Prescription Drug Information: Dabigatran Etexilate (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dabigatran was not carcinogenic when administered by oral gavage to mice and rats for up to 2 years. The highest doses tested (200 mg/kg/day) in mice and rats were approximately 3.6 and 6 times, respectively, the human exposure at MRHD of 300 mg/day based on AUC comparisons.
Dabigatran was not mutagenic in in vitro tests, including bacterial reversion tests, mouse lymphoma assay and chromosomal aberration assay in human lymphocytes, and the in vivo micronucleus assay in rats.
In the rat fertility study with oral gavage doses of 15, 70, and 200 mg/kg, males were treated for 29 days prior to mating, during mating up to scheduled termination, and females were treated 15 days prior to mating through gestation Day 6. No adverse effects on male or female fertility were observed at 200 mg/kg or 9 to 12 times the human exposure at MRHD of 300 mg/day based on AUC comparisons. However, the number of implantations decreased in females receiving 70 mg/kg, or 3 times the human exposure at MRHD based on AUC comparisons.

14 CLINICAL STUDIES

14.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients

The clinical evidence for the efficacy of dabigatran etexilate capsules was derived from RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy), a multi-center, multi-national, randomized, parallel group trial comparing two blinded doses of dabigatran etexilate capsules (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more of the following additional risk factors:
• Previous stroke, transient ischemic attack (TIA), or systemic embolism
• Left ventricular ejection fraction <40%
• Symptomatic heart failure, ≥ New York Heart Association Class 2
• Age ≥75 years
• Age ≥65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or hypertension
The primary objective of this study was to determine if dabigatran etexilate capsules were non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism. The study was designed to ensure that dabigatran etexilate capsules preserved more than 50% of warfarin’s effect as established by previous randomized, placebo-controlled trials of warfarin in atrial fibrillation. Statistical superiority was also analyzed.
A total of 18,113 patients were randomized and followed for a median of 2 years. The patients’ mean age was 71.5 years and the mean CHADS 2 score was 2.1. The patient population was 64% male, 70% Caucasian, 16% Asian, and 1% black. Twenty percent of patients had a history of a stroke or TIA and 50% were Vitamin K antagonist (VKA) naïve, defined as less than 2 months total lifetime exposure to a VKA. Thirty-two percent of the population had never been exposed to a VKA. Concomitant diseases of patients in this trial included hypertension 79%, diabetes 23%, and CAD 28%. At baseline, 40% of patients were on aspirin and 6% were on clopidogrel. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2 to 3) was 64%.
Relative to warfarin and to dabigatran etexilate capsules 110 mg twice daily, dabigatran etexilate capsules 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism (see Table 11 and Figure 4).
Table 11 First Occurrence of Stroke or Systemic Embolism in the RE-LY Study *

Dabigatran etexilatecapsules150 mg twice daily Dabigatran etexilatecapsules 110 mg twice daily Warfarin
Patients randomized 6076 6015 6022
Patients (% per yr) with events 135 (1.12%) 183 (1.54%) 203 (1.72%)
Hazard ratio vs. warfarin (95% CI) 0.65 (0.52, 0.81) 0.89 (0.73, 1.09)
P-value for superiority 0.0001 0.27
Hazard ratio vs. dabigatran etexilate capsules110 mg (95% CI) 0.72 (0.58, 0.91)
P-value for superiority 0.005

* Randomized ITT
Figure 4 Kaplan-Meier Curve Estimate of Time to First Stroke or Systemic Embolism

Dabigatrancapfigure4
(click image for full-size original)

The contributions of the components of the composite endpoint, including stroke by subtype, are shown in Table 12. The treatment effect was primarily a reduction in stroke. Dabigatran etexilate capsules 150 mg twice daily was superior in reducing ischemic and hemorrhagic strokes relative to warfarin. Table 12 Strokes and Systemic Embolism in the RE-LY Study

Dabigatran etexilate capsules 150 mg twice daily Warfarin Hazard ratio vs. warfarin (95% CI)
Patients randomized 6076 6022
Stroke 123 187 0.64 (0.51, 0.81)
Ischemicstroke 104 134 0.76 (0.59, 0.98)
Hemorrhagic stroke 12 45 0.26 (0.14, 0.49)
Systemicembolism 13 21 0.61 (0.30, 1.21)

In the RE-LY trial, the rate of all-cause mortality was lower on dabigatran etexilate capsules 150 mg than on warfarin (3.6% per year versus 4.1% per year). The rate of vascular death was lower on dabigatran 150 mg compared to warfarin (2.3% per year versus 2.7% per year). Non-vascular death rates were similar in the treatment arms.
The efficacy of dabigatran etexilate capsules 150 mg twice daily was generally consistent across major subgroups (see Figure 5). Figure 5 Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics *

dabigatrancapfig5
(click image for full-size original)

* Randomized ITT
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. In RE-LY, a higher rate of clinical myocardial infarction was reported in patients who received dabigatran etexilate capsules (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

14.2 Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients

In the randomized, parallel group, double-blind trials, RE-COVER and RE-COVER II, patients with deep vein thrombosis and pulmonary embolism received dabigatran etexilate capsules 150 mg twice daily or warfarin (dosed to target INR of 2 to 3) following initial treatment with an approved parenteral anticoagulant for 5 to 10 days.
In RE-COVER, the median treatment duration during the oral only treatment period was 174 days. A total of 2539 patients (30.9% patients with symptomatic PE with or without DVT and 68.9% with symptomatic DVT only) were treated with a mean age of 54.7 years. The patient population was 58.4% male, 94.8% white, 2.6% Asian, and 2.6% black. The concomitant diseases of patients in this trial included hypertension (35.9%), diabetes mellitus (8.3%), coronary artery disease (6.5%), active cancer (4.8%), and gastric or duodenal ulcer (4.4%). Concomitant medications included agents acting on renin-angiotensin system (25.2%), vasodilators (28.4%), serum lipid-reducing agents (18.2%), NSAIDs (21%), beta-blockers (14.8%), calcium channel blockers (8.5%), ASA (8.6%), and platelet inhibitors excluding ASA (0.6%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 60% in RE-COVER study.
In RE-COVER II, the median treatment duration during the oral only treatment period was 174 days. A total of 2568 patients (31.8% patients with symptomatic PE with or without DVT and 68.1% with symptomatic DVT only) were treated with a mean age of 54.9 years. The patient population was 60.6% male, 77.6% white, 20.9% Asian, and 1.5% black. The concomitant diseases of patients in this trial included hypertension (35.1%), diabetes mellitus (9.8%), coronary artery disease (7.1%), active cancer (3.9%), and gastric or duodenal ulcer (3.8%). Concomitant medications included agents acting on renin-angiotensin system (24.2%), vasodilators (28.6%), serum lipid-reducing agents (20.0%), NSAIDs (22.3%), beta-blockers (14.8%), calcium channel blockers (10.8%), ASA (9.8%), and platelet inhibitors excluding ASA (0.8%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 57% in RE-COVER II study.
In studies RE-COVER and RE-COVER II, the protocol specified non-inferiority margin (2.75) for the hazard ratio was derived based on the upper limit of the 95% confidence interval of the historical warfarin effect. Dabigatran etexilate capsules were demonstrated to be non-inferior to warfarin (dosed to target INR of 2 to 3) (Table 13) based on the primary composite endpoint (fatal PE or symptomatic non-fatal PE and/or DVT) and retains at least 66.9% (RE-COVER) and 63.9% (RE-COVER II) of the historical warfarin effect, respectively. Table 13 Primary Efficacy Endpoint for RE-COVER and RE-COVER II – Modified ITT a Population

Dabigatran etexilate capsules 150 mg twice daily N (%) Warfarin N (%) Hazard ratio vs warfarin (95% CI)
RE-COVER N=1274 N=1265
Primary Composite Endpoint b 34 (2.7) 32 (2.5) 1.05 (0.65, 1.70)
Fatal PE c 1 (0.1) 3 (0.2)
Symptomatic non-fatal PE c 16 (1.3) 8 (0.6)
Symptomatic recurrent DVT c 17 (1.3) 23 (1.8)
RE-COVER II N=1279 N=1289
Primary Composite Endpoint b 34 (2.7) 30 (2.3) 1.13 (0.69, 1.85)
Fatal PE c 3 (0.2) 0
Symptomatic non-fatal PE c 9 (0.7) 15 (1.2)
Symptomatic recurrent DVT c 30 (2.3) 17 (1.3)

a Modified ITT analyses population consists of all randomized patients who received at least one dose of study medication.
b Number of patients with one or more event.
c Number of events. For patients with multiple events each event is counted independently.
In the randomized, parallel-group, double-blind, pivotal trial, RE-MEDY, patients received dabigatran etexilate capsules 150 mg twice daily or warfarin (dosed to target INR of 2 to 3) following 3 to 12 months of treatment with anticoagulation therapy for an acute VTE. The median treatment duration during the treatment period was 534 days. A total of 2856 patients were treated with a mean age of 54.6 years. The patient population was 61% male, and 90.1% white, 7.9% Asian and 2.0% black. The concomitant diseases of patients in this trial included hypertension (38.6%), diabetes mellitus (9.0%), coronary artery disease (7.2%), active cancer (4.2%), and gastric or duodenal ulcer (3.8%). Concomitant medications included agents acting on renin-angiotensin system (27.9%), vasodilators (26.7%), serum lipid reducing agents (20.6%), NSAIDs (18.3%), beta-blockers (16.3%), calcium channel blockers (11.1%), aspirin (7.7%), and platelet inhibitors excluding ASA (0.9%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 62% in the study.
In study RE-MEDY, the protocol specified non-inferiority margin (2.85) for the hazard ratio was derived based on the point estimate of the historical warfarin effect. Dabigatran etexilate capsules were demonstrated to be non-inferior to warfarin (dosed to target INR of 2 to 3) (Table 14) based on the primary composite endpoint (fatal PE or symptomatic non-fatal PE and/or DVT) and retains at least 63.0% of the historical warfarin effect. If the non-inferiority margin was derived based on the 50% retention of the upper limit of the 95% confidence interval, dabigatran etexilate capsules were demonstrated to retain at least 33.4% of the historical warfarin effect based on the composite primary endpoint. Table 14 Primary Efficacy Endpoint for RE-MEDY — Modified ITT a Population

Dabigatran etexilate capsules 150 mg twice daily N=1430 N (%) Warfarin N=1426 N (%) Hazard ratio vs warfarin (95% CI)
Primary Composite Endpoint b 26 (1.8) 18 (1.3) 1.44 (0.78, 2.64)
Fatal PE c 1 (0.07) 1 (0.07)
Symptomatic non-fatal PE c 10 (0.7) 5 (0.4)
Symptomatic recurrent DVT c 17 (1.2) 13 (0.9)

a Modified ITT analyses population consists of all randomized patients who received at least one dose of study medication.
b Number of patients with one or more event.
c Number of events. For patients with multiple events each event is counted independently.
In a randomized, parallel-group, double-blind, pivotal trial, RE-SONATE, patients received dabigatran etexilate capsules 150 mg twice daily or placebo following 6 to 18 months of treatment with anticoagulation therapy for an acute VTE. The median treatment duration was 182 days. A total of 1343 patients were treated with a mean age of 55.8 years. The patient population was 55.5% male, 89.0% white, 9.3% Asian, and 1.7% black. The concomitant diseases of patients in this trial included hypertension (38.8%), diabetes mellitus (8.0%), coronary artery disease (6.0%), history of cancer (6.0%), gastric or duodenal ulcer (4.5%), and heart failure (4.6%). Concomitant medications included agents acting on renin-angiotensin system (28.7%), vasodilators (19.4%), beta-blockers (18.5%), serum lipid reducing agents (17.9%), NSAIDs (12.1%), calcium channel blockers (8.9%), aspirin (8.3%), and platelet inhibitors excluding ASA (0.7%). Based on the outcome of the primary composite endpoint (fatal PE, unexplained death, or symptomatic non-fatal PE and/or DVT), dabigatran etexilate capsules were superior to placebo (Table 15). Table 15 Primary Efficacy Endpoint for RE-SONATE — Modified ITT a Population

Dabigatran etexilate capsules 150 mg twice daily N=681 N (%) Placebo N=662 N (%) Hazard ratio vs placebo (95% CI)
Primary Composite Endpoint b 3 (0.4) 37 (5.6) 0.08 (0.02, 0.25) p-value <0.0001
Fatal PE and unexplained death c 0 2 (0.3)
Symptomatic non-fatal PE c 1 (0.1) 14 (2.1)
Symptomatic recurrent DVT c 2 (0.3) 23 (3.5)

a Modified ITT analyses population consists of all randomized patients who received at least one dose of study medication.
b Number of patients with one or more events.
c Number of events. For patients with multiple events each event is counted independently. 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.

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