Doptelet 20 mg film-coated tablets

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

 

1. Name of the medicinal product

Doptelet 20 mg film-coated tablets

 

2. Qualitative and quantitative composition

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

Excipient with known effect

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

For the full list of excipients, see section 6.1.

 

3. Pharmaceutical form

Film-coated tablet (tablet).

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

 

4. Clinical particulars

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.

 

4.2 Posology and method of administration

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.

Posology

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

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.

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); however, given the short duration of treatment, no dose adjustment is recommended.

Hepatic impairment

No dosage 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 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 (see sections 4.4 and 5.2).

Paediatric population

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

Method of administration

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

 

4.3 Contraindications

Hypersensitivity to avatrombopag 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 x 10⁹/L receiving a thrombopoietin receptor agonist (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 genetic prothrombotic conditions (Factor V Leiden, Prothrombin 20210A, Antithrombin deficiency or Protein C or S deficiency). Doptelet should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts.

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, 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

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 strong CYP3A4/5 or CYP2C9 inhibitors increases avatrombopag exposure. 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).

Strong CYP3A4/5 or CYP2C9 inducers

Concomitant use of strong CYP3A4/5 or CYP2C9 inducers reduces avatrombopag exposure, and may result in a decreased effect on platelet counts; however, no dose adjustment is recommended (see section 5.2).

 

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. 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

The safety of avatrombopag was evaluated in two randomised, double-blind, placebo-controlled trials, Study 1 and Study 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.

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).

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

Description of selected adverse reactions

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

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

 

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.

 

5. Pharmacological properties

5.1 Pharmacodynamic properties

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

Mechanism of action

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

Clinical efficacy and safety

The efficacy and safety of avatrombopag for the treatment of adult patients with chronic liver disease and a platelet count < 50 x 10⁹/L who were scheduled to undergo a procedure were studied in 2 identically-designed multicenter, randomised, double-blind, placebo-controlled Phase 3 studies (Study 1 and Study 2). In each study, patients were assigned to the low baseline platelet count cohort (< 40 x 10⁹/L) or the high baseline platelet count cohort (≥ 40 to < 50 x 10⁹/L) based on their platelet 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 placebo once daily for 5 days, and patients in the high baseline platelet count cohort received 40 mg avatrombopag or matching placebo once daily for 5 days. Eligible patients were scheduled to undergo their procedure (low bleeding risk procedures, such as endoscopy and colonoscopy (60.8%); moderate bleeding 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 of treatment. 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, 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%) and from > 14 to < 24 (16.2%), and included patients with CTP Class A (56.4%), Class B (38.1%), and Class C (5.6%).

In Study 1, a total of 231 patients were randomised; 149 patients to the avatrombopag group and 82 patients to the placebo group. In the low baseline platelet count cohort, the mean baseline platelet count for the avatrombopag-treated group was 31.1 x 10⁹/L and for placebo-treated patients was 30.7 x 10⁹/L. In the high baseline platelet count cohort, the mean baseline platelet count for the avatrombopag-treated patients was 44.3 x 10⁹/L and for placebo-treated patients was 44.9 x 10⁹/L.

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

Responders were defined as patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomisation and up to 7 days following a scheduled procedure. Results are shown in Table 2.

Table 2: Efficacy results by baseline platelet count cohort and treatment group – Study 1 and Study 2

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

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

The efficacy of avatrombopag was similar across various subgroups for the pooled Phase 3 study population (Study 1 and Study 2). The proportion of subjects not requiring a platelet transfusion or any rescue procedure for bleeding was generally similar across the various subgroups.

Paediatric population

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 (see section 4.2 for information on paediatric use).

 

5.2 Pharmacokinetic properties

Absorption

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

Food interaction

Co-administration of avatrombopag with either a high-fat or low-fat meal did not result in clinically important changes in rate or extent of absorption of avatrombopag. However, administration of avatrombopag with both a high- and low-fat meal reduced inter-subject and intra-subject pharmacokinetic variability of avatrombopag by approximately 50%. Therefore, avatrombopag is recommended to be administered with food (see section 4.2).

Distribution

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

Biotransformation

The oxidative metabolism of avatrombopag is mainly mediated by CYP2C9 and CYP3A4. Avatrombopag is a substrate for p-glycoprotein (P-gp) mediated transport, although no clinically important differences in platelet count elevations are expected when avatrombopag is co-administered with 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 of avatrombopag.

Table 3: Drug interactions: Changes in pharmacokinetics of avatrombopag in the presence of co-administered drug

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

Effect of avatrombopag

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 cation transporter (OCT) 2 in vitro.

Effect of transporting proteins

Avatrombopag is a substrate for P-glycoprotein (P-gp) mediated transport (see Table 3). Avatrombopag is not a substrate for OATP1B1, OATP1B3, OCT2, OAT1, and OAT3.

Elimination

The predominant route of avatrombopag excretion is via faeces. Following administration of a single 20 mg ¹⁴C-avatrombopag dose to healthy male volunteers, 88% of the dose was recovered in faeces and 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%). The mean (%CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29%).

Linearity

Avatrombopag demonstrated dose-proportional pharmacokinetics after single doses from 10 mg (0.25-times the lowest approved dosage) to 80 mg (1.3-times the highest recommended dosage).

Special populations

Elderly

Population pharmacokinetic analysis of avatrombopag plasma concentrations from clinical studies with healthy subjects and patients with thrombocytopenia due to chronic liver disease, that included 11% (84/787) of the study population ≥ 65 years of age, suggested that avatrombopag exposures are not affected by age (see section 4.2).

Racial or Ethnic Groups

Population pharmacokinetic analysis of avatrombopag plasma concentrations from the clinical studies with healthy subjects and patients with thrombocytopenia due to chronic liver disease indicated that avatrombopag exposures were similar across the different races studied.

Renal impairment

Human studies demonstrated that the renal route is not a major pathway for either unchanged avatrombopag or its metabolite's elimination. Based on the known metabolic profile of avatrombopag and the fact that only 6% of the dose is excreted in urine, the likelihood of effects of renal impairment on 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 with thrombocytopenia due to chronic liver disease indicated similar exposures between healthy subjects and subjects with mild and moderate renal impairment (CrCL ≥ 30 mL/min, Cockcroft-Gault).

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

Hepatic impairment

A population pharmacokinetic analysis evaluated avatrombopag plasma exposures in patients with mild to moderate hepatic impairment based on Model for End-Stage Liver Disease (MELD) scores and Child-Turcotte-Pugh scores. No clinically important difference in avatrombopag exposures were observed 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 patients with 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 in healthy subjects (n = 391). Due to the limited information available, avatrombopag should only be used in Child-Pugh class C patients when the expected benefit outweighs the expected risks.

 

5.3 Preclinical safety data

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

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

Carcinogenesis

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 carcinoids were considered likely due to prolonged hypergastrinemia observed in toxicity studies. Hypergastrinemia-related gastric carcinoids in rodents are generally considered to be of low risk or relevance to humans.

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

Animal Toxicology and/or Pharmacology

In 4-week or longer repeated-dose toxicity studies, treatment-related gastric lesions were observed in mice, rats, and cynomolgus monkeys. In these species, avatrombopag was associated with histopathologic changes in the fundic mucosa of the glandular stomach, characterised by degeneration of the glandular epithelium with a decrease in matured parietal cells. This effect was not associated with inflammatory response or any evidence of erosion or ulcer formation. The severity of gastric lesions was dependent on the dose and duration of avatrombopag administration and showed a clear trend towards reversibility during the recovery period. The exposures (AUC) at doses that showed no gastric lesions across the species were 3- to 33-fold higher than the exposures in humans at the maximum recommended human dose (MRHD).

Reproductive and Developmental Toxicity

Avatrombopag did not affect fertility or early embryonic development in male rats at exposures 22-times, or in female rats at exposures 114-times, the AUC observed in patients at the recommended dose of 60 mg once daily.

Excretion in Milk

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

 

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose (E460(i))

Crospovidone type B (E1202)

Silica, colloidal anhydrous (E551)

Magnesium stearate (E470b)

Film coating

Poly(vinyl alcohol) (E1203)

Talc (E553b)

Macrogol 3350 (E1521)

Titanium dioxide (E171)

Iron oxide yellow (E172)

 

6.2 Incompatibilities

Not applicable.

 

6.3 Shelf life

5 years.

 

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

 

6.5 Nature and contents of container

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

Not all pack sizes may be marketed.

 

6.6 Special precautions for disposal and other handling

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

 

7. Marketing authorisation holder

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

 

8. Marketing authorisation number

EU/1/19/1373/001

EU/1/19/1373/002

 

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 20 June 2019

 

10. Date of revision of the text

09/10/2020

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.