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Increased Risk Of Stroke With Discontinuation Of PRADAXA
Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant [see DOSAGE AND ADMINISTRATION].
Risk Of Bleeding
PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate 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 [see DOSAGE AND ADMINISTRATION].
Risk factors for bleeding include the concomitant use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA's anticoagulant activity and half-life are increased in patients with renal impairment [see CLINICAL PHARMACOLOGY].
A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited [see OVERDOSAGE]. Activated prothrombin complex concentrates (aPCCs, e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X may be considered but their use has not been evaluated in clinical trials. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used.
Thromboembolic And Bleeding Events In Patients With Prosthetic Heart Valves
The safety and efficacy of PRADAXA in 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, 220, or 300 mg of PRADAXA 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 treatment arm as compared to the warfarin treatment arm. These bleeding and thromboembolic events were seen both in patients who were initiated on PRADAXA post-operatively 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 patients with mechanical prosthetic valves [see CONTRAINDICATIONS].
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.
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].
P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see CLINICAL PHARMACOLOGY]. 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.
Consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA in patients with moderate renal impairment (CrCl 30-50 mL/min). Avoid use of PRADAXA and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) [see DRUG INTERACTIONS and Use In Specific Populations].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Instructions for Patients
- Tell patients to take PRADAXA exactly as prescribed.
- Remind patients not to discontinue PRADAXA without talking to the health care provider who prescribed it.
- Keep PRADAXA in the original bottle to protect from moisture. Do not put PRADAXA in pill boxes or pill organizers.
- When more than one bottle is dispensed to the patient, instruct them to open only one bottle at a time.
- Instruct patient to remove only one capsule from the opened bottle at the time of use. The bottle should be immediately and tightly closed.
- Advise patients not to chew or break the capsules before swallowing them and not to open the capsules and take the pellets alone.
- Advise patients that the capsule should be taken with a full glass of water.
Inform patients that they may bleed more easily, may bleed longer, and should call their health care provider for any signs or symptoms of bleeding.
Instruct patients to seek emergency care right away if they have any of the following, which may be a sign or symptom of serious bleeding:
- Unusual bruising (bruises that appear without known cause or that get bigger)
- Pink or brown uri ne
- Red or black, tarry stools
- Coughing up blood
- Vomiting blood, or vomit that looks like coffee grounds
Instruct patients to call their health care provider or to get prompt medical attention if they experience any signs or symptoms of bleeding:
- Pain, swelling or discomfort in a joint
- Headaches, dizziness, or weakness
- Reoccurring nose bleeds
- Unusual bleeding from gums
- Bleeding from a cut that takes a long time to stop
- Menstrual bleeding or vaginal bleeding that is heavier than normal
Gastrointestinal Adverse Reactions
- Dyspepsia (upset stomach), burning, or nausea
- Abdominal pain or discomfort
- Epigastric discomfort, GERD (gastric indigestion)
Invasive Or Surgical Procedures
Instruct patients to inform their health care provider that they are taking PRADAXA before any invasive procedure (including dental procedures) is scheduled.
Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so their health care provider knows about other treatments that may affect bleeding risk (e.g., aspirin or NSAIDs) or dabigatran exposure (e.g., dronedarone or systemic ketoconazole).
Prosthetic Heart Valves
Instruct patients to inform their health care provider if they will have or have had surgery to place a prosthetic heart valve.
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.
Use In Specific Populations
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.
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].
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).
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.
Safety and effectiveness of PRADAXA in pediatric patients have not been established.
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, ADVERSE REACTIONS, and Clinical Studies].
No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment [see CLINICAL PHARMACOLOGY]. Reduce the dose of PRADAXA in patients with severe renal impairment (CrCl 15-30 mL/min) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Dosing recommendations for patients with CrCl < 15 mL/min or on dialysis cannot be provided.
Last reviewed on RxList: 12/18/2013
This monograph has been modified to include the generic and brand name in many instances.
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