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PRADAXA(dabigatran etexilate mesylate) capsules for oral use
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HIGHLIGHTS OF PRESCRIBING INFORMATION |
These highlights do not include all the information needed to use PRADAXA safely and effectively. See full prescribing information for PRADAXA.
PRADAXA® (dabigatran etexilate mesylate) capsules for oral use
Initial U.S. Approval: 2010
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INDICATIONS AND USAGE
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PRADAXA is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (1)
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DOSAGE AND ADMINISTRATION
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For patients with CrCl >30 mL/min: 150 mg orally, twice daily (2.1)
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For patients with CrCl 15-30 mL/min: 75 mg orally, twice daily (2.1)
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Instruct patients not to chew, break, or open capsules (2.1)
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Review recommendations for converting to or from other oral or parenteral anticoagulants (2.2, 2.3)
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Temporarily discontinue PRADAXA before invasive or surgical procedures when possible, then restart promptly (2.4)
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DOSAGE FORMS AND STRENGTHS
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Capsules: 75 mg and 150 mg (3)
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CONTRAINDICATIONS
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Active pathological bleeding (4)
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History of serious hypersensitivity reaction to PRADAXA (4)
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WARNINGS AND PRECAUTIONS
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Risk of bleeding: PRADAXA can cause serious and, sometimes, fatal bleeding. Promptly eva luate signs and symptoms of blood loss. (5.1)
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Temporary discontinuation: Avoid lapses in therapy to minimize risk of stroke (5.2)
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P-gp inducers and inhibitors: Avoid coadministration of rifampin with PRADAXA because of effects on dabigatran exposure (5.3)
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ADVERSE REACTIONS
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Most common adverse reactions (>15%) are gastritis-like symptoms and bleeding (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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USE IN SPECIFIC POPULATIONS
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Geriatric use: Risk of bleeding increases with age (8.5)
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See 17 for PATIENT COUNSELING INFORMATION and Medication Guide |
Revised: 08/2011 |
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FULL PRESCRIBING INFORMATION: CONTENTS* |
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
PRADAXA is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally, twice daily, with or without food. For patients with CrCl 15-30 mL/min, the recommended dose is 75 mg twice daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Dosing recommendations for patients with a CrCL <15 mL/min or on dialysis cannot be provided.
Instruct patients to swallow the capsules whole. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure [see Clinical Pharmacology (12.3)].
If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.
2.2 Converting from or to Warfarin
When converting patients from warfarin therapy to PRADAXA, discontinue warfarin and start PRADAXA when the international normalized ratio (INR) is below 2.0.
When converting from PRADAXA to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:
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For CrCl >50 mL/min, start warfarin 3 days before discontinuing PRADAXA.
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For CrCl 31-50 mL/min, start warfarin 2 days before discontinuing PRADAXA.
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For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing PRADAXA.
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For CrCl <15 mL/min, no recommendations can be made.
Because PRADAXA can contribute to an elevated INR, the INR will better reflect warfarin’s effect after PRADAXA has been stopped for at least 2 days.
2.3 Converting from or to Parenteral Anticoagulants
For patients currently receiving a parenteral anticoagulant, start PRADAXA 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin).
For patients currently taking PRADAXA, wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating treatment with a parenteral anticoagulant [see Clinical Pharmacology (12.3)].
2.4 Surgery and Interventions
If possible, discontinue PRADAXA 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
If surgery cannot be delayed, there is an increased risk of bleeding [see Warnings and Precautions (5.1)]. This risk of bleeding should be weighed against the urgency of intervention [see Warnings and Precautions (5.2)]. Bleeding risk can be assessed by the ecarin clotting time (ECT). This test is a better marker of the anticoagulant activity of dabigatran than activated partial thromboplastin time (aPTT), prothrombin time (PT)/INR, or thrombin time (TT). If ECT is not available, the aPTT test provides an approximation of PRADAXA’s anticoagulant activity [see Clinical Pharmacology (12.2)].
3 DOSAGE FORMS AND STRENGTHS
150 mg capsules have a light blue opaque cap imprinted in black with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted in black with "R150".
75 mg capsules have a cream-colored opaque cap imprinted in black with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted in black with "R75".
4 CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:
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Active pathological bleeding [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
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History of a serious hypersensitivity reaction to PRADAXA (e.g., anaphylactic reaction or anaphylactic shock) [see Adverse Reactions (6.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Bleeding
PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Risk factors for bleeding include the use of drugs that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs) and labor and delivery. Promptly eva luate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
In the RE-LY (Randomized eva luation of Long-term Anticoagulant Therapy) study, a life-threatening bleed (bleeding that met one or more of the following criteria: fatal, symptomatic intracranial, 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) occurred at an annualized rate of 1.5% and 1.8% for PRADAXA 150 mg and warfarin, respectively [see Adverse Reactions (6.1)].
5.2 Temporary Discontinuation of PRADAXA
Discontinuing anticoagulants, including PRADAXA, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Lapses in therapy should be avoided, and if anticoagulation with PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.
5.3 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 inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose adjustments. These results should not be extrapolated to other P-gp inhibitors [see Clinical Pharmacology (12.3)].
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
The RE-LY study provided safety information on the use of two doses of PRADAXA and warfarin [see Clinical Studies (14)]. 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
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PRADAXA 110 mg twice daily |
PRADAXA 150 mg twice daily |
Warfarin |
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Total number treated |
5983 |
6059 |
5998 |
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Exposure |
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> 12 months |
4936 |
4939 |
5193 |
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> 24 months |
2387 |
2405 |
2470 |
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Mean exposure (months) |
20.5 |
20.3 |
21.3 |
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Total patient-years |
10,242 |
10,261 |
10,659 |
Because clinical studies are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
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 (5.1)]
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)
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PRADAXA
150 mg twice daily
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Warfarin
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Hazard Ratio
(95% CI**) |
* Patients contributed multiple events and events were counted in multiple categories.
** Confidence interval |
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Randomized patients |
6076 |
6022 |
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Patient-years |
12,033 |
11,794 |
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Intracranial hemorrhage |
38 (0.3) |
90 (0.8) |
0.41 (0.28, 0.60) |
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Life-threatening bleed |
179 (1.5) |
218 (1.9) |
0.80 (0.66, 0.98) |
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Major bleed |
399 (3.3) |
421 (3.6) |
0.93 (0.81, 1.07) |
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Any bleed |
1993 (16.6) |
2166 (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 (6.1% vs. 4.0%, 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.
7 DRUG INTERACTIONS
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 inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose adjustments. These results should not be extrapolated to other P-gp inhibitors [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women.
Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at maximum recommended human dose [MRHD] of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits.
8.2 Labor and Delivery
Safety and effectiveness of PRADAXA during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using PRADAXA in this setting [see Warnings and Precautions (5.1)].
Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons).
8.3 Nursing Mothers
It is not known whether dabigatran is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRADAXA is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of PRADAXA in pediatric patients has not been established.
8.5 Geriatric Use
Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups [see Warnings and Precautions (5), Adverse Reactions (6.1), and Clinical Studies (14)].
8.6 Renal Impairment
No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment. Reduce the dose of PRADAXA in patients with severe renal impairment (CrCl 15-30 mL/min) [see Dosage and Administration (2.1)]. Dosing recommendations for patients with CrCl <15 mL/min or on dialysis cannot be provided.
10 OVERDOSAGE
Accidental overdose may lead to hemorrhagic complications. There is no antidote to dabigatran etexilate or dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily excreted in the urine; therefore, maintain adequate diuresis. Dabigatran can be dialyzed (protein binding is low), with the removal of about 60% of drug over 2 to 3 hours; however, data supporting this approach are limited. Consider surgical hemostasis or the transfusion of fresh frozen plasma or red blood cells. There is some experimental evidence to support the role of activated prothrombin complex concentrates (e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X; however, their usefulness in clinical settings has not been established. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. Measurement of aPTT or ECT may help guide therapy [see Clinical Pharmacology (12.2)].
11 DESCRIPTION
The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The empirical formula is C34H41N7O5 • CH4O3S and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is:
Dabigatran etexilate mesylate is a yellow-white to yellow powder. A saturated solution in pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol.
The 150 mg capsule for oral administration contains 172.95 mg dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate, and the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. The capsule shell is composed of carrageenan, FD&C Blue No. 2 (150 mg only), FD&C Yellow No. 6, hypromellose, potassium chloride, titanium dioxide, and black edible ink. The 75 mg capsule contains 86.48 mg dabigatran etexilate mesylate, equivalent to 75 mg dabigatran etexilate, and is otherwise similar to the 150 mg capsule.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.
12.2 Pharmacodynamics
At recommended therapeutic doses, dabigatran etexilate prolongs the aPTT, ECT, and TT. With an oral dose of 150 mg twice daily the median peak aPTT is approximately 2x control. Twelve hours after the last dose the median aPTT is 1.5x control, with less than 10% of patients exceeding 2x control. In the RE-LY trial, the median (10th to 90th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds. The median (10th to 90th percentile) |
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