal pain

Uncommon

Arthropathy, Limb discomfort, Muscle spasms, Muscular weakness, Musculoskeletal chest pain

Renal and urinary disorders

Uncommon

Haematuria

Reproductive system and breast disorders

Uncommon

Menorrhagia, Nipple pain

General disorders and administration site conditions

Very common

Fatigue

Common

Asthenia

Uncommon

Chest discomfort, Hunger, Pain, Peripheral swelling

Investigations

Common

Blood glucose increased, Platelet count increased, Blood glucose decreased, Blood triglycerides increased, Blood lactate dehydrogenase increased, Platelet count decreased, Alanine aminotransferase increased, Blood gastrin increased

Uncommon

Aspartate aminotransferase increased, Blood pressure increased, Heart rate irregular, Hepatic enzyme increased

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

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 = 1/274 of patients receiving avatrombopag) 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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no specific antidote for overdose with avatrombopag. Should overdose occur or be suspected, Doptelet dosing should be stopped and platelet count should be carefully monitored since avatrombopag increases platelet count in a dose‑dependent fashion.