Doptelet

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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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 

Platelet count (x109/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. 



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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). 



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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.  



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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). 
 
System organ class 
(MedDRA terminology*) Common Uncommon 

Blood and lymphatic system disorders  Anaemia 
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. 
 
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 the national reporting system 
listed in Appendix V. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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. 
 



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

Category 

Study 1 Study 2 

Placebo 
 

(n = 48) 

Avatrombopag 
60 mg 

(n = 90) 

Placebo 
 

(n = 43) 

Avatrombopag 
60 mg 

(n = 70) 
Proportion of subjects not requiring a platelet transfusion or rescue procedure for bleeding 

Responders 
95% CIa 

23% 
(11, 35) 

66% 
(56, 75) 

35% 
(21, 49) 

69% 
(58, 79) 

P-valueb ˂ 0.0001 0.0006 
Proportion of subjects who achieved a platelet count ≥ 50 × 109/L on procedure day 

Responders 
95% CIa 

4% 
(0, 10) 

69% 
(59, 79) 

7% 
(0, 15) 

67% 
(56, 78) 

P-valueb ˂ 0.0001 ˂ 0.0001 
Change in platelet count from baseline to procedure day 

Mean (SD) x 109/L 0.8 (6.4) 32.0 (25.5) 3.0 (10.0) 31.3 (24.1) 
Median x 109/L 0.5 28.3 0.5 28.0 

P-valuec ˂ 0.0001 ˂ 0.0001 
   

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

Category 

Study 1 Study 2 
Placebo 

 
(n = 34) 

Avatrombopag 
40 mg 

(n = 59) 

Placebo 
 

(n = 33) 

Avatrombopag 
40 mg 

(n = 58) 

Proportion of subjects not requiring a platelet transfusion or rescue procedure for bleeding 
Responders 
95% CIa 

38% 
(22, 55) 

88% 
(80, 96) 

33% 
(17, 49) 

88% 
(80, 96) 

P-valueb ˂ 0.0001 ˂ 0.0001 
Proportion of subjects who achieved a platelet count ≥ 50 × 109/L on procedure day 

Responders 
95% CIa 

21% 
(7, 34) 

88% 
(80, 96) 

39% 
(23, 56) 

93% 
(87, 100) 

P-valueb ˂ 0.0001 ˂ 0.0001 
Change in platelet count from baseline to procedure day 

Mean (SD) x 109/L 1.0 (9.3) 37.1 (27.4) 5.9 (14.9) 44.9 (33.0) 
Median x 109/L 0.0 33.0 3.3 41.3 

P-valuec ˂ 0.0001 ˂ 0.0001 

a 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 time 
beginning on Day 4 post-dose, which peaked on Day 10-13 and then returned to near baseline values 



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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). 
 



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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 (Cmax) 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 Cmax 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. 



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

Co-administered drug* 

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

co administered drug (No Effect = 1.00) 

AUC0-inf Cmax 

Strong CYP3A inhibitor 

Itraconazole 1.37 (1.10, 1.72) 
1.07 

(0.86, 1.35) 

Moderate CYP3A and CYP2C9 inhibitor 

Fluconazole 2.16 (1.71, 2.72) 
1.17 

(0.96, 1.42) 

Moderate CYP2C9 and strong CYP3A inducer 

Rifampin 0.57 (0.47, 0.62) 
1.04 

(0.88, 1.23) 

P-gp inhibitor 

Cyclosporine 0.83 (0.65, 1.04) 
0.66 

(0.54, 0.82) 

P-gp and moderate CYP3A inhibitor 

Verapamil 1.61 (1.21, 2.15) 
1.26 

(0.96, 1.66) 
* 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%). 
 



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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. 
 



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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) 
 



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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 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Dova Pharmaceuticals Ireland Limited 
6th Floor, 2 Grand Canal Square 
Dublin 2 
D02 A342 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
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 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 

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


14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



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A.  MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Cilatus Manufacturing Services 
2 Harbour Square 
Crofton Road 
Dun Laoghaire 
Co. Dublin 
IRELAND 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription. 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are 
set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines 
web-portal. 
 
The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



18 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Doptelet 20 mg film-coated tablets 
avatrombopag 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains avatrombopag maleate equivalent to 20 mg of avatrombopag. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
15 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



19 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dova Pharmaceuticals Ireland Limited 
6th Floor, 2 Grand Canal Square 
Dublin 2 
D02 A342 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1373/001 
EU/1/19/1373/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Doptelet 20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 



20 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Doptelet 20 mg tablets 
avatrombopag 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dova Pharmaceuticals Ireland, Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



22 

Package leaflet: Information for the patient 
 

Doptelet 20 mg film-coated tablets 
avatrombopag  

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Doptelet is and what it is used for 
2. What you need to know before you take Doptelet 
3. How to take Doptelet 
4. Possible side effects 
5. How to store Doptelet 
6. Contents of the pack and other information 
 
 
1. What Doptelet is and what it is used for 
 
Doptelet contains an active substance called avatrombopag. It belongs to a group of medicines called 
thrombopoietin receptor agonists. 
 
Doptelet is used in adults with chronic liver disease to treat low platelet count (called 
thrombocytopenia) before having a medical procedure where there is a risk of bleeding. 
 
Doptelet works by helping to increase the number of platelets in the blood. Platelets are blood cells 
that help the blood to clot and so reduce or prevent bleeding. 
 
 
2. What you need to know before you take Doptelet 
 
Do not take Doptelet if: 
- you are allergic to avatrombopag or any of the other ingredients of this medicine (listed in 

section 6). If you are not sure, talk to your doctor or pharmacist before taking Doptelet. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Doptelet if: 
- you are at risk of blood clots in your veins or arteries, or members of your family have had 

blood clots. 
 
You may be at higher risk of blood clots as you get older or if: 
- you have had to stay in bed for a long time 
- you have cancer 
- you are taking the contraceptive birth control pill or hormone replacement therapy 
- you have recently had surgery or been injured 



23 

- you are very overweight 
- you smoke  
- you have advanced chronic liver disease. 
 
If any of the above applies to you, or you are not sure, talk to your doctor or pharmacist before taking 
Doptelet. 
 
Children and adolescents 
Do not give Doptelet to people less than 18 years old. The safety and effectiveness of this medicine in 
this age group is not known. 
 
Other medicines and Doptelet  
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Pregnancy and breast-feeding  
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. Doptelet is not recommended in pregnancy and in 
women who are able to have children and are not using contraception. 
 
If you are breast-feeding, ask your doctor or pharmacist for advice before taking Doptelet. This 
medicine can pass into breast milk. Your doctor will help you decide whether the benefit of 
breast-feeding outweighs any possible risks to your baby while you are breast-feeding. 
 
Driving and using machines 
Doptelet is not expected to affect you being able to drive, cycle or use tools or machines. 
 
Doptelet contains lactose 
Doptelet contains lactose (a type of sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine. 
 
 
3. How to take Doptelet 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. You should be scheduled to undergo your procedure 5 to 8 days after 
the last dose of Doptelet. 
 
How much to take 
• Doptelet is available in 20 mg tablets. The usual recommended dose is either 40 mg (2 tablets) or 

60 mg (3 tablets) every day for 5 days in a row. 
• Your dose will depend on your platelet counts. 
• Your doctor or pharmacist will tell you how many tablets to take and when to take them. 

 
Taking this medicine 
• Start taking Doptelet 10 to 13 days before your planned medical procedure. 
• Swallow the tablets whole, once daily with food. 
 
If you take more Doptelet than you should 
• Talk to a doctor or pharmacist straight away. 
 
If you forget to take Doptelet 
• Take your missed dose as soon as you remember, then take your next dose at the usual time. 
• Do not take a double dose to make up for a forgotten dose. 
 



24 

If you stop taking Doptelet 
Take Doptelet for as long as your doctor tells you. Do not stop taking Doptelet unless your doctor tells 
you to. 
 
If you have any questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor or pharmacist if you notice any of the following side effects: 
 
Common (may affect up to 1 in 10 people) 
• feeling tired 
 
Uncommon (may affect up to 1 in 100 people) 
• low red blood cell count (anaemia) 
• blood clot in the portal vein (blood vessel that carries blood to the liver from the intestines) 

which may result in upper abdominal pain or swelling 
• bone pain 
• muscle aches 
• fever 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Doptelet 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on each blister after 
‘EXP’. The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Doptelet contains  
- The active substance is avatrombopag. Each film-coated tablet contains avatrombopag maleate 

equivalent to 20 mg of avatrombopag. 
 

- The other ingredients are: 
Tablet core: lactose monohydrate (see section 2 “Doptelet contains lactose”); 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]. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


25 

What Doptelet looks like and contents of the pack 
Doptelet 20 mg film-coated tablets are pale yellow, round, rounded on the upper and lower side, 
marked with “AVA” imprinted on one side and “20” on the other. 
 
The tablets are supplied in cartons containing one aluminium blister. Each blister contains either 
10 or 15 tablets. 
 
Marketing Authorisation Holder 
Dova Pharmaceuticals Ireland, Limited 
6th Floor, 2 Grand Canal Square 
Dublin 2 
D02 A342 
Ireland 
 
Manufacturer 
Cilatus Manufacturing Services 
2 Harbour Square 
Crofton Road 
Dun Laoghaire 
Co. Dublin 
IRELAND 
 
This leaflet was last revised in MM/YYYY. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A.  MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET