Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Boehringer Ingelheim International GmbH, Binger Str. 173, 55216 Ingelheim am Rhein, Germany
Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors
ATC code: B01AE07
Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma. Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.
In vivo and ex vivo animal studies have demonstrated antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate after oral administration in various animal models of thrombosis.
There is a clear correlation between plasma dabigatran concentration and degree of anticoagulant effect based on phase II studies. Dabigatran prolongs the thrombin time (TT), ECT, and aPTT.
The calibrated quantitative diluted TT (dTT) test provides an estimation of dabigatran plasma concentration that can be compared to the expected dabigatran plasma concentrations. When the calibrated dTT assay delivers a dabigatran plasma concentration result at or below the limit of quantification, an additional coagulation assay such as TT, ECT or aPTT should be considered.
The ECT can provide a direct measure of the activity of direct thrombin inhibitors.
The aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. Although high aPTT values should be interpreted with caution, a high aPTT value indicates that the patient is anticoagulated.
In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see section 4.4, table 4) is considered to be associated with an increased risk of bleeding.
Steady state (after day 3) geometric mean dabigatran peak plasma concentration, measured around 2 hours after 220 mg dabigatran etexilate administration, was 70.8 ng/mL, with a range of 35.2-162 ng/mL (25th-75th percentile range).The dabigatran geometric mean trough concentration, measured at the end of the dosing interval (i.e. 24 hours after a 220 mg dabigatran dose), was on average 22.0 ng/mL, with a range of 13.0-35.7 ng/mL (25th-75th^ percentile range).
In a dedicated study exclusively in patients with moderate renal impairment (creatinine clearance, CrCL 30-50 mL/min) treated with dabigatran etexilate 150 mg QD, the dabigatran geometric mean trough concentration, measured at the end of the dosing interval, was on average 47.5 ng/mL, with a range of 29.6-72.2 ng/mL (25th-75th percentile range).
In patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mg dabigatran etexilate once daily,
The ECT was not measured in patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mg dabigatran etexilate once daily.
No clinically relevant ethnic differences among Caucasians, African-American, Hispanic, Japanese or Chinese patients were observed.
In 2 large randomised, parallel group, double-blind, dose-confirmatory trials, patients undergoing elective major orthopaedic surgery (one for knee replacement surgery and one for hip replacement surgery) received 75 mg or 110 mg dabigatran etexilate within 1-4 hours of surgery followed by 150 mg or 220 mg once daily thereafter, haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery and daily thereafter.
In the RE-MODEL trial (knee replacement) treatment was for 6-10 days and in the RE-NOVATE trial (hip replacement) for 28-35 days. Totals of 2,076 patients (knee) and 3,494 (hip) were treated respectively.
Composite of total VTE (including pulmonary embolism (PE), proximal and distal deep vein thrombosis (DVT), whatever symptomatic or asymptomatic detected by routine venography) and all-cause mortality constituted the primary end-point for both studies. Composite of major VTE (including PE and proximal DVT, whatever symptomatic or asymptomatic detected by routine venography) and VTE-related mortality constituted a secondary end-point and is considered of better clinical relevance.
Results of both studies showed that the antithrombotic effect of 220 mg and 150 mg dabigatran etexilate were statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. The point estimate for incidence of major VTE and VTE related mortality for the 150 mg dose was slightly worse than enoxaparin (table 13). Better results were seen with the 220 mg dose where the point estimate of Major VTE was slightly better than enoxaparin (table 13).
The clinical studies have been conducted in a patient population with a mean age >65 years.
There were no differences in the phase 3 clinical studies for efficacy and safety data between men and women.
In the studied patient population of RE-MODEL and RE-NOVATE (5,539 patients treated), 51% suffered from concomitant hypertension, 9% from concomitant diabetes, 9% from concomitant coronary artery disease and 20% had a history of venous insufficiency. None of these diseases showed an impact on the effects of dabigatran on VTE-prevention or bleeding rates.
Data for the major VTE and VTE-related mortality endpoint were homogeneous with regards to the primary efficacy endpoint and are shown in table 13.
Data for the total VTE and all cause mortality endpoint are shown in table 14.
Data for adjudicated major bleeding endpoints are shown in table 15 below.
Table 13. Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL and the RE-NOVATE orthopaedic surgery studies:
| Trial | Dabigatran etexilate 220 mg | Dabigatran etexilate 150 mg | Enoxaparin 40 mg |
|---|---|---|---|
| RE-NOVATE (hip) | |||
| N | 909 | 888 | 917 |
| Incidences (%) | 28 (3.1) | 38 (4.3) | 36 (3.9) |
| Risk ratio over enoxaparin | 0.78 | 1.09 | |
| 95 % CI | 0.48, 1.27 | 0.70, 1.70 | |
| RE-MODEL (knee) | |||
| N | 506 | 527 | 511 |
| Incidences (%) | 13 (2.6) | 20 (3.8) | 18 (3.5) |
| Risk ratio over enoxaparin | 0.73 | 1.08 | |
| 95 % CI | 0.36, 1.47 | 0.58, 2.01 | |
Table 14. Analysis of total VTE and all cause mortality during the treatment period in the RE-NOVATE and the RE-MODEL orthopaedic surgery studies:
| Trial | Dabigatran etexilate 220 mg | Dabigatran etexilate 150 mg | Enoxaparin 40 mg |
|---|---|---|---|
| RE-NOVATE (hip) | |||
| N | 880 | 874 | 897 |
| Incidences (%) | 53 (6.0) | 75 (8.6) | 60 (6.7) |
| Risk ratio over enoxaparin | 0.9 | 1.28 | |
| 95 % CI | (0.63, 1.29) | (0.93, 1.78) | |
| RE-MODEL (knee) | |||
| N | 503 | 526 | 512 |
| Incidences (%) | 183 (36.4) | 213 (40.5) | 193 (37.7) |
| Risk ratio over enoxaparin | 0.97 | 1.07 | |
| 95 % CI | (0.82, 1.13) | (0.92, 1.25) | |
Table 15. Major bleeding events by treatment in the individual RE-MODEL and the RE-NOVATE studies:
| Trial | Dabigatran etexilate 220 mg | Dabigatran etexilate 150 mg | Enoxaparin 40 mg |
|---|---|---|---|
| RE-NOVATE (hip) | |||
| Treated patients N | 1,146 | 1,163 | 1,154 |
| Number of MBE N (%) | 23 (2.0) | 15 (1.3) | 18 (1.6) |
| RE-MODEL (knee) | |||
| Treated patients N | 679 | 703 | 694 |
| Number of MBE N (%) | 10 (1.5) | 9 (1.3) | 9 (1.3) |
A phase II study examined dabigatran etexilate and warfarin in a total of 252 patients with recent mechanical valve replacement surgery (i.e. within the current hospital stay) and in patients who received a mechanical heart valve replacement more than three months ago. More thromboembolic events (mainly strokes and symptomatic/asymptomatic prosthetic valve thrombosis) and more bleeding events were observed with dabigatran etexilate than with warfarin. In the early post-operative patients, major bleeding manifested predominantly as haemorrhagic pericardial effusions, specifically in patients who started dabigatran etexilate early (i.e. on Day 3) after heart valve replacement surgery (see section 4.3).
The European Medicines Agency has waived the obligation to submit the results of studies with Pradaxa in all subsets of the paediatric population in prevention of thromboembolic events for the indication of primary prevention of VTE in patients who have undergone elective total hip replacement surgery or total knee replacement surgery (see section 4.2 for information on paediatric use).
The DIVERSITY study was conducted to demonstrate the efficacy and safety of dabigatran etexilate compared to standard of care (SOC) for the treatment of VTE in paediatric patients from birth to less than 18 years of age. The study was designed as an open-label, randomised, parallel-group, noninferiority study. Patients enrolled were randomised according to a 2:1 scheme to either an age-appropriate formulation (capsules, coated granules or oral solution) of dabigatran etexilate (doses adjusted for age and weight) or SOC comprised of low molecular weight heparins (LMWH) or vitamin K antagonists (VKA) or fondaparinux (1 patient 12 years old). The primary endpoint was a composite endpoint of patients with complete thrombus resolution, freedom from recurrent VTE, and freedom from mortality related to VTE. Exclusion criteria included active meningitis, encephalitis and intracranial abscess.
In total, 267 patients had been randomised. Of those, 176 patients were treated with dabigatran etexilate and 90 patients according to SOC (1 randomised patient was not treated). 168 patients were 12 to less than 18 years old, 64 patients 2 to less than 12 years, and 35 patients were younger than 2 years.
Of the 267 randomised patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients (42.2%) in the SOC group met the criteria for the composite primary endpoint (complete thrombus resolution, freedom from recurrent VTE, and freedom from mortality-related VTE). The corresponding rate difference demonstrated non-inferiority of dabigatran etexilate to SOC. Consistent results were also generally observed across subgroups: there were no significant differences in the treatment effect for the subgroups by age, sex, region, and presence of certain risk factors. For the 3 different age strata, the proportions of patients that met the primary efficacy endpoint in the dabigatran etexilate and SOC groups, respectively, were 13/22 (59.1%) and 7/13 (53.8%) for patients from birth to <2 years, 21/43 (48.8%) and 12/21 (57.1%) for patients aged 2 to <12 years, and 47/112 (42.0%) and 19/56 (33.9%) for patients aged 12 to <18 years.
Adjudicated major bleeds were reported for 4 patients (2.3%) in the dabigatran etexilate group and 2 patients (2.2%) in the SOC group. There was no statistically significant difference in the time to first major bleeding event. Thirty-eight patients (21.6%) in the dabigatran etexilate arm and 22 patients (24.4%) in the SOC arm had any adjudicated bleeding event, most of them categorised as minor. The combined endpoint of adjudicated major bleeding event (MBE) or clinically relevant non-major (CRNM) bleeding (on treatment) was reported for 6 (3.4%) patients in the dabigatran etexilate group and 3 (3.3%) patients in the SOC group.
An open label, single arm safety prospective cohort, multi-centre, phase III study (1160.108) was conducted to assess the safety of dabigatran etexilate for the prevention of recurrent VTE in paediatric patients from birth to less than 18 years. Patients who required further anticoagulation due to the presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study were allowed to be included in the study. Eligible patients received age and weight adjusted doses of an age-appropriate formulation (capsules, coated granules or oral solution) of dabigatran etexilate until the clinical risk factor resolved, or up to a maximum of 12 months. The primary endpoints of the study included the recurrence of VTE, major and minor bleeding events and the mortality (overall and related to thrombotic or thromboembolic events) at 6 and 12 months. Outcome events were adjudicated by an independent blinded adjudication committee.
Overall, 214 patients entered the study; among them 162 patients in age stratum 1 (from 12 to less than 18 years of age), 43 patients in age stratum 2 (from 2 to less than 12 years of age) and 9 patients in age stratum 3 (from birth to less than 2 years of age). During the on-treatment period, 3 patients (1.4%) had an adjudication-confirmed recurrent VTE within the first 12 months after treatment start. Adjudication-confirmed bleeding events during the on-treatment period were reported for 48 patients (22.5%) within the first 12 months. The majority of the bleeding events were minor. In 3 patients(1.4%), an adjudication-confirmed major bleeding event occurred within the first 12 months. For 3 patients (1.4%), adjudication-confirmed CRNM bleeding was reported within the first 12 months. No on-treatment deaths occurred. During the on-treatment period, 3 patients (1.4%) developed postthrombotic syndrome (PTS) or had worsening of PTS within the first 12 months.
After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the active form in plasma. The cleavage of the prodrug dabigatran etexilate by esterase-catalysed hydrolysis to the active principle dabigatran is the predominant metabolic reaction. The absolute bioavailability of dabigatran following oral administration of Pradaxa was approximately 6.5%.
After oral administration of Pradaxa in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0 hours post administration.
A study evaluating post-operative absorption of dabigatran etexilate, 1-3 hours following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached at 6 hours following administration in a postoperative period due to contributing factors such as anaesthesia, gastrointestinal paresis, and surgical effects independent of the oral medicinal product formulation. It was demonstrated in a further study that slow and delayed absorption is usually only present on the day of surgery. On subsequent days absorption of dabigatran is rapid with peak plasma concentrations attained 2 hours after medicinal product administration.
Food does not affect the bioavailability of dabigatran etexilate but delays the time to peak plasma concentrations by 2 hours.
Cmax and AUC were dose proportional.
The oral bioavailability may be increased by 75% after a single dose and 37% at steady state compared to the reference capsule formulation when the pellets are taken without the Hydroxypropylmethylcellulose (HPMC) capsule shell. Hence, the integrity of the HPMC capsules should always be preserved in clinical use to avoid unintentionally increased bioavailability of dabigatran etexilate (see section 4.2).
Low (34-35%) concentration independent binding of dabigatran to human plasma proteins was observed. The volume of distribution of dabigatran of 60–70 L exceeded the volume of total body water indicating moderate tissue distribution of dabigatran.
Metabolism and excretion of dabigatran were studied following a single intravenous dose of radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived radioactivity was eliminated primarily in the urine (85%). Faecal excretion accounted for 6% of the administered dose. Recovery of the total radioactivity ranged from 88-94% of the administered dose by 168 hours post dose.
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10% of total dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of approximately 100 mL/min corresponding to the glomerular filtration rate.
Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as shown in table 13.
In phase I studies the exposure (AUC) of dabigatran after the oral administration of Pradaxa is approximately 2.7-fold higher in volunteers with moderate renal insufficiency (CrCL between 30-50 mL/min) than in those without renal insufficiency.
In a small number of volunteers with severe renal insufficiency (CrCL 10-30 mL/min), the exposure (AUC) to dabigatran was approximately 6 times higher and the half-life approximately 2 times longer than that observed in a population without renal insufficiency (see sections 4.2, 4.3 and 4.4).
Table 16. Half-life of total dabigatran in healthy subjects and subjects with impaired renal function:
| glomerular filtration rate (CrCL,) [mL/min] | gMean (gCV%; range) half-life [h] |
|---|---|
| ≥80 | 13.4 (25.7 %; 11.0-21.6) |
| ≥50-<80 | 15.3 (42.7 %;11.7-34.1) |
| ≥30-<50 | 18.4 (18.5 %;13.3-23.0) |
| <30 | 27.2 (15.3 %; 21.6-35.0) |
Additionally, dabigatran exposure (at trough and peak) was assessed in a prospective open label randomised pharmacokinetic study in NVAF patients with severe renal impairment (defined as creatinine clearance [CrCl] 15-30 mL/min) receiving dabigatran etexilate 75 mg twice daily. This regimen resulted in a geometric mean trough concentration of 155 ng/ml (gCV of 76.9%), measured immediately before administration of the next dose and in a geometric mean peak concentration of 202 ng/ml (gCV of 70.6%) measured two hours after the administration of the last dose.
Clearance of dabigatran by haemodialysis was investigated in 7 patients with end-stage renal disease (ESRD) without atrial fibrillation. Dialysis was conducted with 700 mL/min dialysate flow rate, four hour duration and a blood flow rate of either 200 mL/min or 350-390 mL/min. This resulted in a removal of 50% to 60% of dabigatran concentrations, respectively. The amount of substance cleared by dialysis is proportional to the blood flow rate up to a blood flow rate of 300 mL/min. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the PK/PD relationship was not affected by the procedure.
Specific pharmacokinetic phase I studies with elderly subjects showed an increase of 40 to 60% in the AUC and of more than 25% in Cmax compared to young subjects.
The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 31% higher trough concentration for subjects ≥75 years and by about 22% lower trough level for subjects <65 years compared to subjects between 65 and 75 years (see sections 4.2 and 4.4).
No change in dabigatran exposure was seen in 12 subjects with moderate hepatic insufficiency (Child Pugh B) compared to 12 controls (see sections 4.2 and 4.4).
The dabigatran trough concentrations were about 20% lower in patients with a body weight >100 kg compared with 50-100 kg. The majority (80.8%) of the subjects were in the ≥50 kg and <100 kg category with no clear difference detected (see sections 4.2 and 4.4). Limited clinical data in patients <50 kg are available.
Active substance exposure in the primary VTE prevention studies was about 40% to 50% higher in female patients and no dose adjustment is recommended.
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding dabigatran pharmacokinetics and pharmacodynamics.
Oral administration of dabigatran etexilate according to the protocol defined dosing algorithm resulted in exposure within the range observed in adults with DVT/PE. Based on the pooled analysis of pharmacokinetic data of studies DIVERSITY and 1160.108, the observed geometric mean trough exposures were 53.9 ng/mL, 63.0 ng/mL and 99.1 ng/mL in 0 to <2-year-old, 2 to <12-year-old and 12 to <18-year-old paediatric VTE patients, respectively.
In vitro interaction studies did not show any inhibition or induction of the principal isoenzymes of cytochrome P450. This has been confirmed by in vivo studies with healthy volunteers, who did not show any interaction between this treatment and the following active substances: atorvastatin (CYP3A4), digoxin (P-gp transporter interaction) and diclofenac (CYP2C9).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Effects observed in the repeated dose toxicity studies were due to the exaggerated pharmacodynamic effect of dabigatran.
An effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (5-fold the plasma exposure level in patients). At doses that were toxic to the mothers (5- to 10-fold the plasma exposure level in patients), a decrease in foetal body weight and viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).
In a juvenile toxicity study conducted in Han Wistar rats, mortality was associated with bleeding events at similar exposures, at which bleeding was seen in adult animals. In both adult and juvenile rats, mortality is considered to be related to the exaggerated pharmacological activity of dabigatran in association with the exertion of mechanical forces during dosing and handling. Data of the juvenile toxicity study did neither indicate an increased sensitivity in toxicity, nor any toxicity specific to juvenile animals.
In lifetime toxicology studies in rats and mice, there was no evidence for a tumorigenic potential of dabigatran up to maximum doses of 200 mg/kg.
Dabigatran, the active moiety of dabigatran etexilate mesilate, is persistent in the environment.
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