DOPTELET 20mg tablets medication leaflet

Doptelet 20 mg film-coated tablets

Each film-coated tablet contains avatrombopag maleate equivalent to 20 mg of avatrombopag.

Each film-coated tablet contains 120.8 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Pale yellow, round biconvex film-coated 7.6 mm tablet debossed with “AVA” on one side and “20” onthe other.

Doptelet is indicated for the treatment of severe thrombocytopenia in adult patients with chronic liverdisease who are scheduled to undergo an invasive procedure.

Doptelet is indicated for the treatment of primary chronic immune thrombocytopenia (ITP) in adultpatients who are refractory to other treatments (e.g., corticosteroids, immunoglobulins).

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

Obtain a platelet count prior to the administration of Doptelet therapy and on the day of a procedure toensure an adequate increase in platelet count, and no unexpectedly high increase in platelet count inthe 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 theirprocedure 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

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

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

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

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

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

Due to the potential risk of platelet counts above 400 × 109/L within the first weeks of treatmentpatients should be carefully monitored for any signs or symptoms of thrombocytosis. After a stableplatelet count has been achieved, obtain platelet counts at least monthly. After discontinuation ofavatrombopag, 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 adaily dose of 40 mg (2 tablets).

Table 2: Avatrombopag dose adjustments for patients with primary chronic immunethrombocytopenia

Platelet count (× 109/L) Dose adjustment or action

* Increase One Dose Level per Table 3.< 50 after at least 2 weeks ofavatrombopag treatment * Wait 2 weeks to assess the effects of this regimen and anysubsequent dose adjustments.

* Decrease One Dose Level per Table 3.> 150 and ≤ 250 * Wait 2 weeks to assess the effects of this regimen and anysubsequent dose adjustments.

* Stop avatrombopag.

> 250 * 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 * Discontinue avatrombopag.avatrombopag 40 mg once daily> 250 after 2 weeks ofavatrombopag 20 mg weekly * Discontinue avatrombopag.

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

Dose≠ Dose Level40 mg once daily 640 mg three times a week AND 20 mg on the four remaining days of each week 520 mg once daily* 420 mg three times a week 320 mg twice a week OR 40 mg once weekly 220 mg once weekly 1

*Initial dose regimen for all patients except those taking moderate or strong dual inducers ormoderate 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 aconsistent 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 theyremember. Patients should not take two doses at one time to make up for a missed dose, and shouldtake the next dose per the current regimen.

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

Discontinue avatrombopag if the platelet count does not increase to ≥ 50 × 109/L after 4 weeks ofdosing at the maximum dose of 40 mg once daily. Discontinue Doptelet if the platelet count is greaterthan 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 thrombocytopeniareceiving concomitant medicinal products are summarised in Table 4.

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

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, 40 mg (2 tablets) once dailyenzalutamide)

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

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

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

Due to limited information available, the safety and efficacy of avatrombopag in patients with severehepatic impairment (Child-Pugh class C, MELD score > 24) have not been established (seesection 4.4). No dose adjustment is expected for these patients. Avatrombopag therapy should only beinitiated in patients with severe hepatic impairment if the expected benefit outweighs the expectedrisks (see sections 4.4 and 5.2).

Due to limited or no information available, the safety and efficacy of avatrombopag in adult patientswith chronic ITP and human immunodeficiency virus [HIV], hepatitis C virus [HCV] or subjects withknown 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 congestiveheart failure, atrial fibrillation, status post coronary artery bypass or stent placement) have not beenestablished.

The safety and efficacy of avatrombopag in children aged less than 1 year have not been established.

No data are available.

Currently available data for paediatric patients 1 year of age and older and less than 18 years aredescribed in section 4.8 and 5.1.

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

CYP2C9.

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

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

Patients with chronic liver disease are known to be at increased risk for thromboembolic events. Portalvein thrombosis has been reported at an increased frequency in patients with chronic liver disease whohad platelet counts > 200 × 109/L receiving a thrombopoietin receptor agonist (see section 4.8). Inpatients with chronic immune thrombocytopenia, thromboembolic events (arterial or venous) occurredin 7% (9/128) of patients receiving avatrombopag (see section 4.8).

Doptelet was not studied in patients with prior thromboembolic events. Consider the potentialincreased thrombotic risk when administering Doptelet to patients with known risk factors forthromboembolism, 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 periodsof immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma,obesity and smoking. Doptelet should not be administered to patients with chronic liver disease orchronic 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 QTinterval to any clinically relevant extent. Mean QTc prolongation effects > 20 ms are not anticipatedwith the highest recommended therapeutic dosing regimen based on analysis of data from the pooledclinical trials in patients with chronic liver disease. However, caution must be exercised when Dopteletis co-administered with moderate or strong dual CYP3A4/5 and CYP2C9 inhibitors, or with moderateor 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 thesecan increase avatrombopag exposure.

Reoccurrence of thrombocytopenia and bleeding after cessation of treatment in patients with chronicimmune thrombocytopenia

Thrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment withavatrombopag. Following discontinuation of avatrombopag, platelet counts return to baseline levelswithin 2 weeks in the majority of patients, which increases the bleeding risk and in some cases maylead to bleeding. There is an increased risk of bleeding if avatrombopag treatment is discontinued inthe presence of anticoagulants or anti-platelet agents. Patients should be closely monitored for adecrease in platelet count and medically managed to avoid bleeding upon discontinuation of treatmentwith avatrombopag. It is recommended that, if treatment with avatrombopag is discontinued, ITPtreatment be restarted according to current treatment guidelines. Additional medical management mayinclude cessation of anticoagulant and/or antiplatelet therapy, reversal of anticoagulation, or plateletsupport.

Increased bone marrow reticulin is believed to be a result of TPO receptor stimulation, leading to anincreased 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 canbe detected through bone marrow biopsy. Therefore, examinations for cellular morphologicalabnormalities using peripheral blood smear and complete blood count (CBC) prior to and duringtreatment with avatrombopag are recommended.

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

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

There is a theoretical concern that TPO-R agonists may stimulate the progression of existinghaematological malignancies such as MDS. TPO-R agonists are growth factors that lead tothrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R ispredominantly 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 ofother clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must beexcluded. Consideration should be given to performing a bone marrow aspirate and biopsy over thecourse of the disease and treatment, particularly in patients over 60 years of age, for those withsystemic symptoms or abnormal signs such as increased peripheral blast cells.

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 theexpected 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 closemonitoring for early signs of worsening or new onset hepatic encephalopathy, ascites, and thromboticor bleeding tendency, through monitoring of liver function tests, tests used for assessing clotting statusand 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.

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

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

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

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

Concomitant use of avatrombopag with P-gp inhibitors resulted in alterations in exposure that werenot clinically significant. No dose adjustment is recommended (see section 5.2).

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

The increase in avatrombopag exposure is not expected to have a clinically important effect on plateletcounts due to the 5-day treatment duration, and no dose adjustment is recommended. However, thesepatients should be evaluated on the day of the procedure for an unexpectedly high increase in plateletcount (see section 4.2 and 5.2).

Reduce the starting dose of avatrombopag when used concomitantly with a moderate or strong dualinhibitor of CYP2C9 and CYP3A4/5 (see Table 4 and section 4.2). Reduction of the starting doseshould 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 orstrong inhibitors of CYP2C9, while receiving avatrombopag, monitor platelet counts and adjust theavatrombopag dose as necessary (see Table 2, Table 3 and section 4.2).

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 reduceavatrombopag exposure.

The decrease in avatrombopag exposure is not expected to have a clinically important effect onplatelet counts due to the 5-day treatment duration. No dose adjustment is recommended (seesection 5.2).

Increase the recommended starting dose of Doptelet when used concomitantly with a moderate orstrong dual inducer of CYP2C9 and CYP3A4/5 (see Table 4 and section 4.2). An increase in thestarting 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 orstrong inducers of CYP2C9, while receiving avatrombopag, monitor platelet counts and adjust dose asnecessary (see Table 2, Table 3 and section 4.2).

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

There are no or limited amount of data from the use of avatrombopag in pregnant women. Animalstudies are insufficient with respect to reproductive toxicity (see section 5.3). Doptelet is notrecommended 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 excretedin human milk. Avatrombopag was present in the milk of lactating rats, see section 5.3. A risk to thebreast-feeding child cannot be excluded. A decision must be made whether to discontinuebreast-feeding or to discontinue/abstain from Doptelet therapy taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

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 inrats (see section 5.3).

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

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 thrombocytopeniareceived either avatrombopag (n = 274) or placebo (n = 156), and had 1 post-dose safety assessment.

The safety of avatrombopag in adult patients was evaluated in three controlled trials and oneuncontrolled trial which enrolled 161 patients with chronic immune thrombocytopenia. The pooledsafety data from these four trials includes 128 patients who were exposed to avatrombopag for amedian duration of 29 weeks.

The safety of avatrombopag in paediatric patients ≥ 1 to < 18 years of age with persistent or chronicthrombocytopenia 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 receiveavatrombopag for up to 2 years. The safety data from the Core Phase includes 54 patients who wereexposed to avatrombopag for a median duration of 12 weeks. The overall safety profile in paediatricpatients treated with avatrombopag is comparable to that in adult patients.

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 beestimated from the available data).

Chronic liver disease study population

System organ class

Common Uncommon Not known(MedDRA terminology*)

Blood and lymphatic system Anaemiadisorders

Immune system disorders Hypersensitivity

Vascular disorders Portal veinthrombosis

Musculoskeletal & connective Bone paintissue disorders Myalgia

General disorders and Fatigue Pyrexiaadministration site conditions

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

Chronic primary immune thrombocytopenia study population

System organ class Frequency Adverse reaction

MedDRA terminology

Infections and infestations Uncommon Furuncle, Thrombophlebitis septic, Upperrespiratory tract infection

Neoplasms benign, malignant Uncommon Myelofibrosisand unspecified (includingcysts and polyps)

Blood and lymphatic system Common Thrombocytopenia, Anaemia, Splenomegalydisorders Uncommon Leukocytosis

Immune system disorders Not known Hypersensitivity

Metabolism and nutrition Common Hyperlipidaemia, Decreased appetitedisorders Uncommon Dehydration, Hypertriglyceridaemia, Increasedappetite, Iron deficiency

Psychiatric disorders Uncommon Mood swings

System organ class Frequency Adverse reaction

MedDRA terminology

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, Eyepruritus, Eye swelling, Lacrimation increased,

Ocular discomfort, Photophobia, Retinal arteryocclusion, 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 Common Epistaxis, Dyspnoeamediastinal disorders Uncommon Haemoptysis, Nasal congestion, Pulmonaryembolism

Gastrointestinal disorders Common Nausea, Diarrhoea, Vomiting, Abdominal painupper, Flatulence

Uncommon Abdominal discomfort, Abdominal distension,

Abdominal pain lower, Anorectal varices,

Constipation, Eructation, Gastrooesophagealreflux disease, Glossodynia, Haemorrhoids,

Paraesthesia oral, Swollen tongue, Tonguedisorder

Hepatobiliary disorders Uncommon Portal vein thrombosis

Skin and subcutaneous tissue Common Rash, Acne, Petechiae, Pruritisdisorders Uncommon Alopecia, Dry skin, Ecchymosis, Hyperhidrosis,

Pigmentation disorder, Rash pruritic, Skinhaemorrhage, Skin irritation

Musculoskeletal and Common Arthralgia, Back pain, Pain in extremity,connective tissue disorders Myalgia, Musculoskeletal pain

Uncommon Arthropathy, Limb discomfort, Muscle spasms,

Muscular weakness, Musculoskeletal chest pain

Renal and urinary disorders Uncommon Haematuria

Reproductive system and Uncommon Menorrhagia, Nipple painbreast disorders

General disorders and Very common Fatigueadministration site conditions Common Asthenia

Uncommon Chest discomfort, Hunger, Pain, Peripheralswelling

System organ class Frequency Adverse reaction

MedDRA terminology

Investigations Common Blood glucose increased, Platelet countincreased**, Blood glucose decreased, Bloodtriglycerides increased, Blood lactatedehydrogenase increased, Platelet countdecreased, Alanine aminotransferase increased,

Blood gastrin increased

Uncommon Aspartate aminotransferase increased, Bloodpressure increased, Heart rate irregular, Hepaticenzyme increased

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

** In the clinical trial in paediatric patients, thrombocytosis was reported in one patient during the Core

Phase of the study and in one patient during the open-label Extension Phase.

In the ADAPT-1 and ADAPT-2 clinical trials in patients with thrombocytopenia and chronic liverdisease, there was 1 treatment-emergent event of portal vein thrombosis in a patient (n = 1/274 ofpatients 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 adult patients with chronic immune thrombocytopenia,thromboembolic events were observed in 7% (9/128) of patients. The only thromboembolic eventwhich occurred in more than 1 individual patient was cerebrovascular accident, occurring in 1.6%(2/128). In paediatric patients with persistent or chronic immune thrombocytopenia, thromboembolicevents occurred in 1.4% (1/73) of patients receiving avatrombopag.

Thrombocytopenia following discontinuation of treatment in patients with chronic immunethrombocytopenia

In the 4 pooled clinical trials in patients with chronic immune thrombocytopenia, transient decreasesin platelet counts to levels lower than baseline were observed following discontinuation of treatment in8.6% (11/128) of patients treated with avatrombopag.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 sinceavatrombopag increases platelet count in a dose-dependent fashion.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics, ATC code: B02BX08

Avatrombopag is an orally active, small molecule thrombopoietin (TPO) receptor agonist thatstimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cellsresulting in increased production of platelets. Avatrombopag does not compete with TPO for bindingto the TPO receptor and has an additive effect with TPO on platelet production.

The efficacy and safety of avatrombopag for the treatment of adult patients with chronic liver diseaseand a platelet count ˂ 50 × 109/L who were scheduled to undergo a procedure were studied in2 identically-designed multicenter, randomised, double-blind, placebo-controlled Phase 3 studies(ADAPT-1 and ADAPT-2). In each study, patients were assigned to the low baseline platelet countcohort (˂ 40 × 109/L) or the high baseline platelet count cohort (≥ 40 to ˂ 50 × 109/L) based on theirplatelet count at baseline. Patients were then randomised 2:1 to either avatrombopag or placebo.

Patients in the low baseline platelet count cohort received 60 mg avatrombopag or matching placeboonce daily for 5 days, and patients in the high baseline platelet count cohort received 40 mgavatrombopag or matching placebo once daily for 5 days. Eligible patients were scheduled to undergotheir procedure (low bleeding risk procedures, such as endoscopy and colonoscopy (60.8%); moderatebleeding risk, such as liver biopsy and chemoembolization for HCC (17.2%); or high bleeding risk,such as dental procedures and radiofrequency ablation (22.1%)) 5 to 8 days after their last dose oftreatment. Patient populations were similar between the low and high baseline platelet count cohorts,and consisted of 66% male and 35% female; median age 58 years and 61% White, 34% Asian, and 3%

Black. A total of 24.8% of patients were ≥ 65 years of age, pct. 4.6% ≥ 75 years of age, and only 1(0.2%) ≥ 85 years of age. Patients’ MELD scores ranged from < 10 (37.5%), 10 to 14 (46.3%) andfrom > 14 to < 24 (16.2%), and included patients with CTP Class A (56.4%), Class B (38.1%), and

Class C (5.6%).

In ADAPT-1, a total of 231 patients were randomised; 149 patients to the avatrombopag group and82 patients to the placebo group. In the low baseline platelet count cohort, the mean baseline plateletcount for the avatrombopag-treated group was 31.1 × 109/L and for placebo-treated patients was30.7 × 109/L. In the high baseline platelet count cohort, the mean baseline platelet count for theavatrombopag-treated patients was 44.3 × 109/L and for placebo-treated patients was 44.9 × 109/L.

In ADAPT-2, a total of 204 patients were randomised; 128 patients to the avatrombopag treatmentgroup and 76 patients to the placebo treatment group. In the low baseline platelet count cohort, themean baseline platelet count for the avatrombopag-treated group was 32.7 × 109/L and forplacebo-treated patients was 32.5 × 109/L. In the high baseline platelet count cohort, the mean baselineplatelet count for the avatrombopag-treated patients was 44.3 × 109/L and for placebo-treated patientswas 44.5 × 109/L.

Responders were defined as patients who did not require a platelet transfusion or any rescue procedurefor bleeding after randomisation and up to 7 days following a scheduled procedure. Results are shownin Table 5.

Table 5: Efficacy results by baseline platelet count cohort and treatment group - ADAPT-1 and

ADAPT-2

Low baseline platelet count cohort (< 40 × 109/L)

ADAPT-1 ADAPT-2

Category Placebo Avatrombopag Placebo Avatrombopag60 mg 60 mg(n = 48) (n = 90) (n = 43) (n = 70)

Proportion of subjects not requiring a platelet transfusion or rescue procedure for bleeding

Responders 23% 66% 35% 69%95% CIa (11, 35) (56, 75) (21, 49) (58, 79)

P-valueb ˂ 0.0001 0.0006

Proportion of subjects who achieved a platelet count ≥ 50 × 109/L on procedure day

Responders 4% 69% 7% 67%95% CIa (0, 10) (59, 79) (0, 15) (56, 78)

P-valueb ˂ 0.0001 ˂ 0.0001

Change in platelet count from baseline to procedure day

Mean (SD) × 109/L 0.8 (6.4) 32.0 (25.5) 3.0 (10.0) 31.3 (24.1)

Median × 109/L 0.5 28.3 0.5 28.0

P-valuec ˂ 0.0001 ˂ 0.0001

High baseline platelet count (≥ 40 to < 50 × 109/L)

ADAPT-1 ADAPT-2

Category Placebo Avatrombopag Placebo Avatrombopag40 mg 40 mg(n = 34) (n = 59) (n = 33) (n = 58)

Proportion of subjects not requiring a platelet transfusion or rescue procedure for bleeding

Responders 38% 88% 33% 88%95% CIa (22, 55) (80, 96) (17, 49) (80, 96)

P-valueb ˂ 0.0001 ˂ 0.0001

Proportion of subjects who achieved a platelet count ≥ 50 × 109/L on procedure day

Responders 21% 88% 39% 93%95% CIa (7, 34) (80, 96) (23, 56) (87, 100)

P-valueb ˂ 0.0001 ˂ 0.0001

Change in platelet count from baseline to procedure day

Mean (SD) × 109/L 1.0 (9.3) 37.1 (27.4) 5.9 (14.9) 44.9 (33.0)

Median × 109/L 0.0 33.0 3.3 41.3

P-valuec ˂ 0.0001 ˂ 0.0001a Two-sided 95% confidence interval based on normal approximation.b Cochran-Mantel-Haenszel Test.c Wilcoxon Rank Sum Test.

A measured increase in platelet counts was observed in both avatrombopag treatment groups over timebeginning on Day 4 post-dose, which peaked on Day 10-13 and then returned to near baseline valuesby Day 35 (Figure 1); mean platelet count remained greater than or equal to 50 × 109/L on Day 17(Visit 5).

Figure 1: Mean platelet count (+/- standard error) by days from start of dosing by baselineplatelet count cohort and treatment group - pooled ADAPT-1 and ADAPT-2

The efficacy of avatrombopag was similar across various subgroups for the pooled Phase 3 studypopulation (ADAPT-1 and ADAPT-2). The proportion of subjects not requiring a platelet transfusionor any rescue procedure for bleeding was generally similar across the various subgroups.

The efficacy of Doptelet in adult patients with chronic immune thrombocytopenia was evaluated in a

Phase 3, multicentre, randomised, double-blind, placebo-controlled trial (Study 302). Patients hadpreviously received one or more prior chronic immune thrombocytopenia therapies and had anaverage of screening and baseline platelet counts < 30 × 109/L. Patients were centrally stratified bysplenectomy status, baseline platelet count (≤ 15 or > 15 × 109/L), and use of concomitant chronicimmune thrombocytopenia medicinal products, and then randomised (2:1) to receive eitheravatrombopag or placebo for 6 months. Patients received a starting dose of 20 mg once daily, withdoses subsequently titrated based on platelet response.

In addition, patients could taper off concomitant ITP medicinal products and receive rescue treatmentsas dictated by local standard of care. More than half of all patients in each treatment group had ≥ 3prior ITP therapies and 29% of placebo patients and 34% of avatrombopag patients had a priorsplenectomy.

Forty-nine patients were randomised, 32 to avatrombopag and 17 to placebo, with similar mean [SD]baseline platelet counts in the 2 treatment groups (14.1 [8.6] × 109/L and 12.7 [7.8] × 109/L,respectively). The median age was 44 years, 63% were female, and 94% were Caucasian, 4% Asianand 2% Black. A total of 8.2% of patients were ≥ 65 years of age, and no patients were ≥ 75 years ofage. The median duration of exposure was 26 weeks for avatrombopag-treated patients and 6 weeksfor placebo-treated patients. The primary efficacy outcome in this trial was the cumulative number ofweeks in which the platelet count was ≥ 50 × 109/L during the 6-month treatment period in the absenceof rescue therapy. Avatrombopag-treated patients had a longer duration of platelet counts ≥ 50 × 109/Lin the absence of rescue therapy than those who received placebo (median 12.4 [0, 25] vs 0 [0, 2]weeks, respectively, p < 0.0001) (see Table 6).

Table 6: Cumulative number of weeks of platelet response - Study 302

Primary efficacy outcome Avatrombopag Placebo(n = 32) (n = 17)

Cumulative number of weeks with a platelet response*

Mean (SD) 12.0 (8.75) 0.1 (0.49)

Median 12.4 0.0

Min, Max 0, 25 0, 2p-value of Wilcoxon rank sum test < 0.0001

* Cumulative number of weeks of platelet response is defined as the total numbers of weeks in whichthe platelet count was ≥ 50 × 109/L during 6 months of treatment in the absence of rescue therapy.

In addition, a larger proportion of patients in the avatrombopag treatment group had plateletcounts ≥ 50 × 109/L at Day 8 compared to placebo (21/32; 66% vs 0/17; 0.0%, respectively; 95% CI(47, 86); p < 0.0001). Though few subjects were receiving concomitant ITP medicinal products atbaseline, a larger proportion of patients in the avatrombopag treatment group had a reduction in use ofconcomitant ITP medicinal products from baseline compared to placebo (5/15; 33% vs 0/7; 0.0%,respectively; 95% CI (12, 62); p = 0.1348).

Persistent or chronic immune thrombocytopenia study in paediatric patients

The efficacy of Doptelet was evaluated in paediatric patients ≥ 1 to < 18 years of age with persistent orchronic immune thrombocytopenia in a randomized, double-blind, placebo-controlled trial. A 12-weekrandomized treatment phase (Core Phase) was followed by an optional Extension Phase in which allpatients received avatrombopag.

Patients were required to have had a diagnosis of primary ITP for ≥ 6 months and had an insufficientresponse to at least one previous treatment. The study enrolled 75 patients randomized 3:1avatrombopag: placebo in 3 age cohorts: ≥ 12 to < 18 years of age (n = 29); ≥ 6 to < 12 years of age(n = 28); and ≥ 1 to < 6 years of age (n = 18).

The primary endpoint was durable platelet response, defined as the proportion of patients achieving atleast 6 out of 8 weekly platelet counts ≥ 50×109/L during the last 8 weeks of the 12-week Treatment

Period in the Core Phase in the absence of rescue medication.

The alternative primary endpoint (analysed as a secondary endpoint) was platelet response, defined asthe proportion of subjects achieving at least 2 consecutive platelet assessments ≥ 50×109/L in the Core

Phase in the absence of rescue medication.

Table 7: Durable Platelet Response and Platelet Response - Phase 3 Trial in Paediatric Patientswith Persistent or Chronic ITP

Endpoint Avatrombopag (n = 54) Placebo (n = 21)

Durable platelet response, n% (primary)

Yes 15 (27.8) 0

No 39 (72.2) 21 (100.0)

Difference of proportion (avatrombopag - 27.8 (15.8, 39.7)placebo) (95% CI)

Cochran-Mantel-Haenszel (avatrombopag vs. p = 0.0077aplacebo) p-value

Platelet response, n% (alternative primary)

Yes 44 (81.5) 0

No 10 (18.5) 21 (100.0)

Difference of proportion (avatrombopag - 81.5 (71.1, 91.8)placebo) (95% CI)

Cochran-Mantel-Haenszel (avatrombopag vs. p < 0.0001aplacebo) p-valuea Denotes p-value from Fisher’s Exact Test, which was used in place of Cochran-Mantel-Haenszel test due tosparse number of responders in the strata.

Note: The Cochran-Mantel-Haenszel test is adjusted for age cohort and baseline platelet counts.

The proportion of subjects who required rescue therapy was significantly lower (p = 0.0008) in theavatrombopag group (7.4%) than in the placebo (42.9%) group.

The European Medicines Agency has waived the obligation to submit the results of studies with

Doptelet in all subsets of the paediatric population in thrombocytopenia secondary to liver disease (seesection 4.2 for information on paediatric use).

The plasma concentration-time profiles following the oral administration of avatrombopag werecharacterised by a short lag time (0.5 - 0.75 hours) with peak exposure at 6 - 8 hours post dose. In amultiple-dose pharmacokinetic study in healthy volunteers, steady state was reached by day 5 ofdosing. Open label, randomised, cross-over replicate design clinical trials were conducted in healthysubjects to assess the effects of high-fat and low-fat food on the bioavailability and pharmacokineticvariability of avatrombopag. Administration with either type of food did not have any clinicallyimportant effects on rate (Cmax) or extent (AUC) of avatrombopag exposure. However, there was asignificant reduction (by approximately 50%) in the between- and within-subject variability ofavatrombopag AUC and Cmax when administered with food (see sections 4.2 and 4.5).

Coadministration of avatrombopag with either a high-fat or low-fat meal did not result in clinicallyimportant changes in rate or extent of absorption of avatrombopag. However, administration ofavatrombopag with both a high and low-fat meal reduced intersubject and intrasubjectpharmacokinetic variability of avatrombopag by approximately 50%. Therefore, avatrombopag isrecommended to be administered with food (see section 4.2).

In vitro studies suggest that avatrombopag is highly bound to human plasma proteins (> 96%). Theapparent volume of distribution of avatrombopag in patients with thrombocytopenia and chronic liverdisease based on population pharmacokinetic analysis is approximately 180 L, and the apparentvolume of distribution with patients with chronic immune thrombocytopenia is approximately 235 L,suggesting that avatrombopag is extensively distributed.

The oxidative metabolism of avatrombopag is mainly mediated by CYP2C9 and CYP3A4/5.

Avatrombopag is a substrate for p-glycoprotein (P-gp) mediated transport, although no clinicallyimportant differences in platelet count elevations are expected when avatrombopag is co-administeredwith a strong P-gp inhibitor. Based on in vitro studies, no other transporting proteins (OATP1B1,

OATP1B3, OCT2, OAT1, and OAT3) are expected to play a significant role in the disposition ofavatrombopag.

Table 8: Drug interactions: Changes in pharmacokinetics of avatrombopag in the presence ofco-administered medicinal product

Geometric mean ratio[90% CI] of avatrombopag PK with/without

Co-administered medicinal product* co administered drug (No Effect = 1.00)

AUC0-inf Cmax

Strong CYP3A inhibitor

Itraconazole 1.37 1.07(1.10, 1.72) (0.86, 1.35)

Moderate CYP3A and CYP2C9 inhibitor

Fluconazole 2.16 1.17(1.71, 2.72) (0.96, 1.42)

Moderate CYP2C9 and strong CYP3A inducer

Rifampin 0.57 1.04(0.47, 0.62) (0.88, 1.23)

P-gp inhibitor

Cyclosporine 0.83 0.66(0.65, 1.04) (0.54, 0.82)

P-gp and moderate CYP3A inhibitor

Verapamil 1.61 1.26(1.21, 2.15) (0.96, 1.66)

* at steady state, except for cyclosporine which was administered as a single dose

Avatrombopag does not inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6,

CYP2E1, or CYP3A, does not induce CYP1A, CYP2B6, CYP2C, and CYP3A, and weakly induces

CYP2C8 and CYP2C9 in vitro.

Avatrombopag inhibits organic anion transporter (OAT) 1 and 3 and breast cancer resistance protein(BCRP) but not organic anion transporter polypeptide (OATP) 1B1 and 1B3, and organic cationtransporter (OCT) 2 in vitro.

Avatrombopag is a substrate for P-glycoprotein (P-gp) mediated transport (see Table 8).

Avatrombopag is not a substrate for OATP1B1, OATP1B3, OCT2, OAT1, and OAT3.

The predominant route of avatrombopag excretion is via faeces. Following administration of a single20 mg 14C-avatrombopag dose to healthy male volunteers, 88% of the dose was recovered in faecesand 6% in urine. Of the 88% of drug-related material in the faeces, 77% was identified as parent(34%) and the 4-hydroxy metabolite (44%). No metabolites of avatrombopag were detected in plasma.

The mean plasma elimination half-life (%CV) of avatrombopag is approximately 19 hours (19%). Themean (%CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29%).

Avatrombopag demonstrated dose-proportional pharmacokinetics after single doses from 10 mg(0.5-times the lowest approved dose) to 80 mg (1.3-times the highest recommended dose).

Population pharmacokinetic analysis of avatrombopag plasma concentrations from clinical trials withhealthy subjects and patients with thrombocytopenia due to chronic liver disease or healthy subjectsand patients with ITP, that included 11% (84/787) and 4% (24/577) of the study population ≥ 65 yearsof age, respectively, suggested that avatrombopag exposures are not affected by age (see section 4.2).

Population pharmacokinetic analysis of avatrombopag plasma concentrations from the clinical trialswith healthy subjects, patients with thrombocytopenia due to chronic liver disease, and patients with

ITP indicated that avatrombopag exposures were similar across the different races studied.

Human studies demonstrated that the renal route is not a major pathway for either unchangedavatrombopag or its metabolite’s elimination. Based on the known metabolic profile of avatrombopagand the fact that only 6% of the dose is excreted in urine, the likelihood of effects of renal impairmenton pharmacokinetics of avatrombopag is considered to be very low (see sections 4.2 and 4.8).

The population pharmacokinetic analysis of avatrombopag in healthy subjects and subjects withthrombocytopenia due to chronic liver disease indicated similar exposures between healthy subjectsand subjects with mild and moderate renal impairment (CrCL ≥ 30 mL/min, Cockcroft-Gault).

Pharmacokinetics and pharmacodynamics of avatrombopag have not been investigated in patients withsevere renal impairment (CrCL < 30 mL/min, Cockcroft-Gault) including patients requiringhaemodialysis.

A population pharmacokinetic analysis evaluated avatrombopag plasma exposures in patients withmild to moderate hepatic impairment based on Model for End-Stage Liver Disease (MELD) scoresand Child-Turcotte-Pugh scores. No clinically important difference in avatrombopag exposures wereobserved between patients with Child-Turcotte-Pugh Scores (Range = 5 to 12) or MELD scores(Range = 4 to 23) and healthy subjects. Avatrombopag plasma exposure was comparable in patientswith chronic liver disease secondary to viral hepatitis (n = 242), non-alcoholic steatohepatitis (n = 45)and alcoholic liver disease (n = 49) in the pivotal Phase 3 studies, and also comparable to that inhealthy subjects (n = 391). Due to the limited information available, avatrombopag should only beused in Child-Pugh class C patients when the expected benefit outweighs the expected risks.

Avatrombopag does not stimulate platelet production in mice, rats, monkeys, or dogs because of theunique TPO receptor specificity. Therefore, data from these animal studies do not fully modelpotential adverse effects related to platelet count increases due to avatrombopag in humans.

Effects in non-clinical trials were observed only at exposures considered sufficiently in excess of themaximum human exposure indicating little relevance to clinical use. The primary toxicity ofavatrombopag in pivotal repeated-dose studies was in the stomach at high doses with adequate safetymargins when compared to the exposure at the maximum recommended human dose; these effectswere reversible even in the chronic toxicity studies.

In two-year carcinogenicity studies in mice and rats, neuroendocrine cell (enterochromaffin-like cell,

ECL cell) gastric tumours (carcinoids) occurred in the stomach at high doses. The gastric carcinoidswere considered likely due to prolonged hypergastrinemia observed in toxicity studies.

Hypergastrinemia-related gastric carcinoids in rodents are generally considered to be of low risk orrelevance to humans.

Avatrombopag was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay orclastogenic in an in vitro human lymphocyte chromosomal aberrations assay or in an in vivo rat bonemarrow micronucleus assay.

In 4-week or longer repeated-dose toxicity studies, treatment-related gastric lesions were observed inmice, rats, and cynomolgus monkeys. In these species, avatrombopag was associated withhistopathologic changes in the fundic mucosa of the glandular stomach, characterised by degenerationof the glandular epithelium with a decrease in matured parietal cells. This effect was not associatedwith inflammatory response or any evidence of erosion or ulcer formation. The severity of gastriclesions was dependent on the dose and duration of avatrombopag administration and showed a cleartrend towards reversibility during the recovery period. The exposures (AUC) at doses that showed nogastric lesions across the species were 3- to 33-fold higher than the exposures in humans at themaximum recommended human dose (MRHD).

Avatrombopag did not affect fertility or early embryonic development in male rats at exposures22-times, or in female rats at exposures 114-times, the AUC observed in patients at the recommendeddose of 60 mg once daily.

Avatrombopag was present in milk of lactating rats after oral administration of radioactive labeledavatrombopag. The pharmacokinetic parameters of avatrombopag in milk were similar to those inplasma with an exposure ratio of avatrombopag-related radioactivity (milk to plasma) of 0.94.

In a 10-week juvenile toxicology study in rats, avatrombopag was administered at doses ranging from20 to 300 mg/kg/day. There were no test article-related mortality or clinical signs at doses up to300 mg/kg/day. In the stomach, dose-dependent degeneration, regenerative hyperplasia, and atrophyof the glandular epithelium occurred at 100 and 300 mg/kg/day; exposures at 100 mg/kg/day in malerats were 14-times the AUC in patients at the maximum recommended dose of 60 mg once daily.

Avatrombopag did not cause gastric changes in male juvenile rats at exposures 7 times the AUCobserved in patients at the maximum recommended dose of 60 mg once daily. An increased incidenceof background focal mineralization was also observed in the kidneys of females at 300 mg/kg/day(female rat exposure was 50-times the human exposure based on AUC at the 60 mg daily dose).

Lactose monohydrate

Microcrystalline cellulose (E460(i))

Crospovidone type B (E1202)

Silica, colloidal anhydrous (E551)

Magnesium stearate (E470b)

Poly(vinyl alcohol) (E1203)

Talc (E553b)

Macrogol 3350 (E1521)

Titanium dioxide (E171)

Iron oxide yellow (E172)

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Blister (polyamide and polyvinyl chloride-laminated aluminium film with push-through aluminiumand polyethylene terephthalate foil) containing either 10 or 15 film-coated tablets. Each cartoncontains one blister of 10 or 15 film-coated tablets or two blisters of 15 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

EU/1/19/1373/001

EU/1/19/1373/002

EU/1/19/1373/003

Date of first authorisation: 20 June 2019

Date of latest renewal: 09 February 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.