ADVERSE REACTIONS
The most serious adverse reactions reported
with PRADAXA were related to bleeding [see Warnings and Precautions ].
Clinical TrialsExperience
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.
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 PRADAXA and warfarin [see Clinical Studies ]. The numbers of patients and their exposures are described in Table
1. Limited information is presented on the 110 mg dosing arm because
this dose is not approved.
Table 1 Summary of Treatment Exposure in RE-LY
| |
PRADAXA 110
mg twice daily
|
PRADAXA 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 PRADAXA 150 mg and 16% for warfarin.
The most frequent adverse reactions leading to discontinuation of
PRADAXA were bleeding and gastrointestinal events (i.e., dyspepsia,
nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).
Bleeding
[see Warnings and Precautions ]
Table 2 shows the number of patients experiencing serious
bleeding during the treatment period in the RE-LY study, with the
bleeding rate per 100 patient-years (%). Major bleeds fulfilled one
or more of the following criteria: bleeding associated with a reduction
in hemoglobin of at least 2 grams per deciliter or leading to a transfusion
of at least 2 units of blood, or symptomatic bleeding in a critical
area or organ (intraocular, intracranial, intraspinal or intramuscular
with compartment syndrome, retroperitoneal bleeding, intra-articular
bleeding, or pericardial bleeding). A life-threatening bleed met
one or more of the following criteria: fatal, symptomatic intracranial
bleed, reduction in hemoglobin of at least 5 grams per deciliter,
transfusion of at least 4 units of blood, associated with hypotension
requiring the use of intravenous inotropic agents, or necessitating
surgical intervention. Intracranial hemorrhage included intracerebral
(hemorrhagic stroke), subarachnoid, and subdural bleeds.
Table 2 Bleeding Events* (per 100 Patient-Years)
* Patients contributed multiple events and events
were counted in multiple categories.
** Confidence interval |
| |
PRADAXA
150 mg twice daily
N (%)
|
Warfarin
N (%)
|
Hazard Ratio
(95% CI**)
|
| Randomized patients |
6076 |
6022 |
|
| Patient-years |
12,033 |
11,794 |
|
| Intracranial hemorrhage |
39 |
91 (0.8) |
0.42 (0.29, 0.61) |
| Life-threatening bleed |
183 (1.5) |
221 (1.9) |
0.81 (0.67, 0.99) |
| Major bleed |
409 (3.4) |
426 (3.6) |
0.94 (0.82, 1.08) |
| Any bleed |
1997 (16.6) |
2169 (18.4) |
0.91 (0.85, 0.96) |
The risk of major bleeds was similar
with PRADAXA 150 mg and warfarin across major subgroups defined by
baseline characteristics, with the exception of age, where there was
a trend towards a higher incidence of major bleeding on PRADAXA (hazard
ratio 1.2, 95% CI: 1.0 to 1.4) for patients ≥75 years of age.
There was a higher rate of major gastrointestinal
bleeds in patients receiving PRADAXA 150 mg than in patients receiving
warfarin (1.6% vs. 1.1%, respectively, with a hazard ratio vs. warfarin
of 1.5, 95% CI, 1.2 to 1.9), and a higher rate of any gastrointestinal
bleeds (5.7% vs. 3.9%, respectively).
Gastrointestinal
Adverse Reactions
Patients on PRADAXA 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
PRADAXA.
Treatment and Reduction in the Risk of Recurrence of Deep
Venous Thrombosis and Pulmonary Embolism
PRADAXA was 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
PRADAXA 150 mg twice daily and warfarin for the treatment of deep
vein thrombosis and pulmonary embolism. Patients received 5-10 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 3 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 3 Bleeding Events in RE-COVER and RE-COVER II Treated
Patients
Note: MBE can belong to more than one criterion.
aPatients with at least one MBE.
bBleeding site based on investigator
assessment. Patients can have more than one site of bleeding.
cConfidence interval |
| |
Bleeding Events-Full
Treatment Period
Including Parenteral Treatment
|
| |
PRADAXA
150
mg twice daily
N (%)
|
Warfarin
N
(%)
|
Hazard Ratio
(95% CI)c
|
|
Patients
|
N=2553
|
N=2554
|
|
| Major bleeding eventa
|
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 ≥2g/dL or transfusion
≥2 units of whole blood or packed red blood cells |
32 (1.3) |
38 (1.5) |
|
| Bleeding sites for
MBEb
|
|
|
|
| |
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) |
The rate of any gastrointestinal
bleeds in patients receiving PRADAXA 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 PRADAXA 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 PRADAXA 150 mg twice
daily following 6 to 18 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 4 shows the number of patients experiencing
bleeding events in the study.
Table 4 Bleeding Events in RE-MEDY Treated Patients
Note: MBE can belong to more than one criterion.
aPatients with at least one MBE.
bBleeding site based on investigator
assessment. Patients can have more than one site of bleeding.
cConfidence interval |
| |
PRADAXA
150
mg twice daily
N (%)
|
Warfarin
N
(%)
|
Hazard Ratio
(95% CI)c
|
|
Patients
|
N=1430
|
N=1426
|
|
| Major bleeding eventa
|
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 ≥2g/dL or transfusion
≥2 units of whole blood or packed red blood cells |
7 (0.5) |
16 (1.1) |
|
| Bleeding sites for
MBEb
|
|
|
|
| |
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) |
In the RE-MEDY study,
the rate of any gastrointestinal bleeds in patients receiving PRADAXA
150 mg was 3.1% (2.2% on warfarin).
RE-SONATE was a placebo-controlled study
in which 684 patients received PRADAXA 150 mg twice daily following
3 to 6 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 5 shows
the number of patients experiencing bleeding events in the study.
Table 5 Bleeding Events in RE-SONATE Treated Patients
Note: MBE can belong to more than one criterion.
aPatients with at least one MBE.
bBleeding site based on investigator
assessment. Patients can have more than one site of bleeding.
cConfidence interval |
| |
PRADAXA
150
mg twice daily
N (%)
|
Placebo
N (%)
|
Hazard Ratio
(95% CI)c
|
|
Patients
|
N=684
|
N=659
|
|
| Major bleeding eventa
|
2 (0.3) |
0 |
|
| |
Bleeding in a critical area or organ |
2 (0.3) |
0 |
|
| |
Gastrointestinalb
|
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) |
In the RE-SONATE study,
the rate of any gastrointestinal bleeds in patients receiving PRADAXA
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
PRADAXA [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 non-fatal and fatal clinical myocardial infarction
was reported in patients who received PRADAXA [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 PRADAXA 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 PRADAXA in 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
PRADAXA.
Postmarketing Experience
The following adverse reactions have been
identified during post approval use of PRADAXA. Because these reactions
are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish
a causal relationship to drug exposure. The following adverse reactions
have been identified during post approval use of PRADAXA: angioedema,
thrombocytopenia, esophageal ulcer.
|
