Dabigatran

Selective serotonin norepinephrine re-uptake inhibitors (SNRIs) increased the risk of bleeding in RE-LY in all treatment groups, in co-administration with dabigatran.

Concomitant administration is expected to result in decreased dabigatran concentrations.

Selective serotonin re-uptake inhibitors (SSRIs) increased the risk of bleeding in RE-LY in all treatment groups, in co-administration with dabigatran.

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors 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.

It is recommended to reduce the dose of dabigatran to 75 mg ασ τreatment initiation on the day of surgery (1-4 hours after completed surgery) and then 150 mg as maintenance dose starting on the first day after surgery.

NSAIDs given for short-term analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use, NSAIDs increased the risk of bleeding by approximately 50% on both dabigatran etexilate and warfarin.

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).

Co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12% to 18% and 24% with 81 mg and 325 mg ASA, respectively.

When dabigatran was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and C_max were increased by about 1.6-fold and 1.5-fold, respectively. In view of the long half-life of amiodarone the potential for an interaction may exist for weeks after discontinuation of amiodarone.

Concomitant administration is expected to result in decreased dabigatran concentrations.

When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, increase of AUC by about 1.19-fold and C_max by about 1.15-fold was observed.

In young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. In addition, dabigatran AUC_τ,ss and C_max,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUC_τ,ss and C_max,ss were increased by about 30-40%.

When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC_0-∞ and C_max values increased by about 2.4-fold and 2.3-fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold, respectively, after a single dose of 400 mg. Concomitant treatment is contraindicated.

The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin.

Ketoconazole increased total dabigatran AUC_0-∞ and C_max values by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. Concomitant treatment is contraindicated.

When dabigatran was co-administered with pantoprazole, a decrease in the dabigatran AUC of approximately 30% was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with dabigatran in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of dabigatran.

Concomitant administration is expected to result in decreased dabigatran concentrations.

Posaconazole also inhibits P-gp to some extent but has not been clinically studied. Caution should be exercised when dabigatran is co-administered with posaconazole.

Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1,000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUC_τ,ss and C_max,ss were increased on average by 1.53-fold and 1.56-fold, respectively with concomitant quinidine.

Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total dabigatran peak and total exposure by 65.5% and 67%, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.

Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors. Concomitant use not recommended.

When a single dose of 75 mg dabigatran etexilate was coadministered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and C_max were increased by 1.73-fold and 1.95-fold, respectively. After multiple doses of ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is 1.56-fold and 1.46-fold for C_max and AUC, respectively.

Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (in steady state) increased the dabigatran AUC_τ,ss and C_max,ss by 1.49-fold and 1.65-fold, respectively, compared with dabigatran etexilate given alone. When a loading dose of 180 mg ticagrelor was given 2 hours after 110 mg dabigatran etexilate (in steady state), the increase of dabigatran AUC_τ,ss and C_max,ss was reduced to 1.27-fold and 1.23-fold, respectively, compared with dabigatran etexilate given alone. This staggered intake is the recommended administration for start of ticagrelor with a loading dose.

Concomitant administration of 90 mg ticagrelor b.i.d. (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted dabigatran AUC_τ,ss and C_max,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilate given alone.

When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the C_max and AUC of dabigatran were increased but the magnitude of this change differs depending on timing of administration and formulation of verapamil.

The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to the dabigatran etexilate intake (increase of C_max by about 2.8-fold and AUC by about 2.5-fold). The effect was progressively decreased with administration of an extended release formulation (increase of C_max by about 1.9-fold and AUC by about 1.7-fold) or administration of multiple doses of verapamil (increase of C_max by about 1.6-fold and AUC by about 1.5-fold).

There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increase of C_max by about 1.1-fold and AUC by about 1.2-fold). This is explained by completed dabigatran absorption after 2 hours.

There is limited amount of data from the use of dabigatran in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Dabigatran should not be used during pregnancy unless clearly necessary.

There are no clinical data of the effect of dabigatran on infants during breast-feeding.

Breast-feeding should be discontinued during treatment with dabigatran.

Women of childbearing potential

Women of childbearing potential should avoid pregnancy during treatment with dabigatran.

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).

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

Summary of the safety profile

The safety of dabigatran has been evaluated in ten phase III studies including 23,393 patients exposed to dabigatran (see Table 1).

Table 1. Number of patients studied, maximum daily dose in phase III studies:

In total, about 9% of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days), 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 3-7 below.

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 2 shows the adverse reactions identified from the primary VTE prevention studies after hip or knee replacement surgery, the study in the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation, and the studies in DVT/PE treatment and in 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).

Table 2. Adverse reactions:

Description of selected adverse reactions

Bleeding reactions

Due to the pharmacological mode of action, the use of dabigatran 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 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. 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. 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.

Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery

The table 3 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.

Table 3. Number (%) of patients experiencing the adverse reaction bleeding:

Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors

The table 4 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.

Table 4. Bleeding events in a study testing the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation:

Subjects randomized to dabigatran 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 had also a statistically significant lower total bleed rate. Subjects randomized to 110 mg dabigatran 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 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 therapy.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (DVT/PE treatment)

Table 5 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%.

Table 5. Bleeding events in the studies RE-COVER and RE-COVER II testing the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE):

Bleeding events for both treatments are counted from the first intake of dabigatran or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events, which occurred during dabigatran therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.

Table 6 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 as compared with those receiving warfarin.

Table 6. Bleeding events in study RE-MEDY testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE):

* HR not estimable as there is no event in either one cohort/treatment

Table 7 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.

Table 7. Bleeding events in study RE-SONATE testing prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE):

* HR not estimable as there is no event in either one treatment

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.