Prescription Drug Information: Dabigatran Etexilate (Page 3 of 8)

5.6 Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome


Direct-acting oral anticoagulants (DOACs), including dabigatran etexilate capsules, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple-positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

6 ADVERSE REACTIONS


The following clinically significant adverse reactions are described elsewhere in the labeling:
• Increased Risk of Thrombotic Events after Premature Discontinuation [see Warnings and Precautions (5.1)]
• Risk of Bleeding [see Warnings and Precautions (5.2)]
• Spinal/Epidural Anesthesia or Puncture [see Warnings and Precautions (5.3)]
• Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves [see Warnings and Precautions (5.4)]
• Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome [see Warnings and Precautions (5.6)]
The most serious adverse reactions reported with dabigatran etexilate capsules were related to bleeding [see Warnings and Precautions (5.2)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Trials

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation The RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study provided safety information on the use of two doses of dabigatran etexilate capsules and warfarin [see Clinical Studies ( 14.1)]. The numbers of patients and their exposures are described in Table 2. Limited information is presented on the 110 mg dosing arm because this dose is not approved.

Table 2 Summary of Treatment Exposure in RE-LY

Dabigatran etexilate capsules 110 mg twice daily Dabigatran etexilate capsules 150 mg twice daily Warfarin
Total number treated 5983 6059 5998
Exposure
> 12 months 4936 4939 5193
> 24 months 2387 2405 2470
Mean exposure (months) 20.5 20.3 21.3
Total patient-years 10,242 10,261 10,659

Drug Discontinuation in RE-LY
The rates of adverse reactions leading to treatment discontinuation were 21% for dabigatran etexilate capsules 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of dabigatran etexilate capsules were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).
Bleeding [see Warnings and Precautions ( 5.2)]
Table 3 shows the number of adjudicated major bleeding events during the treatment period in the RE-LY study, with the bleeding rate per 100 subject-years (%). Major bleeding is defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells, bleeding at a critical site or with a fatal outcome. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. Table 3 Adjudicated Major Bleeding Events in Treated Patients a

Event Dabigatran etexilate capsules 150 mg N = 6059 n (%/year b) Warfarin N = 5998 n (%/year b) Dabigatran etexilate capsules 150 mg vs Warfarin HR (95% CI)
Major Bleeding c 350 (3.47) 374 (3.58) 0.97 (0.84, 1.12)
Intracranial Hemorrhage (ICH) d 23 (0.22) 82 (0.77) 0.29 (0.18, 0.46)
Hemorrhagic Stroke e 6 (0.06) 40 (0.37) 0.16 (0.07, 0.37)
Other ICH 17 (0.17) 46 (0.43) 0.38 (0.22, 0.67)
Gastrointestinal 162 (1.59) 111 (1.05) 1.51 (1.19, 1.92)
Fatal Bleeding f 7 (0.07) 16 (0.15) 0.45 (0.19, 1.10)
ICH 3 (0.03) 9 (0.08) 0.35 (0.09, 1.28)
Non-intracranial g 4 (0.04) 7 (0.07) 0.59 (0.17, 2.02)

a Patients during treatment or within 2 days of stopping study treatment. Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.
b Annual event rate per 100 pt-years = 100 * number of subjects with event/subject-years. Subject-years is defined as cumulative number of days from first drug intake to event date, date of last drug intake + 2, death date (whatever occurred first) across all treated subjects divided by 365.25. In case of recurrent events of the same category, the first event was considered.
c Defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site or with fatal outcome.
d Intracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
e On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14 Clinical Studies.
f Fatal bleed: Adjudicated major bleed as defined above with investigator reported fatal outcome and adjudicated death with primary cause from bleeding.
g Non-intracranial fatal bleed: Adjudicated major bleed as defined above and adjudicated death with primary cause from bleeding but without symptomatic intracranial bleed based on investigator’s clinical assessment.
There was a higher rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate capsules 150 mg than in patients receiving warfarin (6.6% vs 4.2%, respectively). The risk of major bleeds was similar with dabigatran etexilate capsules 150 mg and warfarin across major subgroups defined by baseline characteristics (see Figure 1), with the exception of age, where there was a trend toward a higher incidence of major bleeding on dabigatran etexilate capsules (hazard ratio 1.2, 95% CI: 1.0 to 1.5) for patients ≥75 years of age.

Figure 1 Adjudicated Major Bleeding by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients

dabigatrancapfigure1
(click image for full-size original)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Gastrointestinal Adverse Reactions
Patients on dabigatran etexilate capsules 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).
Hypersensitivity Reactions
In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving dabigatran etexilate capsules.
Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
Dabigatran etexilate capsules were studied in 4387 patients in 4 pivotal, parallel, randomized, double-blind trials. Three of these trials were active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY), and one study (RE-SONATE) was placebo-controlled. The demographic characteristics were similar among the 4 pivotal studies and between the treatment groups within these studies. Approximately 60% of the treated patients were male, with a mean age of 55.1 years. The majority of the patients were white (87.7%), 10.3% were Asian, and 1.9% were black with a mean CrCl of 105.6 mL/min.
Bleeding events for the 4 pivotal studies were classified as major bleeding events if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L or more, or leading to transfusion of 2 or more units of whole blood or red cells).
RE-COVER and RE-COVER II studies compared dabigatran etexilate capsules 150 mg twice daily and warfarin for the treatment of deep vein thrombosis and pulmonary embolism. Patients received 5 to 10 days of an approved parenteral anticoagulant therapy followed by 6 months, with mean exposure of 164 days, of oral only treatment; warfarin was overlapped with parenteral therapy. Table 4 shows the number of patients experiencing bleeding events in the pooled analysis of RE-COVER and RE-COVER II studies during the full treatment including parenteral and oral only treatment periods after randomization. Table 4 Bleeding Events in RE-COVER and RE-COVER II Treated Patients

Bleeding Events-Full Treatment Period Including Parenteral Treatment
Dabigatran etexilate capsules 150 mg twice daily N (%) Warfarin N (%) Hazard Ratio (95% CI) c
Patients N=2553 N=2554
Major bleeding event a 37 (1.4) 51 (2.0) 0.73 (0.48, 1.11)
Fatal bleeding 1 (0.04) 2 (0.1)
Bleeding in a critical area or organ 7 (0.3) 15 (0.6)
Fall in hemoglobin ≥2 g/dL or transfusion ≥2 units of whole blood or packed red blood cells 32 (1.3) 38 (1.5)
Bleeding sites for MBE b
Intracranial 2 (0.1) 5 (0.2)
Retroperitoneal 2 (0.1) 1 (0.04)
Intraarticular 2 (0.1) 4 (0.2)
Intramuscular 2 (0.1) 6 (0.2)
Gastrointestinal 15 (0.6) 14 (0.5)
Urogenital 7 (0.3) 14 (0.5)
Other 8 (0.3) 8 (0.3)
Clinically relevant non-major bleeding 101 (4.0) 170 (6.7) 0.58 (0.46, 0.75)
Any bleeding 411 (16.1) 567 (22.7) 0.70 (0.61, 0.79)

Note: MBE can belong to more than one criterion.
a Patients with at least one MBE.
b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding.
c Confidence interval
The rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate capsules 150 mg in the full treatment period was 3.1% (2.4% on warfarin).
The RE-MEDY and RE-SONATE studies provided safety information on the use of dabigatran etexilate capsules for the reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism.
RE-MEDY was an active-controlled study (warfarin) in which 1430 patients received dabigatran etexilate capsules 150 mg twice daily following 3 to 12 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-MEDY study had a combined treatment duration of up to more than 3 years, with mean exposure of 473 days. Table 5 shows the number of patients experiencing bleeding events in the study. Table 5 Bleeding Events in RE-MEDY Treated Patients

Dabigatran etexilate capsules 150 mg twice daily N (%) Warfarin N (%) Hazard Ratio (95% CI) c
Patients N=1430 N=1426
Major bleeding event a 13 (0.9) 25 (1.8) 0.54 (0.25, 1.16)
Fatal bleeding 0 1 (0.1)
Bleeding in a critical area or organ 7 (0.5) 11 (0.8)
Fall in hemoglobin ≥2 g/dL or transfusion ≥2 units of whole blood or packed red blood cells 7 (0.5) 16 (1.1)
Bleeding sites for MBE b
Intracranial 2 (0.1) 4 (0.3)
Intraocular 4 (0.3) 2 (0.1)
Retroperitoneal 0 1 (0.1)
Intraarticular 0 2 (0.1)
Intramuscular 0 4 (0.3)
Gastrointestinal 4 (0.3) 8 (0.6)
Urogenital 1 (0.1) 1 (0.1)
Other 2 (0.1) 4 (0.3)
Clinically relevant non-major bleeding 71 (5.0) 125 (8.8) 0.56 (0.42, 0.75)
Any bleeding 278 (19.4) 373 (26.2) 0.71 (0.61, 0.83)

Note: MBE can belong to more than one criterion.
a Patients with at least one MBE.
b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding.
c Confidence interval
In the RE-MEDY study, the rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate capsules 150 mg was 3.1% (2.2% on warfarin).
RE-SONATE was a placebo-controlled study in which 684 patients received dabigatran etexilate capsules 150 mg twice daily following 6 to 18 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-SONATE study had combined treatment duration up to 9 months, with mean exposure of 165 days. Table 6 shows the number of patients experiencing bleeding events in the study. Table 6 Bleeding Events in RE-SONATE Treated Patients

Dabigatran etexilate capsules 150 mg twice daily N (%) Placebo N (%) Hazard Ratio (95% CI) c
Patients N=684 N=659
Major bleeding event a 2 (0.3) 0
Bleeding in a critical area or organ 0 0
Gastrointestinal b 2 (0.3) 0
Clinically relevant non-major bleeding 34 (5.0) 13 (2.0) 2.54 (1.34, 4.82)
Any bleeding 72 (10.5) 40 (6.1) 1.77 (1.20, 2.61)

Note: MBE can belong to more than one criterion.
a Patients with at least one MBE.
b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding.
c Confidence interval
In the RE-SONATE study, the rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate capsules 150 mg was 0.7% (0.3% on placebo).
Clinical Myocardial Infarction Events
In the active-controlled VTE studies, a higher rate of clinical myocardial infarction was reported in patients who received dabigatran etexilate capsules [20 (0.66 per 100 patient-years)] than in those who received warfarin [5 (0.17 per 100 patient-years)]. In the placebo-controlled study, a similar rate of nonfatal and fatal clinical myocardial infarction was reported in patients who received dabigatran etexilate capsules [1 (0.32 per 100 patient-years)] and in those who received placebo [1 (0.34 per 100 patient-years)].
Gastrointestinal Adverse Reactions
In the four pivotal studies, patients on dabigatran etexilate capsules 150 mg had a similar incidence of gastrointestinal adverse reactions (24.7% vs 22.7% on warfarin). Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred in patients on dabigatran etexilate capsules 7.5% vs 5.5% on warfarin, and gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage) occurred at 3.0% vs 1.7%, respectively.
Hypersensitivity Reactions
In the 4 pivotal studies, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in 0.1% of patients receiving dabigatran etexilate capsules.
Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

RxDrugLabels.com provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by RxDrugLabels.com. Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.

As a leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. RxDrugLabels.com provides the full prescription-only subset of the FDA's repository. Medication information provided here is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2022. All Rights Reserved.