Prescription Drug Information: Pradaxa (Page 3 of 9)
5.4 Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The safety and efficacy of PRADAXA Capsules in adult patients with bileaflet mechanical prosthetic heart valves was evaluated in the RE-ALIGN trial, in which patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than three months prior to enrollment) were randomized to dose-adjusted warfarin or 150 mg, 220 mg, or 300 mg of PRADAXA Capsules twice a day. RE-ALIGN was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) in the PRADAXA Capsules treatment arm as compared to the warfarin treatment arm. These bleeding and thromboembolic events were seen both in patients who were initiated on PRADAXA Capsules postoperatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment. Therefore, the use of PRADAXA is contraindicated in all patients with mechanical prosthetic valves [see Contraindications (4)].
The use of PRADAXA for the prophylaxis of thromboembolic events in patients with atrial fibrillation in the setting of other forms of valvular heart disease, including the presence of a bioprosthetic heart valve, has not been studied and is not recommended.
5.5 Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3)].
P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology (12.3)]. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.
Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients
Reduce the dose of PRADAXA Capsules to 75 mg twice daily when dronedarone or systemic ketoconazole is co-administered with PRADAXA Capsules in patients with moderate renal impairment (CrCl 30-50 mL/min). Avoid use of PRADAXA Capsules and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) [see Drug Interactions (7.1) and Use in Specific Populations (8.6)].
Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
Avoid use of PRADAXA Capsules and concomitant P-gp inhibitors in patients with CrCl <50 mL/min [see Drug Interactions (7.2) and Use in Specific Populations (8.6)].
Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery
Avoid use of PRADAXA Capsules and concomitant P-gp inhibitors in patients with CrCl <50 mL/min [see Drug Interactions (7.3) and Use in Specific Populations (8.6)].
Treatment and reduction in risk of recurrence of VTE in pediatric patients
The concomitant use of PRADAXA Capsules with P-gp-inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.
5.6 Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome
Direct-acting oral anticoagulants (DOACs), including PRADAXA, 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 PRADAXA 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 PRADAXA 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.
| PRADAXA Capsules 110 mg twice daily | PRADAXA 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 PRADAXA Capsules 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of PRADAXA 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.
| Event | PRADAXA Capsules 150 mgN = 6059n (%/yearb) | WarfarinN = 5998n (%/yearb) | PRADAXA Capsules 150 mg vs WarfarinHR (95% CI) |
|---|---|---|---|
| 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. | |||
| Major Bleedingc | 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 Strokee | 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 Bleedingf | 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-intracranialg | 4 (0.04) | 7 (0.07) | 0.59 (0.17, 2.02) |
There was a higher rate of any gastrointestinal bleeds in patients receiving PRADAXA Capsules 150 mg than in patients receiving warfarin (6.6% vs 4.2%, respectively).
The risk of major bleeds was similar with PRADAXA 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 PRADAXA 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
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 PRADAXA 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 PRADAXA Capsules.
Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
PRADAXA Capsules 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 Capsules 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 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.
| Bleeding Events—Full Treatment Period Including Parenteral Treatment | |||
|---|---|---|---|
| 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 | |||
| PRADAXA Capsules150 mg twice dailyN (%) | WarfarinN (%) | 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 ≥2 g/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 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 PRADAXA 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 PRADAXA 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.
| PRADAXA Capsules150 mg twice dailyN (%) | WarfarinN (%) | Hazard Ratio(95% CI)c | |
|---|---|---|---|
| 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 | |||
| 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 ≥2 g/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 Capsules 150 mg was 3.1% (2.2% on warfarin).
RE-SONATE was a placebo-controlled study in which 684 patients received PRADAXA 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.
| PRADAXA Capsules150 mg twice dailyN (%) | PlaceboN (%) | Hazard Ratio(95% CI)c | |
|---|---|---|---|
| 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 | |||
| Patients | N=684 | N=659 | |
| Major bleeding eventa | 2 (0.3) | 0 | |
| Bleeding in a critical area or organ | 0 | 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 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 PRADAXA 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 PRADAXA 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 PRADAXA 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 PRADAXA 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 PRADAXA Capsules.
Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery
PRADAXA Capsules was studied in 5476 patients, randomized and treated in two double-blind, active-controlled non-inferiority trials (RE-NOVATE and RE-NOVATE II). The demographic characteristics were similar across the two studies and between the treatment groups within these studies. Approximately 45.3% of the treated patients were male, with a mean age of 63.2 years. The majority of the patients were white (96.1%), 3.6% were Asian, and 0.3% were black with a mean CrCl of 92 mL/min.
Bleeding events for the RE-NOVATE and RE-NOVATE II 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 retroperitoneal 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, requiring treatment cessation or leading to re-operation.
The RE-NOVATE study compared PRADAXA Capsules 75 mg taken orally 1-4 hours after surgery followed by 150 mg once daily, PRADAXA Capsules 110 mg taken orally 1-4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery. The RE-NOVATE II study compared PRADAXA Capsules 110 mg taken orally 1-4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery. In the RE-NOVATE and RE-NOVATE II studies, patients received 28-35 days of PRADAXA Capsules or enoxaparin with median exposure of 33 days. Tables 7 and 8 show the number of patients experiencing bleeding events in the analysis of RE-NOVATE and RE-NOVATE II.
| PRADAXA Capsules 220 mgN (%) | EnoxaparinN (%) | |
|---|---|---|
| Patients | N=1146 | N=1154 |
| Major bleeding event | 23 (2.0) | 18 (1.6) |
| Clinically relevant non-major bleeding | 48 (4.2) | 40 (3.5) |
| Any bleeding | 141 (12.3) | 132 (11.4) |
| PRADAXA Capsules 220 mgN (%) | EnoxaparinN (%) | |
|---|---|---|
| Patients | N=1010 | N=1003 |
| Major bleeding event | 14 (1.4) | 9 (0.9) |
| Clinically relevant non-major bleeding | 26 (2.6) | 20 (2.0) |
| Any bleeding | 98 (9.7) | 83 (8.3) |
In the two studies, the rate of major gastrointestinal bleeds in patients receiving PRADAXA Capsules and enoxaparin was the same (0.1%) and for any gastrointestinal bleeds was 1.4% for PRADAXA Capsules 220 mg and 0.9% for enoxaparin.
Gastrointestinal Adverse Reactions
In the two studies, the incidence of gastrointestinal adverse reactions for patients on PRADAXA Capsules 220 mg and enoxaparin was 39.5% and 39.5%, respectively. Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred in patients on PRADAXA Capsules 220 mg in 4.1% vs. 3.8% on enoxaparin, and gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage) occurred at 0.6% vs 1.0%, respectively.
Hypersensitivity Reactions
In the two studies, drug hypersensitivity (such as urticaria, rash, and pruritus) was reported in 0.3% of patients receiving PRADAXA Capsules 220 mg.
Clinical Myocardial Infarction Events
In the two studies, clinical myocardial infarction was reported in 2 (0.1%) of patients who received PRADAXA Capsules 220 mg and 6 (0.3%) of patients who received enoxaparin.
Pediatric Trials
Treatment of VTE in Pediatric Patients
The safety of PRADAXA in the treatment of VTE in pediatric patients was studied in one phase III trial (DIVERSITY). The DIVERSITY study was a randomized, open-label, active-controlled, parallel-group trial comparing PRADAXA with standard of care – SOC (vitamin K antagonists, low molecular weight heparin, or fondaparinux). There were 266 pediatric patients who received study treatment, 176 patients treated with PRADAXA and 90 patients treated with SOC. Patients on PRADAXA received age- and weight-adjusted doses of an age-appropriate formulation of PRADAXA (capsules, pellets, or oral solution) twice daily.
Patients had a median age of 14 years (range: 0-17 years), 92% were white, and half the patients were male (50%). Following at least 5 days of parenteral anticoagulant therapy, the median duration of treatment with PRADAXA was 85 days (range: 1-105). Patients with estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m2 were excluded from the trial.
Bleeding
Data on adjudicated major bleeding, clinically relevant non-major (CRNM) bleeding and minor bleeding events, for the PRADAXA group and the SOC group in the DIVERSITY study, are reported in Table 9. There was no statistically significant difference in the time to first major bleeding event.
| PRADAXA N (%) | Standard of Care (SOC)N (%) | |
|---|---|---|
| 1 Major bleeding event 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. | ||
| Patients | N=176 | N=90 |
| Major bleeding event1 | 4 (2.3) | 2 (2.2) |
| Fatal bleeding | 0 | 1 (1.1) |
| Clinically relevant non-major bleeding | 2 (1.1) | 1 (1.1) |
| Minor bleeding | 33 (19) | 21 (23) |
| Major and clinically relevant non-major bleeding | 6 (3.4) | 3 (3.3) |
| Any bleeding | 38 (22) | 22 (24) |
Site-specific bleeding rates were comparable between the two arms, with the exception of the rate of any gastrointestinal bleeds (5.7% in PRADAXA arm vs 1.8% in SOC arm).
Gastrointestinal Adverse Reactions
The incidence of gastrointestinal adverse reactions for patients on PRADAXA and SOC was 32% and 12%, respectively, with the following occurring in ≥5% of patients taking PRADAXA: dyspepsia (including term gastro-esophageal reflux disease, gastric pH decreased and esophagitis) in 9% (vs 2%), upper abdominal pain in 5% (vs 1%), vomiting in 8% (vs 2%), nausea 5% (vs 4%), and diarrhea 5% (vs 1%).
Reduction in Risk of Recurrence of VTE in Pediatric Patients
The safety of PRADAXA in the reduction in the risk of recurrence of VTE in pediatric patients was studied in one open-label single-arm trial (Study 2). Study 2 enrolled patients who required further anticoagulation due to the presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study and received PRADAXA until the clinical risk factor resolved, or up to a maximum of 12 months. There were 213 pediatric patients treated with PRADAXA, in a similar fashion as in the DIVERSITY trial.
Patients had a median age of 14 years (range: 0-18 years), 91% were white, and 55% of patients were male. Patients previously enrolled on DIVERSITY accounted for 43% of patients enrolled on Study 2 (29% from PRADAXA arm and 14% from SOC arm). The median duration of treatment with PRADAXA in Study 2 was 42 weeks (range: 0-56 weeks), with 45% of patients completing the 12-month planned duration, 17% stopping due to resolution of VTE risk factors, 12% stopping due to failure to attain target dabigatran concentration and 6% had an adverse event leading to discontinuation.
During the on-treatment period of Study 2, 3 patients (1.4%) had a major bleeding event, 3 patients (1.4%) had a clinically relevant non-major bleeding event, and 44 patients (20%) had a minor bleeding event. The most common drug-related adverse reactions were dyspepsia (5%), epistaxis (3.3%), nausea (3.3%) and menorrhagia (2.8%).
The adverse reaction profile in pediatric patients was generally consistent with that of adult patients.
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