Dabigatran Sandoz

White to light yellow colored blend compressing granular powder, pellets in Size "2", "1", or "0" capsules, having white opaque cap imprinted "MD" and white opaque body imprinted "75","110", or "150", respectively, with black ink.
Each hard capsule contains 75 mg, 110 mg, or 150 mg of Dabigatran etexilate (as mesilate), respectively.
Excipients/Inactive Ingredients: Capsule content: Tartaric acid, Hypromellose, Talc, Hydroxy propyl cellulose, Croscarmellose sodium, Magnesium stearate.
Capsule shell: Titanium dioxide (E171), Hypromellose (E 464).
Black printing ink: Shellac, Dehydrated alcohol, Isopropyl alcohol, Butyl alcohol, Propylene glycol, Strong ammonia solution, Potassium hydroxide, Iron oxide black (E172), Potassium hydroxide.

Pharmacotherapeutic group: Antithrombotic agents, direct thrombin inhibitors. ATC code: B01AE07.
Pharmacology: Pharmacodynamics: Mechanism of action: 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.
Pharmacodynamic effects: 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 90^th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough (for aPTT thresholds see Table 6 under Precautions) is considered to be associated with an increased risk of bleeding.
Clinical efficacy and safety: Ethnic origin: No clinically relevant ethnic differences among Caucasians, African-American, Hispanic, Japanese or Chinese patients were observed.
Pharmacokinetics: 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 Dabigatran etexilate was approximately 6.5%.
After oral administration of Dabigatran etexilate in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in plasma concentrations with C_max attained within 0.5 and 2.0 hours post administration.
Absorption: 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, GI 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.
C_max 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 Dosage & Administration).
Distribution: 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.
Biotransformation: 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.
Elimination: 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 1.
Special populations: Renal insufficiency: In phase I studies the exposure (AUC) of dabigatran after the oral administration of Dabigatran etexilate is approximately 2.7-fold higher in volunteers with moderate renal insufficiency (CrCL between 30 and 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 Dosage & Administration, Contraindications and Precautions). (See Table 1.)

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Additionally, dabigatran exposure (at trough and peak) was assessed in a prospective open label randomized 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.
The median CrCL in RE-LY was 68.4 mL/min. Almost half (45.8%) of the RE-LY patients had a CrCL >50-<80 mL/min. Patients with moderate renal impairment (CrCL between 30-50 mL/min) had on average 2.29-fold and 1.81-fold higher pre- and post-dose dabigatran plasma concentrations, respectively, when compared with patients without renal impairment (CrCL ≥80 mL/min).
The median CrCL in the RE-COVER study was 100.4 mL/min. 21.7% of patients had mild renal impairment (CrCL >50-<80 mL/min) and 4.5% of patients had a moderate renal impairment (CrCL between 30 and 50 mL/min). Patients with mild and moderate renal impairment had at steady state an average 1.8-fold and 3.6-fold higher pre-dose dabigatran plasma concentrations compared with patients with CrCL >80 mL/min, respectively. Similar values for CrCL were found in RE-COVER II.
The median CrCL in the RE-MEDY and RE-SONATE studies were 99.0 mL/min and 99.7 mL/min, respectively. 22.9% and 22.5% of the patients had a CrCL >50-<80 mL/min, and 4.1% and 4.8% had a CrCL between 30 and 50 mL/min in the RE-MEDY and RESONATE studies.
Elderly patients: Specific pharmacokinetic phase I studies with elderly subjects showed an increase of 40 to 60% in the AUC and of more than 25% in C_max 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 Dosage & Administration and Precautions).
Hepatic impairment: No change in dabigatran exposure was seen in 12 subjects with moderate hepatic insufficiency (Child Pugh B) compared to 12 controls (see Dosage & Administration and Precautions).
Body weight: 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 Dosage & Administration and Precautions). Limited clinical data in patients <50 kg are available.
Gender: Active substance exposure in the primary VTE prevention studies was about 40% to 50% higher in female patients and no dose adjustment is recommended. In atrial fibrillation patients females had on average 30% higher trough and post-dose concentrations. No dose adjustment is required (see Dosage & Administration).
Ethnic origin: No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding dabigatran pharmacokinetics and pharmacodynamics.
Pharmacokinetic interactions: 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).
Toxicology: Preclinical safety data: 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 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.

Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischemic attack (TIA); age ≥75 years; heart failure (NYHA Class ≥II); diabetes mellitus; hypertension.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Posology: Primary prevention of Venous Thromboembolism in Orthopaedic Surgery: The recommended doses of Dabigatran etexilate and the duration of therapy for primary prevention of venous thromboembolism in orthopaedic surgery are shown in Table 2. (See Table 2.)

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For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules once daily.
Assessment of renal function prior to and during Dabigatran etexilate treatment: In all patients and especially in the elderly (>75 years), as renal impairment may be frequent in this age group: Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Dabigatran etexilate to exclude patients with severe renal impairment (i.e. CrCL <30 mL/min) (see Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions).
Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).
The method to be used to estimate renal function (CrCL in mL/min) is the Cockcroft-Gault method.
It is recommended to continue with the remaining daily doses of Dabigatran etexilate at the same time of the next day.
No double dose should be taken to make up for missed individual doses.
Discontinuation of Dabigatran etexilate: Dabigatran etexilate treatment should not be discontinued without medical advice. Patients should be instructed to contact the treating physician if they develop gastrointestinal symptoms such as dyspepsia (see Adverse Reactions).
Switching: Dabigatran etexilate treatment to parenteral anticoagulant: It is recommended to wait 24 hours after the last dose before switching from Dabigatran etexilate to a parenteral anticoagulant (see Interactions).
Parenteral anticoagulants to Dabigatran etexilate: The parenteral anticoagulant should be discontinued and Dabigatran etexilate should be started 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see Interactions).
Special populations: Renal impairment: Treatment with Dabigatran etexilate in patients with severe renal impairment (CrCL <30 mL/min) is contraindicated (see Contraindications).
In patients with moderate renal impairment (CrCL 30-50 mL/min), a dose reduction is recommended (see Table 2 as previously mentioned, Precautions and Pharmacology: Pharmacodynamics under Actions).
Concomitant use of Dabigatran etexilate with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil: Dosing should be reduced as indicated in Table 2 (see also Precautions and Interactions). In this situation Dabigatran etexilate and these medicinal products should be taken at the same time.
In patients with moderate renal impairment and concomitantly treated with verapamil, a dose reduction of Dabigatran etexilate to 75 mg daily should be considered (see Precautions and Interactions).
Elderly: For elderly patients >75 years, a dose reduction is recommended (see Table 2 as previously mentioned, and Precautions and Pharmacology: Pharmacodynamics under Actions).
Weight: There is very limited clinical experience in patients with a body weight <50 kg or >110 kg at the recommended posology. Given the available clinical and kinetic data no adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions), but close clinical surveillance is recommended (see Precautions).
Gender: No dose adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: There is no relevant use of Dabigatran etexilate in the paediatric population for the indication of primary prevention of venous thromboembolic events in patients who have undergone elective total hip replacement surgery or total knee replacement surgery.
Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors (SPAF): Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE): The recommended doses of Dabigatran etexilate in the indications SPAF, DVT and PE are shown in Table 3. (See Table 3.)

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For DVT/PE the recommendation for the use of Dabigatran etexilate 220 mg taken as one 110 mg capsule twice daily is based on pharmacokinetic and pharmacodynamic analyses and has not been studied in this clinical setting. See following text and Precautions, Interactions, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions.
In case of intolerability to Dabigatran etexilate, patients should be instructed to immediately consult their treating physician in order to be switched to alternate acceptable treatment options for prevention of stroke and systemic embolism associated with atrial fibrillation or for DVT/PE.
Assessment of renal function prior to and during Dabigatran etexilate treatment: In all patients and especially in the elderly (>75 years), as renal impairment may be frequent in this age group: Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Dabigatran etexilate to exclude patients with severe renal impairment (i.e. CrCL <30 mL/min) (see Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions).
Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).
Additional requirements in patients with mild to moderate renal impairment and in patients aged over 75 years: Renal function should be assessed during treatment with Dabigatran etexilate at least once a year or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).
The method to be used to estimate renal function (CrCL in mL/min) is the Cockcroft-Gault method.
Duration of use: The duration of use of Dabigatran etexilate in the indications SPAF, DVT and PE are shown in Table 4. (See Table 4.)

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Missed dose: A forgotten Dabigatran etexilate dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted.
No double dose should be taken to make up for missed individual doses.
Discontinuation of Dabigatran etexilate: Dabigatran etexilate treatment should not be discontinued without medical advice. Patients should be instructed to contact the treating physician if they develop gastrointestinal symptoms such as dyspepsia (see Adverse Reactions).
Switching: Dabigatran etexilate treatment to parenteral anticoagulant: It is recommended to wait 12 hours after the last dose before switching from Dabigatran etexilate to a parenteral anticoagulant (see Interactions).
Parenteral anticoagulants to Dabigatran etexilate: The parenteral anticoagulant should be discontinued and Dabigatran etexilate should be started 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see Interactions).
Dabigatran etexilate treatment to Vitamin K antagonists (VKA): The starting time of the VKA should be adjusted based on CrCL as follows: CrCL ≥50 mL/min, VKA should be started 3 days before discontinuing Dabigatran etexilate; CrCL ≥30-<50 mL/min, VKA should be started 2 days before discontinuing Dabigatran etexilate.
Because Dabigatran etexilate can impact the International Normalized Ratio (INR), the INR will better reflect VKA's effect only after Dabigatran etexilate has been stopped for at least 2 days. Until then, INR values should be interpreted with caution.
VKA to Dabigatran etexilate: The VKA should be stopped. Dabigatran etexilate can be given as soon as the INR is <2.0.
Cardioversion (SPAF): Patients can stay on Dabigatran etexilate while being cardioverted.
Catheter ablation for atrial fibrillation (SPAF): There are no data available for 110 mg twice daily Dabigatran etexilate treatment.
Percutaneous coronary intervention (PCI) with stenting (SPAF): Patients with non valvular atrial fibrillation who undergo a PCI with stenting can be treated with Dabigatran etexilate in combination with antiplatelets after haemostasis is achieved (see Pharmacology: Pharmacodynamics under Actions).
Special populations: Elderly: For dose modifications in this population see Table 3 as previously mentioned.
Patients at risk of bleeding: Patients with an increased bleeding risk (see Precautions, Interactions, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions) should be closely monitored clinically (looking for signs of bleeding or anaemia). Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient (see Table 3 as previously mentioned). A coagulation test (see Precautions) may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. When excessive dabigatran exposure is identified in patients at high risk of bleeding, a reduced dose of 220 mg taken as one 110 mg capsule twice daily is recommended. When clinically relevant bleeding occurs, treatment should be interrupted.
For subjects with gastritis, esophagitis, or gastroesophageal reflux, a dose reduction may be considered due to the elevated risk of major gastro-intestinal bleeding (see Table 3 as previously mentioned and Precautions).
Renal impairment: Treatment with Dabigatran etexilate in patients with severe renal impairment (CrCL <30 mL/min) is contraindicated (see Contraindications).
No dose adjustment is necessary in patients with mild renal impairment (CrCL 50-≤80 mL/min). For patients with moderate renal impairment (CrCL 30-50 mL/min) the recommended dose of Dabigatran etexilate is also 300 mg taken as one 150 mg capsule twice daily. However, for patients with high risk of bleeding, a dose reduction of Dabigatran etexilate to 220 mg taken as one 110 mg capsule twice daily should be considered (see Precautions and Pharmacology: Pharmacokinetics under Actions). Close clinical surveillance is recommended in patients with renal impairment.
Concomitant use of Dabigatran etexilate with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil: No dose adjustment is necessary for concomitant use of amiodarone or quinidine (see Precautions, Interactions and Pharmacology: Pharmacokinetics under Actions).
Dose reductions are recommended for patients who receive concomitantly verapamil (see Table 3 as previously mentioned and Precautions and Interactions). In this situation Dabigatran etexilate and verapamil should be taken at the same time.
Weight: No dose adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions), but close clinical surveillance is recommended in patients with a body weight <50 kg (see Precautions).
Gender: No dose adjustment is necessary (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: There is no relevant use of Dabigatran etexilate in the paediatric population for the indication of prevention of stroke and systemic embolism in patients with NVAF.
For the indication DVT/PE, the safety and efficacy of Dabigatran etexilate in children from birth to less than 18 years of age have not yet been established. Currently available data are described in Adverse Reactions and Pharmacology: Pharmacodynamics under Actions, but no recommendation on a posology can be made.
Method of administration: Dabigatran etexilate is for oral use.
The capsules can be taken with or without food. Dabigatran etexilate should be swallowed as a whole with a glass of water, to facilitate delivery to the stomach.
Patients should be instructed not to open the capsule as this may increase the risk of bleeding (see Pharmacology: Pharmacokinetics under Actions and Special precautions for disposal and other handling under Cautions for Usage).

Dabigatran etexilate doses beyond those recommended expose the patient to increased risk of bleeding.
In case of an overdose suspicion, coagulation tests can help to determine a bleeding risk (see Precautions and Pharmacology: Pharmacodynamics under Actions). A calibrated quantitative dTT test or repetitive dTT measurements allow prediction of the time by when certain dabigatran levels will be reached (see Pharmacology: Pharmacodynamics under Actions), also in case additional measures e.g. dialysis have been initiated.
Excessive anticoagulation may require interruption of Dabigatran etexilate treatment. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained. As protein binding is low, dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies (see Pharmacology: Pharmacokinetics under Actions).
Management of bleeding complications: In the event of haemorrhagic complications, Dabigatran etexilate treatment must be discontinued and the source of bleeding investigated. Depending on the clinical situation appropriate supportive treatment, such as surgical haemostasis and blood volume replacement, should be undertaken at the prescriber's discretion.
For situations when rapid reversal of the anticoagulant effect of Dabigatran etexilate is required the specific reversal agent (idarucizumab) antagonizing the pharmacodynamic effect of Dabigatran etexilate is available (see Precautions).
Coagulation factor concentrates (activated or non-activated) or recombinant Factor VIIa may be taken into account. There is some experimental evidence to support the role of these medicinal products in reversing the anticoagulant effect of dabigatran, but data on their usefulness in clinical settings and also on the possible risk of rebound thromboembolism is very limited. Coagulation tests may become unreliable following administration of suggested coagulation factor concentrates. Caution should be exercised when interpreting these tests. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet medicinal products have been used. All symptomatic treatment should be given according to the physician's judgement.
Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Patients with severe renal impairment (CrCL <30 mL/min).
Active clinically significant bleeding.
Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances. These are switching anticoagulant therapy (see Dosage & Administration), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see Interactions).
Hepatic impairment or liver disease expected to have any impact on survival.
Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir (see Interactions)
Prosthetic heart valves requiring anticoagulant treatment (see Pharmacology: Pharmacodynamics under Actions).

Haemorrhagic risk: Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy with Dabigatran etexilate. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site.
For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent (idarucizumab) is available (see Overdosage).
In clinical trials, Dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) bleeding. An increased risk was seen in the elderly (≥75 years) for the 150 mg twice daily dose regimen. Further risk factors (see also Table 5) comprise comedication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal anti-inflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux.
Risk factors: Table 5 summarises factors which may increase the haemorrhagic risk. (See Table 5.)

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Limited data is available in patients <50 kg (see Pharmacology: Pharmacokinetics under Actions).
Precautions and management of the haemorrhagic risk: For the management of bleeding complications, see also Overdosage.
Benefit-risk assessment: The presence of lesions, conditions, procedures and/or pharmacological treatment (such as NSAIDs, antiplatelets, SSRIs and SNRIs, see Interactions), which significantly increase the risk of major bleeding requires a careful benefit-risk assessment. Dabigatran etexilate should only be given if the benefit outweighs bleeding risks.
Close clinical surveillance: Close observation for signs of bleeding or anaemia is recommended throughout the treatment period, especially if risk factors are combined (see Table 5 as previously mentioned). Particular caution should be exercised when Dabigatran etexilate is co-administered with verapamil, amiodarone, quinidine or clarithromycin (P-gp inhibitors) and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment (see Interactions).
Close observation for signs of bleeding is recommended in patients concomitantly treated with NSAIDs (see Interactions).
Discontinuation of Dabigatran etexilate: Patients who develop acute renal failure must discontinue Dabigatran etexilate (see also Contraindications).
When severe bleedings occur, treatment must be discontinued, the source of bleeding investigated and use of the specific reversal agent idarucizumab may be considered (see Management of bleeding complications under Overdosage).
Dose reduction: A dose reduction should be either considered or is recommended as indicated in Dosage & Administration.
Use of proton-pump inhibitors: The administration of a proton-pump inhibitor (PPI) can be considered to prevent GI bleeding.
Laboratory coagulation parameters: Although Dabigatran etexilate does not in general require routine anticoagulant monitoring, the measurement of dabigatran related anticoagulation may be helpful to detect excessive high exposure to dabigatran in the presence of additional risk factors.
Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but results should be interpreted with caution due to inter-test variability (see Pharmacology: Pharmacodynamics under Actions). The International Normalised Ratio (INR) test is unreliable in patients on Dabigatran etexilate and false positive INR elevations have been reported. Therefore, INR tests should not be performed.
Table 6 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding (see Pharmacology: Pharmacodynamics under Actions). (See Table 6.)

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Use of fibrinolytic medicinal products for the treatment of acute ischemic stroke: The use of fibrinolytic medicinal products for the treatment of acute ischemic stroke may be considered if the patient presents with a dTT, ECT or aPTT not exceeding the upper limit of normal (ULN) according to the local reference range.
Surgery and interventions: Patients on Dabigatran etexilate who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore, surgical interventions may require the temporary discontinuation of Dabigatran etexilate.
Patients can stay on Dabigatran etexilate while being cardioverted. There are no data available for 110 mg twice daily Dabigatran etexilate treatment in patients undergoing catheter ablation for atrial fibrillation (see Dosage & Administration).
Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see Pharmacology: Pharmacokinetics under Actions). This should be considered in advance of any procedures. In such cases a coagulation test (see Precautions and Pharmacology: Pharmacodynamics under Actions) may help to determine whether haemostasis is still impaired.
Emergency surgery or urgent procedures: Dabigatran etexilate should be temporarily discontinued. When rapid reversal of the anticoagulation effect is required the specific reversal agent (idarucizumab) to Dabigatran etexilate is available.
Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Dabigatran etexilate treatment can be re-initiated 24 hours after administration of idarucizumab, if the patient is clinically stable and adequate haemostasis has been achieved.
Subacute surgery/interventions: Dabigatran etexilate should be temporarily discontinued. A surgery/intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention.
Elective surgery: If possible, Dabigatran etexilate should be discontinued at least 24 hours before invasive or surgical procedures. In patients at higher risk of bleeding or in major surgery where complete haemostasis may be required consider stopping Dabigatran etexilate 2-4 days before surgery.
Table 7 summarises discontinuation rules before invasive or surgical procedures. (See Table 7.)

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Spinal anaesthesia/epidural anaesthesia/lumbar puncture: Procedures such as spinal anaesthesia may require complete haemostatic function.
The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of Dabigatran etexilate. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.
Postoperative phase: Dabigatran etexilate treatment should be resumed/started after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.
Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 mL/min), should be treated with caution (see Precautions and Pharmacology: Pharmacodynamics under Actions).
Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events: There are limited efficacy and safety data for Dabigatran etexilate available in these patients and therefore they should be treated with caution.
Hip fracture surgery: There is no data on the use of Dabigatran etexilate in patients undergoing hip fracture surgery. Therefore treatment is not recommended.
Hepatic impairment: Patients with elevated liver enzymes >2 ULN were excluded in the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of Dabigatran etexilate is not recommended in this population. Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see Contraindications).
Interaction with P-gp inducers: Concomitant administration of P-gp inducers is expected to result in decreased dabigatran plasma concentrations, and should be avoided (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs) including Dabigatran etexilate are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
Myocardial Infarction (MI): In the phase III study RE-LY (SPAF, see Pharmacology: Pharmacodynamics under Actions) the overall rate of MI was 0.82, 0.81, and 0.64%/year for Dabigatran etexilate 110 mg twice daily, Dabigatran etexilate 150 mg twice daily and warfarin, respectively, an increase in relative risk for dabigatran of 29% and 27% compared to warfarin. Irrespective of therapy, the highest absolute risk of MI was seen in the following subgroups, with similar relative risk: patients with previous MI, patients ≥65 years with either diabetes or coronary artery disease, patients with left ventricular ejection fraction <40%, and patients with moderate renal dysfunction. Furthermore a higher risk of MI was seen in patients concomitantly taking ASA plus clopidogrel or clopidogrel alone.
In the three active controlled DVT/PE phase III studies, a higher rate of MI was reported in patients who received Dabigatran etexilate than in those who received warfarin: 0.4% vs. 0.2% in the short-term RE-COVER and RE-COVER II studies; and 0.8% vs. 0.1% in the long-term RE-MEDY trial. The increase was statistically significant in this study (p=0.022).
In the RE-SONATE study, which compared Dabigatran etexilate to placebo, the rate of MI was 0.1% for patients who received Dabigatran etexilate and 0.2% for patients who received placebo.
Active Cancer Patients (DVT/PE): The efficacy and safety have not been established for DVT/PE patients with active cancer.
Information about excipients: Dabigatran etexilate contains less than 1 mmol sodium (23 mg) per hard capsules, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: Dabigatran etexilate has no or negligible influence on the ability to drive and use machines.

Women of childbearing potential: Women of childbearing potential should avoid pregnancy during treatment with Dabigatran etexilate.
Pregnancy: There is limited amount of data from the use of Dabigatran etexilate in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown.
Dabigatran etexilate should not be used during pregnancy unless clearly necessary.
Breast-feeding: There are no clinical data of the effect of dabigatran on infants during breast-feeding. Breastfeeding should be discontinued during treatment with Dabigatran etexilate.
Fertility: No human data available.
In animal studies 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 (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal 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).

Summary of the safety profile: Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64,000 patients; thereof approximately 35,000 patients were treated with Dabigatran etexilate. In total, 22% of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14% of patients treated for DVT/PE and 15% of patients treated for DVT/PE prevention experienced adverse reactions.
The most commonly reported events are bleedings occurring in approximately 14% of patients treated short-term for elective hip or knee replacement surgery, 16.6% in patients with atrial fibrillation treated long-term for the prevention of stroke and systemic embolism, and in 14.4% of patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4% of patients in the DVT/PE prevention trial RE-MEDY and in 10.5% of patients in the DVT/PE prevention trial RE-SONATE.
Since the patient populations treated in the three indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and provided in Tables 9-13 as follows.
Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.
Tabulated list of adverse reactions: Table 8 shows the adverse reactions identified from studies and post-marketing data in the indications primary VTE prevention after hip or knee replacement surgery, prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation, DVT/PE treatment and DVT/PE prevention. They are ranked under headings of System Organ Class (SOC) and frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 8.)

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Description of selected adverse reactions: Bleeding reactions: Due to the pharmacological mode of action, the use of Dabigatran etexilate may be associated with an increased risk of occult or overt bleeding from any tissue or organ. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia. In the clinical studies mucosal bleedings (e.g. gastrointestinal, genitourinary) were seen more frequently during long term Dabigatran etexilate treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit is of value to detect occult bleeding. The risk of bleedings may be increased in certain patient groups e.g. those patients with moderate renal impairment and/or on concomitant treatment affecting haemostasis or strong P-gp inhibitors (see Haemorrhagic risk under Precautions). Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock.
Known bleeding complications such as compartment syndrome and acute renal failure due to hypoperfusion have been reported for Dabigatran etexilate. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient. A specific reversal agent for dabigatran, idarucizumab, is available in case of uncontrollable bleeding (see Overdosage).
Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery: The Table 9 shows the number (%) of patients experiencing the adverse reaction bleeding during the treatment period in the VTE prevention in the two pivotal clinical trials, according to dose. (See Table 9.)

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Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors: The Table 10 shows bleeding events broken down to major and any bleeding in the pivotal study testing the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation. (See Table 10.)

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Subjects randomized to Dabigatran etexilate 110 mg twice daily or 150 mg twice daily had a significantly lower risk for life-threatening bleeds and intracranial bleeding compared to warfarin [p<0.05]. Both dose strengths of Dabigatran etexilate had also a statistically significant lower total bleed rate. Subjects randomized to 110 mg Dabigatran etexilate twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.81 [p=0.0027]). Subjects randomized to 150 mg Dabigatran etexilate twice daily had a significantly higher risk for major GI bleeds compared with warfarin (hazard ratio 1.48 [p=0.0005]. This effect was seen primarily in patients ≥75 years.
The clinical benefit of dabigatran with regard to stroke and systemic embolism prevention and decreased risk of ICH compared to warfarin is preserved across individual subgroups, e.g. renal impairment, age, concomitant medicinal product use such as anti-platelets or P-gp inhibitors. While certain patient subgroups are at an increased risk of major bleeding when treated with an anticoagulant, the excess bleeding risk for dabigatran is due to GI bleeding, typically seen within the first 3-6 months following initiation of Dabigatran etexilate therapy.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (DVT/PE treatment): Table 11 shows bleeding events in the pooled pivotal studies RE-COVER and RE-COVER II testing the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). In the pooled studies the primary safety endpoints of major bleeding, major or clinically relevant bleeding and any bleeding were significantly lower than warfarin at a nominal alpha level of 5%. (See Table 11.)

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Bleeding events for both treatments are counted from the first intake of Dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events, which occurred during Dabigatran etexilate therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.
Table 12 shows bleeding events in pivotal study RE-MEDY testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). Some bleeding events (MBEs/CRBEs; any bleeding) were significantly lower at a nominal alpha level of 5% in patients receiving Dabigatran etexilate as compared with those receiving warfarin. (See Table 12.)

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Table 13 shows bleeding events in pivotal study RE-SONATE testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). The rate of the combination of MBEs/CRBEs and the rate of any bleeding was significantly lower at a nominal alpha level of 5% in patients receiving placebo as compared with those receiving Dabigatran etexilate. (See Table 13.)

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Agranulocytosis and neutropenia: Agranulocytosis and neutropenia have been reported very rarely during post approval use of Dabigatran etexilate. Because adverse reactions are reported in the postmarketing surveillance setting from a population of uncertain size, it is not possible to reliably determine their frequency. The reporting rate was estimated as 7 events per 1 million patient years for agranulocytosis and as 5 events per 1 million patient years for neutropenia.
Paediatric population (DVT/PE): In the clinical study 1160.88 in total, 9 adolescent patients (age 12 to <18 years) with diagnosis of primary VTE received an initial oral dose of Dabigatran etexilate of 1.71 (±10%) mg/kg bodyweight. Based on dabigatran concentrations as determined by the diluted thrombin time test and clinical assessment, the dose was adjusted to the target dose of 2.14 (±10%) mg/kg bodyweight of Dabigatran etexilate. On treatment 2 (22.1%) patients experienced mild related adverse events (gastrooesophageal reflux/abdominal pain; abdominal discomfort) and 1 (11.1%) patient experienced a not related serious adverse event (recurrent VTE of the leg) in the post treatment period >3 days after stop of Dabigatran etexilate.

Transporter interactions: Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see Table 14) is expected to result in increased dabigatran plasma concentrations.
If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions may be required in combination with some P-gp inhibitors (see Dosage & Administration, Contraindications, Precautions and Pharmacology: Pharmacodynamics under Actions). (See Table 14.)

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Anticoagulants and antiplatelet aggregation medicinal products: There is no or only limited experience with the following treatments which may increase the risk of bleeding when used concomitantly with Dabigatran etexilate: anticoagulants such as unfractionated heparin (UFH), low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic medicinal products, and vitamin K antagonists, rivaroxaban or other oral anticoagulants (see Contraindications), and antiplatelet aggregation medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see Precautions).
From the data collected in the phase III study RE-LY (see Pharmacology: Pharmacodynamics under Actions) it was observed that the concomitant use of other oral or parenteral anticoagulants increases major bleeding rates with both Dabigatran etexilate and warfarin by approximately 2.5-fold, mainly related to situations when switching from one anticoagulant to another (see Contraindications). Furthermore, concomitant use of antiplatelets, ASA or clopidogrel approximately doubled major bleeding rates with both Dabigatran etexilate and warfarin (see Precautions).
UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter or during catheter ablation for atrial fibrillation (see Contraindications). (See Table 15.)

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Other interactions: See Table 16.

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Interactions linked to Dabigatran etexilate and dabigatran metabolic profile: Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no in vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactions are not expected with dabigatran.

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Special precautions for storage: No special storage conditions are required.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AE07 - dabigatran etexilate ; Belongs to the class of direct thrombin inhibitors. Used in the treatment of thrombosis.

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