PRADAXA (Page 4 of 6)

Other Drugs

Clopidogrel: When dabigatran etexilate was given concomitantly with a loading dose of 300 mg or 600 mg clopidogrel, the dabigatran AUC and Cmax increased by approximately 30% and 40%, respectively. The concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. When comparing combined treatment and the respective mono-treatments, the coagulation measures for dabigatran’s effect (aPTT, ECT, and TT) remained unchanged, and inhibition of platelet aggregation (IPA), a measurement of clopidogrel’s effect, remained unchanged.

Enoxaparin: Enoxaparin 40 mg given subcutaneously for 3 days with the last dose given 24 hours before a single dose of PRADAXA had no impact on the exposure to dabigatran or the coagulation measures aPTT, ECT, or TT.

Diclofenac, Ranitidine, and Digoxin: None of these drugs alters exposure to dabigatran.

In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change the trough concentration of dabigatran.

Impact of Dabigatran on Other Drugs

In clinical studies exploring CYP3A4, CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alter the pharmacokinetics of amiodarone, atorvastatin, clarithromycin, diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine.

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

The clinical evidence for the efficacy of PRADAXA 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 PRADAXA (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 PRADAXA was 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 PRADAXA 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 patient’s mean age was 71.5 years and the mean CHADS2 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%; the mean percentages of time INR measurements were greater than 4 or less than 1.5 were 2% and 5%, respectively.

Relative to warfarin and to PRADAXA 110 mg twice daily, PRADAXA 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism (see Table 4 and Figure 1).

Table 4 First Occurrence of Stroke or Systemic Embolism in the RE-LY Study
PRADAXA 150 mg twice dailyPRADAXA 110 mg twice dailyWarfarin
Patients randomized607660156022
Patients (%) with events 134 (2.2%)183 (3%)202 (3.4%)
Hazard ratio vs. warfarin (95% CI)0.65 (0.52, 0.81)0.90 (0.74, 1.10)
P-value for superiority0.00010.3
Hazard ratio vs. PRADAXA 110 mg (95% CI)0.72 (0.58, 0.90)
P-value for superiority0.004

Figure 1 Kaplan-Meier Curve Estimate of Time to First Stroke or Systemic Embolism

Kaplan-Meier Curve Estimate of Time to First Stroke or Systemic Embolism
(click image for full-size original)

The contributions of the components of the composite endpoint, including stroke by subtype, are shown in Table 5. The treatment effect was primarily a reduction in stroke. PRADAXA 150 mg twice daily significantly reduced both ischemic and hemorrhagic strokes relative to warfarin.

Table 5 Strokes and Systemic Embolism in the RE-LY Study
PRADAXA 150 mg twice dailyWarfarin Hazard ratio vs. warfarin(95% CI)
Patients randomized60766022
Stroke 122 186 0.64 (0.51, 0.81)
Ischemic stroke1031340.75 (0.58, 0.97)
Hemorrhagic stroke12450.26 (0.14, 0.49)
Systemic embolism13210.61 (0.30, 1.21)

The efficacy of PRADAXA 150 mg twice daily was generally consistent across major subgroups (see Figure 2).

Figure 2 Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics

Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics
(click image for full-size original)

Centers were ranked post hoc by the percentage of time that warfarin-treated patients were in therapeutic range (INR 2 to 3). Findings for stroke/systemic embolism, all-cause mortality, and major bleeds are shown for centers above and below the median level of INR control in Table 6. The benefits of PRADAXA 150 mg relative to warfarin were most apparent in patients enrolled at centers with INR control below the median.

Table 6 Center INR Control in the RE-LY Study
Centers with INR control below the median of 67%Centers with INR control above the median of 67%
Stroke/systemic embolism0.57 (0.42, 0.76)0.76 (0.55, 1.05)
All-cause mortality0.78 (0.66, 0.93)1.01 (0.84, 1.23)
Major bleed0.82 (0.68, 0.99)1.08 (0.89, 1.31)

The risk of myocardial infarction was numerically greater in patients who received PRADAXA (1.5% for 150 mg dose) than in those who received warfarin (1.1%).

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