Pradaxa

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Pradaxa uses

• Warning: (a) premature discontinuation of pradaxa increases the riskof thrombotic events, and (b) spinal/epidural hematoma
•   indications and usage
•   dosage and administration
•   dosage forms and strengths
•   contraindications
•   warnings and precautions
•   adverse reactions
•   drug interactions
•   use in specific populations
•   overdosage
•   description
•   clinical pharmacology
•   nonclinical toxicology
•   clinical studies
•   how supplied/storageand handling
•   patient counseling information
• Pradaxa reviews

WARNING: PREMATURE DISCONTINUATION OF Pradaxa INCREASES THE RISKOF THROMBOTIC EVENTS, and (B) SPINAL/EPIDURAL HEMATOMA

(A) PREMATURE DISCONTINUATIONOF Pradaxa INCREASES THE RISK OF THROMBOTIC EVENTS

Prematurediscontinuation of any oral anticoagulant, including Pradaxa, increasesthe risk of thrombotic events. If anticoagulation with Pradaxa isdiscontinued for a reason other than pathological bleeding or completionof a course of therapy, consider coverage with another anticoagulant .

(B) SPINAL/EPIDURALHEMATOMA

Epidural or spinal hematomas may occur in patientstreated with Pradaxa who are receiving neuraxial anesthesia or undergoingspinal puncture. These hematomas may result in long-term or permanentparalysis. Consider these risks when scheduling patients for spinalprocedures. Factors that can increase the risk of developing epiduralor spinal hematomas in these patients include:

 - use of indwelling epidural catheters

 - concomitant use of other drugs that affect hemostasis, such asnon-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors,other anticoagulants

 - a history of traumatic or repeatedepidural or spinal punctures

 - a history of spinal deformityor spinal surgery

 - optimal timing between the administrationof Pradaxa and neuraxial procedures is not known .

Monitor patientsfrequently for signs and symptoms of neurological impairment. If neurologicalcompromise is noted, urgent treatment is necessary .

Consider the benefits and risks before neuraxial interventionin patients anticoagulated or to be anticoagulated .

WARNING: (A) PREMATURE DISCONTINUATIONOF Pradaxa INCREASES THE RISK OF THROMBOTIC EVENTS, and (B) SPINAL/EPIDURALHEMATOMA

See full prescribing informationfor complete boxed warning

(A)PREMATURE DISCONTINUATION OF Pradaxa INCREASES THE RISK OF THROMBOTICEVENTS: Premature discontinuation of any oral anticoagulant, includingPRADAXA, increases the risk of thrombotic events. To reduce thisrisk, consider coverage with another anticoagulant if Pradaxa is discontinuedfor a reason other than pathological bleeding or completion of a courseof therapy (2.4, 2.5, 2.6, 5.1).

(B) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomasmay occur in patients treated with Pradaxa who are receiving neuraxialanesthesia or undergoing spinal puncture. These hematomas may resultin long-term or permanent paralysis (5.3). Monitor patients frequently for signs and symptoms of neurologicalimpairment and if observed, treat urgently. Consider the benefitsand risks before neuraxial intervention in patients who are or whoneed to be anticoagulated (5.3).

1  INDICATIONS AND USAGE

Pradaxa is a direct thrombin inhibitor indicated:

• To reduce the risk of stroke and systemic embolism in patientswith non-valvular atrial fibrillation
• For the treatment of deep venous thrombosis (DVT) and pulmonaryembolism (PE) in patients who have been treated with a parenteralanticoagulant for 5-10 days (1.2)
• To reduce the risk of recurrence of DVT and PE in patientswho have been previously treated (1.3)
• For the prophylaxis of DVT and PE in patients who have undergonehip replacement surgery (1.4)

1.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvularAtrial Fibrillation

Pradaxa is indicated to reduce the riskof stroke and systemic embolism in patients with non-valvular atrialfibrillation.

1.2 Treatment of Deep Venous Thrombosis and Pulmonary Embolism

Pradaxa is indicated for thetreatment of deep venous thrombosis and pulmonary embolism in patientswho have been treated with a parenteral anticoagulant for 5-10 days.

1.3 Reduction in the Risk of Recurrence of Deep Venous Thrombosisand Pulmonary Embolism

Pradaxa is indicated to reduce the risk ofrecurrence of deep venous thrombosis and pulmonary embolism in patientswho have been previously treated.

1.4 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism FollowingHip Replacement Surgery

Pradaxa is indicated for the prophylaxisof deep vein thrombosis and pulmonary embolism, in patients who haveundergone hip replacement surgery.

2  DOSAGE AND ADMINISTRATION

• Non-valvular Atrial Fibrillation:
  • For patients with CrCl >30 mL/min: 150 mg orally, twicedaily
  • For patients with CrCl 15-30 mL/min: 75 mg orally, twicedaily (2.1)
• Treatment of DVT and PE:
  • For patients with CrCl >30 mL/min: 150 mg orally, twicedaily after 5-10 days of parenteral anticoagulation (2.1)
• Reduction in the Risk of Recurrence of DVT andPE:
  • For patients with CrCl >30 mL/min: 150 mg orally, twicedaily after previous treatment (2.1)
• Prophylaxis of DVT and PE Following Hip ReplacementSurgery:
  • For patients with CrCl >30 mL/min: 110 mg orally first day,then 220 mg once daily (2.1)
• Review recommendations for converting to or from other oralor parenteral anticoagulants (2.4, 2.5)
• Temporarily discontinue Pradaxa before invasive or surgicalprocedures when possible, then restart promptly (2.6)

2.1 Recommended Dose

Indication	Dosage
Reductionin Risk of Stroke and Systemic Embolism in Non-valvular AF	CrCl >30 mL/min:	150 mg twice daily
	CrCl 15 to 30 mL/min:	75 mg twice daily
	CrCl <15 mL/min or on dialysis:	Dosing recommendations cannot be provided
	CrCl 30 to 50 mL/min with concomitant use of P-gpinhibitors:	Reduce dose to 75 mg twice daily if givenwith P-gp inhibitors dronedarone or systemic ketoconazole.
	CrCl <30 mL/min with concomitant use ofP-gp inhibitors:	Avoid co-administration
Treatment of DVT and PE Reduction in the Riskof Recurrence of DVT and PE	CrCl >30 mL/min:	150 mg twice daily
	CrCl ≤30 mL/min or on dialysis:	Dosing recommendations cannot be provided
	CrCl <50 mL/min with concomitant useof P-gp inhibitors:	Avoid co-administration
Prophylaxis of DVT and PE Following Hip Replacement Surgery	CrCl >30 mL/min:	110 mg for first day, then220 mg once daily
	CrCl ≤30 mL/min or on dialysis:	Dosing recommendations cannotbe provided
	CrCl <50 mL/min with concomitantuse of P-gp inhibitors:	Avoid co-administration

Reductionof Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation

For patients with creatinineclearance (CrCl) >30 mL/min, the recommended dose of Pradaxa is 150mg taken orally, twice daily. For patients with severe renal impairment(CrCl 15-30 mL/min), the recommended dose of Pradaxa is 75 mg twicedaily . Dosing recommendations for patients witha CrCl <15 mL/min or on dialysis cannot be provided.

Treatment ofDeep Venous Thrombosis and Pulmonary Embolism

For patients withCrCl >30 mL/min, the recommended dose of Pradaxa is 150 mg taken orally,twice daily, after 5-10 days of parenteral anticoagulation. Dosingrecommendations for patients with a CrCl ≤30 mL/min or on dialysiscannot be provided .

Reduction in the Riskof Recurrence of Deep Venous Thrombosis and Pulmonary Embolism

For patientswith CrCl >30 mL/min, the recommended dose of Pradaxa is 150 mg takenorally, twice daily after previous treatment. Dosing recommendationsfor patients with a CrCl ≤30 mL/min or on dialysis cannot be provided .

Prophylaxis of Deep Vein Thrombosis and Pulmonary EmbolismFollowing Hip Replacement Surgery

For patients with CrCl >30 mL/min,the recommended dose of Pradaxa is 110 mg taken orally 1-4 hours aftersurgery and after hemostasis has been achieved, then 220 mg takenonce daily for 28-35 days. If Pradaxa is not started on the day ofsurgery, after hemostasis has been achieved initiate treatment with220 mg once daily. Dosing recommendations for patients with a CrCl≤30 mL/min or on dialysis cannot be provided .

2.2 Dosing Adjustments

Assess renal function prior to initiationof treatment with Pradaxa. Periodically assess renal function asclinically indicated and adjusttherapy accordingly. Discontinue Pradaxa in patients who developacute renal failure while on Pradaxa and consider alternative anticoagulanttherapy.

Generally, the extentof anticoagulation does not need to be assessed. When necessary, useaPTT or ECT, and not INR, to assess for anticoagulant activity inpatients on Pradaxa .

Reduction of Risk of Stroke and SystemicEmbolism in Non-valvular Atrial Fibrillation

In patients with moderate renalimpairment (CrCl 30-50 mL/min), concomitant use of the P-gp inhibitordronedarone or systemic ketoconazole can be expected to produce dabigatranexposure similar to that observed in severe renal impairment. Reducethe dose of Pradaxa to 75 mg twice daily .

Treatment and Reductionin the Risk of Recurrence of Deep Venous Thrombosis and PulmonaryEmbolism

Dosing recommendations for patients withCrCl ≤30 mL/min cannot be provided. Avoid use of concomitant P-gpinhibitors in patients with CrCl <50 mL/min .

Prophylaxis of Deep VeinThrombosis and Pulmonary Embolism Following Hip Replacement Surgery

Dosingrecommendations for patients with CrCl ≤30 mL/min or on dialysis cannotbe provided. Avoid use of concomitant P-gp inhibitors in patientswith CrCl <50 mL/min .

2.3 Instructions toPatients

Instruct patientsto swallow the capsules whole. Pradaxa should be taken with a fullglass of water. Breaking, chewing, or emptying the contents of thecapsule can result in increased exposure .

If a dose of Pradaxa is nottaken at the scheduled time, the dose should be taken as soon as possibleon the same day; the missed dose should be skipped if it cannot betaken at least 6 hours before the next scheduled dose. The dose ofPRADAXA should not be doubled to make up for a missed dose.

2.4 Converting fromor to Warfarin

When convertingpatients from warfarin therapy to Pradaxa, discontinue warfarin andstart Pradaxa when the INR is below 2.0.

When converting from Pradaxa to warfarin, adjust thestarting time of warfarin based on creatinine clearance as follows:

• For CrCl ≥50 mL/min, start warfarin 3 days before discontinuingPRADAXA.
• For CrCl 30-50 mL/min, start warfarin 2 days before discontinuingPRADAXA.
• For CrCl 15-30 mL/min, start warfarin 1 day before discontinuingPRADAXA.
• For CrCl <15 mL/min, no recommendations can be made.

Because Pradaxa can increase INR,the INR will better reflect warfarin’s effect only after Pradaxa hasbeen stopped for at least 2 days .

2.5 Converting fromor to Parenteral Anticoagulants

For patients currently receiving a parenteral anticoagulant,start Pradaxa 0 to 2 hours before the time that the next dose of theparenteral drug was to have been administered or at the time of discontinuationof a continuously administered parenteral drug (e.g., intravenousunfractionated heparin).

For patientscurrently taking Pradaxa, wait 12 hours (CrCl ≥30 mL/min) or 24 hours(CrCl <30 mL/min) after the last dose of Pradaxa before initiatingtreatment with a parenteral anticoagulant .

2.6 Discontinuation forSurgery and Other Interventions

If possible, discontinue Pradaxa 1 to 2 days (CrCl ≥50mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgicalprocedures because of the increased risk of bleeding. Consider longertimes for patients undergoing major surgery, spinal puncture, or placementof a spinal or epidural catheter or port, in whom complete hemostasismay be required .

If surgery cannot be delayed, there is anincreased risk of bleeding . This risk ofbleeding should be weighed against the urgency of intervention . Use a specific reversal agent (idarucizumab) in case of emergencysurgery or urgent procedures when reversal of the anticoagulant effectof dabigatran is needed. Refer to the idarucizumab prescribing informationfor additional information. Restart Pradaxa as soon as medically appropriate.

3  DOSAGE FORMS AND STRENGTHS

150 mg capsules with a light blue opaquecap imprinted in black with the Boehringer Ingelheim company symboland a white opaque body imprinted in black with “R150”.

110 mg capsules with a lightblue opaque cap imprinted in black with the Boehringer Ingelheim companysymbol and a light blue opaque body imprinted in black with “R110”.

75 mg capsules with a white opaque cap imprintedin black with the Boehringer Ingelheim company symbol and a whiteopaque body imprinted in black with “R75”.

Capsules: 75 mg, 110 mg and 150 mg (3)

4  CONTRAINDICATIONS

Pradaxa is contraindicated in patients with:

• Active pathological bleeding .
• History of a serious hypersensitivity reaction to PRADAXA(e.g., anaphylactic reaction or anaphylactic shock) .
• Mechanical prosthetic heart valve .

• Active pathological bleeding (4)
• History of serious hypersensitivity reaction to Pradaxa (4)
• Mechanical prosthetic heart valve (4)

5  WARNINGS AND PRECAUTIONS

• Bleeding: Pradaxa can cause serious and fatal bleeding
• Bioprosthetic heart valves: Pradaxa use not recommended (5.4)

5.1 Increased Risk ofThrombotic Events after Premature Discontinuation

Premature discontinuation ofany oral anticoagulant, including Pradaxa, in the absence of adequatealternative anticoagulation increases the risk of thrombotic events. If Pradaxa is discontinued for a reason other than pathological bleedingor completion of a course of therapy, consider coverage with anotheranticoagulant and restart Pradaxa as soon as medically appropriate .

5.2 Risk of Bleeding

Pradaxa increases the risk of bleeding andcan cause significant and, sometimes, fatal bleeding. Promptly evaluateany signs or symptoms of blood loss. Discontinue Pradaxa in patients withactive pathological bleeding .

Risk factors for bleeding include the concomitant useof other drugs that increase the risk of bleeding (e.g., anti-plateletagents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA’s anticoagulant activity and half-life are increased in patientswith renal impairment .

Reversal of AnticoagulantEffect:

A specific reversalagent (idarucizumab) for dabigatran is available when reversal ofthe anticoagulant effect of dabigatran is needed:

• For emergency surgery/urgent procedures
• In life-threatening or uncontrolled bleeding

Hemodialysis can removedabigatran; however the clinical experience supporting the use ofhemodialysis as a treatment for bleeding is limited . Prothrombin complexconcentrates, or recombinant Factor VIIa may be considered but theiruse has not been evaluated in clinical trials. Protamine sulfate andvitamin K are not expected to affect the anticoagulant activity ofdabigatran. Consider administration of platelet concentrates in caseswhere thrombocytopenia is present or long-acting antiplatelet drugshave been used.

5.3 Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia)or spinal puncture is employed, patients treated with anticoagulantagents are at risk of developing an epidural or spinal hematoma whichcan result in long-term or permanent paralysis .

To reduce the potential risk of bleedingassociated with the concurrent use of dabigatran and epidural or spinalanesthesia/analgesia or spinal puncture, consider the pharmacokineticprofile of dabigatran . Placement or removalof an epidural catheter or lumbar puncture is best performed whenthe anticoagulant effect of dabigatran is low; however, the exacttiming to reach a sufficiently low anticoagulant effect in each patientis not known.

Shouldthe physician decide to administer anticoagulation in the contextof epidural or spinal anesthesia/analgesia or lumbar puncture, monitorfrequently to detect any signs or symptoms of neurological impairment,such as midline back pain, sensory and motor deficits (numbness, tingling,or weakness in lower limbs), bowel and/or bladder dysfunction. Instructpatients to immediately report if they experience any of the abovesigns or symptoms. If signs or symptoms of spinal hematoma are suspected,initiate urgent diagnosis and treatment including consideration forspinal cord decompression even though such treatment may not preventor reverse neurological sequelae.

5.4 Thromboembolic and Bleeding Events in Patients with ProstheticHeart Valves

The safety and efficacy of Pradaxa in patients with bileaflet mechanicalprosthetic heart valves was evaluated in the RE-ALIGN trial, in whichpatients with bileaflet mechanical prosthetic heart valves were randomized to dose adjusted warfarin or 150, 220, or 300 mg ofPRADAXA twice a day. RE-ALIGN was terminated early due to the occurrenceof significantly more thromboembolic events (valve thrombosis, stroke,transient ischemic attack, and myocardial infarction) and an excessof major bleeding (predominantly post-operative pericardial effusionsrequiring intervention for hemodynamic compromise) in the PRADAXAtreatment arm as compared to the warfarin treatment arm. These bleedingand thromboembolic events were seen both in patients who were initiatedon Pradaxa post-operatively within three days of mechanical bileafletvalve implantation, as well as in patients whose valves had been implantedmore than three months prior to enrollment. Therefore, the use ofPRADAXA is contraindicated in patients with mechanical prostheticvalves.

The useof Pradaxa for the prophylaxis of thromboembolic events in patientswith atrial fibrillation in the setting of other forms of valvularheart disease, including the presence of a bioprosthetic heart valve,has not been studied and is not recommended.

5.5 Effect of P-gp Inducersand 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 .

P-gp inhibition andimpaired renal function are the major independent factors that resultin increased exposure to dabigatran . Concomitant use of P-gpinhibitors in patients with renal impairment is expected to produceincreased exposure of dabigatran compared to that seen with eitherfactor alone.

Reduction of Risk of Stroke and Systemic Embolism in Non-valvularAtrial Fibrillation

Reduce the dose of Pradaxa to 75 mg twicedaily when dronedarone or systemic ketoconazole is coadministeredwith Pradaxa in patients with moderate renal impairment (CrCl 30-50mL/min). Avoid use of Pradaxa and P-gp inhibitors in patients withsevere renal impairment (CrCl 15-30 mL/min) .

Treatment and Reductionin the Risk of Recurrence of Deep Venous Thrombosis and PulmonaryEmbolism

Avoid use of Pradaxa and concomitant P-gpinhibitors in patients with CrCl <50 mL/min .

Prophylaxis of Deep VeinThrombosis and Pulmonary Embolism Following Hip Replacement Surgery

Avoid useof Pradaxa and concomitant P-gp inhibitors in patients with CrCl <50mL/min .

6  ADVERSE REACTIONS

The following serious adversereactions are described elsewhere in the labeling:

• Increased Risk of Thrombotic Events after Premature Discontinuation
• Risk of Bleeding
• Spinal/Epidural Anesthesia or Puncture
• Thromboembolic and Bleeding Events in Patients with ProstheticHeart Valves

The most serious adversereactions reported with Pradaxa were related to bleeding [seeWarnings and Precautions (5.2)].

Most common adverse reactions (>15%) aregastritis-like symptoms and bleeding (6.1)

To report SUSPECTED ADVERSE REACTIONS,contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical TrialsExperience

Because clinicaltrials are conducted under widely varying conditions, adverse reactionsrates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.

Reduction of Risk of Strokeand Systemic Embolism in Non-valvular Atrial Fibrillation

The RE-LY (RandomizedEvaluation of Long-term Anticoagulant Therapy) study provided safetyinformation on the use of two doses of Pradaxa and warfarin . The numbers of patients and their exposures are described in Table1. Limited information is presented on the 110 mg dosing arm becausethis dose is not approved.

		Pradaxa 110mg twice daily	Pradaxa 150mg 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 Discontinuationin RE-LY

The rates of adverse reactions leading to treatmentdiscontinuation were 21% for Pradaxa 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation ofPRADAXA were bleeding and gastrointestinal events (i.e., dyspepsia,nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).

Bleeding

Table 2 shows the number of adjudicated major bleedingevents during the treatment period in the RE-LY study, with the bleedingrate per 100 subject-years (%). Major bleeding is defined as bleedingaccompanied by one or more of the following: a decrease in hemoglobinof ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells, bleedingat a critical site or with a fatal outcome. Intracranial hemorrhageincluded intracerebral (hemorrhagic stroke), subarachnoid, and subduralbleeds.

aPatients during treatment or within 2 days of stopping study treatment. Major bleeding events within each subcategory were counted once perpatient, but patients may have contributed events to multiple subcategories. bAnnualevent rate per 100 pt-years = 100 * number of subjects with event/subject-years. Subject-years is defined as cumulative number of days from first drugintake to event date, date of last drug intake + 2, death date (whateveroccurred first) across all treated subjects divided by 365.25. Incase of recurrent events of the same category, the first event wasconsidered. cDefined as bleeding accompanied by one or more ofthe following: a decrease in hemoglobin of ≥2 g/dL, a transfusionof 2 or more units of packed red blood cells, bleeding at a criticalsite or with fatal outcome. dIntracranial bleedincluded intracerebral (hemorrhagic stroke), subarachnoid, and subduralbleeds. eOn-treatment analysis based on the safety population,compared to ITT analysis presented in Section 14 Clinical Studies. fFatalbleed: Adjudicated major bleed as defined above with investigatorreported fatal outcome and adjudicated death with primary cause frombleeding. gNon-intracranial fatal bleed: Adjudicated major bleedas defined above and adjudicated death with primary cause from bleedingbut without symptomatic intracranial bleed based on investigator’sclinical assessment.
Event	Pradaxa 150 mg N = 6059 n (%/yearb)	Warfarin N= 5998 n (%/yearb)	Pradaxa 150 mg vs. Warfarin HR (95% CI)
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 rateof any gastrointestinal bleeds in patients receiving Pradaxa 150 mgthan in patients receiving warfarin (6.6% vs. 4.2%, respectively).

The risk of major bleeds was similar withPRADAXA 150 mg and warfarin across major subgroups defined by baselinecharacteristics, with the exception of age, where therewas a trend towards a higher incidence of major bleeding on PRADAXA(hazard ratio 1.2, 95% CI: 1.0 to 1.5) for patients ≥75 years of age.

Figure 1 Adjudicated MajorBleeding by Baseline Characteristics Including Hemorrhagic StrokeTreated Patients

Note: The figure above presents effects invarious subgroups all of which are baseline characteristics and allof which were pre-specified. The 95% confidence limits that are showndo not take into account how many comparisons were made, nor do theyreflect the effect of a particular factor after adjustment for allother factors. Apparent homogeneity or heterogeneity among groupsshould not be over-interpreted.

Figure 1 GastrointestinalAdverse Reactions

Patients on Pradaxa 150 mg had an increased incidenceof gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominalpain, abdominal discomfort, and epigastric discomfort) and gastritis-likesymptoms (including GERD, esophagitis, erosive gastritis, gastrichemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis,and gastrointestinal ulcer).

HypersensitivityReactions

In the RE-LY study, drug hypersensitivity (includingurticaria, rash, and pruritus), allergic edema, anaphylactic reaction,and anaphylactic shock were reported in <0.1% of patients receivingPRADAXA.

Treatmentand Reduction in the Risk of Recurrence of Deep Venous Thrombosisand Pulmonary Embolism

Pradaxa was studied in 4387 patients in 4pivotal, parallel, randomized, double-blind trials. Three of thesetrials were active-controlled (warfarin) (RE-COVER, RE-COVER II, andRE-MEDY), and one study (RE-SONATE) was placebo-controlled. The demographiccharacteristics were similar among the 4 pivotal studies and betweenthe treatment groups within these studies. Approximately 60% of thetreated patients were male, with a mean age of 55.1 years. The majorityof the patients were white (87.7%), 10.3% were Asian, and 1.9% wereblack with a mean CrCl of 105.6 mL/min.

Bleeding events for the 4 pivotal studieswere classified as major bleeding events if at least one of the followingcriteria applied: fatal bleeding, symptomatic bleeding in a criticalarea or organ (intraocular, intracranial, intraspinal or intramuscularwith compartment syndrome, retroperitoneal bleeding, intra-articularbleeding, or pericardial bleeding), bleeding causing a fall in hemoglobinlevel of 2.0 g/dL (1.24 mmol/L or more, or leading to transfusionof 2 or more units of whole blood or red cells).

RE-COVER and RE-COVER II studies comparedPRADAXA 150 mg twice daily and warfarin for the treatment of deepvein thrombosis and pulmonary embolism. Patients received 5-10 daysof an approved parenteral anticoagulant therapy followed by 6 months,with mean exposure of 164 days, of oral only treatment; warfarin wasoverlapped with parenteral therapy. Table 3 shows the number of patientsexperiencing bleeding events in the pooled analysis of RE-COVER andRE-COVER II studies during the full treatment including parenteraland oral only treatment periods after randomization.

Note: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigatorassessment. Patients can have more than one site of bleeding. cConfidence interval
		Bleeding Events-FullTreatment Period Including Parenteral Treatment
		Pradaxa 150mg 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 ≥2 g/dL or transfusion≥2 units of whole blood or packed red blood cells	32 (1.3)	38 (1.5)
Bleeding sites forMBEb
	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 relevantnon-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 gastrointestinalbleeds in patients receiving Pradaxa 150 mg in the full treatmentperiod was 3.1% (2.4% on warfarin).

The RE-MEDY and RE-SONATE studies providedsafety information on the use of Pradaxa for the reduction in therisk of recurrence of deep vein thrombosis and pulmonary embolism.

RE-MEDY was an active-controlledstudy (warfarin) in which 1430 patients received Pradaxa 150 mg twicedaily following 3 to 12 months of oral anticoagulant regimen. Patientsin the treatment studies who rolled over into the RE-MEDY study hada combined treatment duration of up to more than 3 years, with meanexposure of 473 days. Table 4 shows the number of patients experiencingbleeding events in the study.

Note: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigatorassessment. Patients can have more than one site of bleeding. cConfidence interval
		Pradaxa 150mg 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 ≥2 g/dL or transfusion≥2 units of whole blood or packed red blood cells	7 (0.5)	16 (1.1)
Bleeding sites forMBEb
	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 relevantnon-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 PRADAXA150 mg was 3.1% (2.2% on warfarin).

RE-SONATE was a placebo-controlled studyin which 684 patients received Pradaxa 150 mg twice daily following6 to 18 months of oral anticoagulant regimen. Patients in the treatmentstudies who rolled over into the RE-SONATE study had combined treatmentduration up to 9 months, with mean exposure of 165 days. Table 5 showsthe number of patients experiencing bleeding events in the study.

Note: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigatorassessment. Patients can have more than one site of bleeding. cConfidence interval
		Pradaxa 150mg 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	0	0
	Gastrointestinalb	2 (0.3)	0
Clinically relevantnon-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 PRADAXA150 mg was 0.7% (0.3% on placebo).

Clinical Myocardial Infarction Events

In the active-controlled VTE studies, a higher rate ofclinical myocardial infarction was reported in patients who receivedPRADAXA [20 (0.66 per 100 patient-years)] than in those who receivedwarfarin [5 (0.17 per 100 patient-years)]. In the placebo-controlledstudy, a similar rate of non-fatal and fatal clinical myocardial infarctionwas 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 AdverseReactions

In the four pivotal studies, patientson Pradaxa 150 mg had a similar incidence of gastrointestinal adversereactions (24.7% vs. 22.7% on warfarin). Dyspepsia (including abdominalpain upper, abdominal pain, abdominal discomfort, and epigastric discomfort)occurred in patients on Pradaxa in 7.5% vs. 5.5% on warfarin, andgastritis-like symptoms (including gastritis, GERD, esophagitis, erosivegastritis and gastric hemorrhage) occurred at 3.0% vs. 1.7%, respectively.

Hypersensitivity Reactions

In the 4 pivotal studies, drug hypersensitivity (includingurticaria, rash, and pruritus), allergic edema, anaphylactic reaction,and anaphylactic shock were reported in 0.1% of patients receivingPRADAXA.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism FollowingHip Replacement Surgery

Pradaxa wasstudied in 5476 patients, randomized and treated in two double-blind,active-controlled non-inferiority trials (RE-NOVATE and RE-NOVATEII). The demographic characteristics were similar across the twostudies and between the treatment groups within these studies. Approximately45.3 % of the treated patients were male, with a mean age of 63.2years. The majority of the patients were white (96.1%), 3.6% wereAsian, and 0.3% were black with a mean CrCl of 92 mL/min.

Bleeding events for the RE-NOVATEand RE-NOVATE II studies were classified as major bleeding eventsif 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 fallin hemoglobin level of 2.0 g/dL (1.24 mmol/L) or more, or leadingto transfusion of 2 or more units of whole blood or red cells, requiringtreatment cessation or leading to re-operation.

The RE-NOVATE study compared Pradaxa 75mg taken orally 1-4 hours after surgery followed by 150 mg once daily,PRADAXA 110 mg taken orally 1-4 hours after surgery followed by 220mg once daily and subcutaneous enoxaparin 40 mg once daily initiatedthe evening before surgery for the prophylaxis of deep vein thrombosisand pulmonary embolism in patients who had undergone hip replacementsurgery. The RE-NOVATE II study compared Pradaxa 110 mg taken orally1-4 hours after surgery followed by 220 mg once daily and subcutaneousenoxaparin 40 mg once daily initiated the evening before surgery forthe prophylaxis of deep vein thrombosis and pulmonary embolism inpatients who had undergone hip replacement surgery. In the RE-NOVATEand RE-NOVATE II studies, patients received 28-35 days of PRADAXAor enoxaparin with median exposure of 33 days. Tables 6 and 7 showthe number of patients experiencing bleeding events in the analysisof RE-NOVATE and RE-NOVATE II.

	Pradaxa 220 mg N (%)	Enoxaparin N(%)
Patients	N=1146	N=1154
Major bleeding event	23 (2.0)	18 (1.6)
Clinically relevant non-majorbleeding	48 (4.2)	40 (3.5)
Any bleeding	141 (12.3)	132 (11.4)

	Pradaxa 220 mg N (%)	Enoxaparin N(%)
Patients	N=1010	N=1003
Major bleeding event	14 (1.4)	9 (0.9)
Clinically relevant non-majorbleeding	26 (2.6)	20 (2.0)
Any bleeding	98 (9.7)	83 (8.3)

In the two studies, therate of major gastrointestinal bleeds in patients receiving PRADAXAand enoxaparin was the same (0.1%) and for any gastrointestinal bleedswas 1.4% for Pradaxa 220 mg and 0.9% for enoxaparin.

Gastrointestinal Adverse Reactions

In the two studies, the incidence of gastrointestinaladverse reactions for patients on Pradaxa 220 mg and enoxaparin was39.5% and 39.5%, respectively. Dyspepsia (including abdominal painupper, abdominal pain, abdominal discomfort, and epigastric discomfort)occurred in patients on Pradaxa 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) wasreported in 0.3% of patients receiving Pradaxa 220 mg.

Clinical MyocardialInfarction Events

In the two studies, clinicalmyocardial infarction was reported in 2 (0.1%) of patients who receivedPRADAXA 220 mg and 6 (0.3%) of patients who received enoxaparin.

6.2 Postmarketing Experience

The following adverse reactions have beenidentified during post approval use of Pradaxa. Because these reactionsare reported voluntarily from a population of uncertain size, it isnot always possible to reliably estimate their frequency or establisha causal relationship to drug exposure. The following adverse reactionshave been identified during post approval use of Pradaxa: angioedema,thrombocytopenia, esophageal ulcer.

7  DRUG INTERACTIONS

• P-gp inducers rifampin: Avoid coadministration with Pradaxa
• P-gp inhibitors in patients with CrCl 30-50 mL/min: Reducedose or avoid (7)
• P-gp inhibitors in patients with CrCl <30 mL/min: Notrecommended (7)

7.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvularAtrial Fibrillation

The concomitant use of Pradaxa with P-gp inducers(e.g., rifampin) reduces exposure to dabigatran and should generallybe avoided .

P-gp inhibition and impaired renal function are the major independentfactors that result in increased exposure to dabigatran [seeClinical Pharmacology (12.3)]. Concomitant use of P-gp inhibitors in patients with renal impairmentis expected to produce increased exposure of dabigatran compared tothat seen with either factor alone.

In patients with moderate renal impairment(CrCl 30-50 mL/min), reduce the dose of Pradaxa to 75 mg twice dailywhen administered concomitantly with the P-gp inhibitors dronedaroneor systemic ketoconazole. The use of the P-gp inhibitors verapamil,amiodarone, quinidine, clarithromycin, and ticagrelor does not requirea dose adjustment of Pradaxa. These results should not be extrapolatedto other P-gp inhibitors .

The concomitant use of Pradaxa and P-gp inhibitorsin patients with severe renal impairment (CrCl 15-30 mL/min) shouldbe avoided .

7.2 Treatment and Reduction in the Risk of Recurrence of Deep VenousThrombosis and Pulmonary Embolism

Avoid use of Pradaxa and P-gp inhibitors inpatients with CrCl <50 mL/min .

7.3 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism FollowingHip Replacement Surgery

In patients with CrCl ≥50 mL/min who haveconcomitant administration of P-gp inhibitors such as dronedaroneor systemic ketoconazole, it may be helpful to separate the timingof administration of dabigatran and the P-gp inhibitor by severalhours. The concomitant use of Pradaxa and P-gp inhibitors in patientswith CrCl <50 mL/min should be avoided .

8  USE IN SPECIFIC POPULATIONS

Geriatric use: Risk of bleeding increaseswith age

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies inpregnant women.

Dabigatran hasbeen shown to decrease the number of implantations when male and femalerats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 timesthe human exposure at maximum recommended human dose [MRHD] of 300mg/day based on area under the curve [AUC] comparisons) prior to matingand up to implantation (gestation Day 6). Treatment of pregnant ratsafter implantation with dabigatran at the same dose increased thenumber of dead offspring and caused excess vaginal/uterine bleedingclose to parturition. Although dabigatran increased the incidenceof delayed or irregular ossification of fetal skull bones and vertebraein 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 havenot been studied in clinical trials. Consider the risks of bleedingand of stroke in using Pradaxa in this setting .

Death of offspring and mother rats duringlabor in association with uterine bleeding occurred during treatmentof pregnant rats from implantation (gestation Day 7) to weaning (lactationDay 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times thehuman 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. Becausemany drugs are excreted in human milk and because of the potentialfor serious adverse reactions in nursing infants from Pradaxa, a decisionshould be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safetyand effectiveness of Pradaxa in pediatric patients have not been established.

8.5 Geriatric Use

Ofthe 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 increaseswith age, but the risk-benefit profile is favorable in all age groups .

8.6 Renal Impairment

Reduction of Risk of Stroke and Systemic Embolism in Non-valvularAtrial Fibrillation

No dose adjustment of Pradaxa is recommended in patientswith mild or moderate renal impairment . Reduce the dose of PRADAXAin patients with severe renal impairment (CrCl 15-30 mL/min) . Dosing recommendationsfor patients with CrCl <15 mL/min or on dialysis cannot be provided.

Adjust dose appropriately in patients withrenal impairment receiving concomitant P-gp inhibitors [seeWarnings and Precautions (5.5), DrugInteractions (7.1), and ClinicalPharmacology (12.3)].

Treatmentand Reduction in the Risk of Recurrence of Deep Venous Thrombosisand Pulmonary Embolism

Patients with severe renal impairment (CrCl≤30 mL/min) were excluded from RE-COVER.

Dosing recommendations for patients withCrCl ≤30 mL/min or on dialysis cannot be provided. Avoid use of PRADAXAwith concomitant P-gp inhibitors in patients with CrCl <50 mL/min.

Prophylaxisof Deep Vein Thrombosis and Pulmonary Embolism Following Hip ReplacementSurgery

Patients with severe renalimpairment (CrCl <30 mL/min) were excluded from RE-NOVATE and RE-NOVATEII.

Dosing recommendationsfor patients with CrCl <30 mL/min or on dialysis cannot be provided.

Avoid use of Pradaxa with concomitantP-gp inhibitors in patients with CrCl <50 mL/min .

10  OVERDOSAGE

Accidentaloverdose may lead to hemorrhagic complications. In the event of hemorrhagiccomplications, initiate appropriate clinical support, discontinuetreatment with Pradaxa, and investigate the source of bleeding. Aspecific reversal agent (idarucizumab) is available.

Dabigatran is primarily eliminated by thekidneys with a low plasma protein binding of approximately 35%. Hemodialysiscan remove dabigatran; however, data supporting this approach arelimited. Using a high-flux dialyzer, blood flow rate of 200 mL/min,and dialysate flow rate of 700 mL/min, approximately 49% of totaldabigatran can be cleared from plasma over 4 hours. At the same dialysateflow rate, approximately 57% can be cleared using a dialyzer bloodflow rate of 300 mL/min, with no appreciable increase in clearanceobserved at higher blood flow rates. Upon cessation of hemodialysis,a redistribution effect of approximately 7% to 15% is seen. The effectof dialysis on dabigatran’s plasma concentration would be expectedto vary based on patient specific characteristics. Measurement ofaPTT or ECT may help guide therapy .

11  DESCRIPTION

The chemical name for dabigatran etexilatemesylate, 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-,ethylester, methanesulfonate. The empirical formula is C₃₄H₄₁N₇O₅ ⋅ CH₄O₃S and the molecularweight is 723.86 (mesylate salt), 627.75 (free base). The structuralformula is:

Pradaxa 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, andsparingly soluble in isopropanol.

Pradaxa capsules are supplied in 75, 110,and 150 mg strengths for oral administration. Each capsule containsdabigatran etexilate mesylate as the active ingredient: 172.95 mgdabigatran etexilate mesylate (equivalent to 150 mg dabigatran etexilate),126.83 mg Pradaxa (equivalent to 110 mg dabigatranetexilate), or 86.48 mg Pradaxa (equivalentto 75 mg dabigatran etexilate) along with the following inactive ingredients:acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc,and tartaric acid. The capsule shell is composed of carrageenan,hypromellose, potassium chloride, titanium dioxide, black edible ink,and FD&C Blue No. 2 (150 mg and 110 mg capsules only).

Praxada (dabigatran etexilate mesylate) structure

12  CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Dabigatran and its acyl glucuronides are competitive, direct thrombininhibitors. Because thrombin enables the conversionof fibrinogen into fibrin during the coagulation cascade, its inhibitionprevents the development of a thrombus. Both free and clot-boundthrombin, and thrombin-induced platelet aggregation are inhibitedby the active moieties.

12.2 Pharmacodynamics

At recommended therapeutic doses, dabigatran etexilate prolongs thecoagulation markers such as aPTT, ECT, and TT. INR is relativelyinsensitive to the exposure to dabigatran and cannot be interpretedthe same way as used for warfarin monitoring.

The aPTT test provides an approximation of PRADAXA’santicoagulant effect. The average time course for effects on aPTT,following approved dosing regimens in patients with various degreesof renal impairment is shown in Figure 2. The curves represent meanlevels without confidence intervals; variations should be expectedwhen measuring aPTT. While advice cannot be provided on the levelof recovery of aPTT needed in any particular clinical setting, thecurves can be used to estimate the time to get to a particular levelof recovery, even when the time since the last dose of Pradaxa isnot precisely known. In the RE-LY trial, the median (10^th to 90^th percentile) troughaPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

*Simulations based onPK data from a study in subjects with renal impairment and PK/aPTTrelationships derived from the RE-LY study; aPTT prolongation in RE-LYwas measured centrally in citrate plasma using PTT Reagent Roche DiagnosticsGmbH, Mannheim, Germany. There may be quantitative differences betweenvarious established methods for aPTT assessment.

The degree of anticoagulant activity can also be assessedby the ecarin clotting time (ECT). This test is a more specific measureof the effect of dabigatran than activated partial thromboplastintime (aPTT). In the RE-LY trial, the median (10^th to 90^th percentile) trough ECT in patientsreceiving the 150 mg dose was 63 (44 to 103) seconds.

In orthopedic hip surgery patients,maximum aPTT response (Emax) to dabigatran and baseline aPTT werehigher shortly after surgery than at later time points (e.g. ≥3 daysafter surgery).

Cardiac Electrophysiology

No prolongation of the QTc interval was observed withdabigatran etexilate at doses up to 600 mg.

Figure 2

12.3 Pharmacokinetics

Pradaxa is absorbed as the dabigatran etexilateester. The ester is then hydrolyzed, forming dabigatran, the activemoiety. Dabigatran is metabolized to four different acyl glucuronidesand both the glucuronides and dabigatran have similar pharmacologicalactivity. Pharmacokinetics described here refer to the sum of dabigatranand its glucuronides. Dabigatran displays dose-proportional pharmacokineticsin healthy subjects and patients in the range of doses from 10 to400 mg.

Absorption

The absolutebioavailability of dabigatran following oral administration of dabigatranetexilate is approximately 3 to 7%. Dabigatran etexilate is a substrateof the efflux transporter P-gp. After oral administration of dabigatranetexilate in healthy volunteers, C_max occursat 1 hour post-administration in the fasted state. Coadministrationof Pradaxa with a high-fat meal delays the time to C_max by approximately 2 hours but has no effect on the bioavailabilityof dabigatran; Pradaxa may be administered with or without food.

The oral bioavailability of dabigatran etexilateincreases by 75% when the pellets are taken without the capsule shellcompared to the intact capsule formulation. Pradaxa capsules shouldtherefore not be broken, chewed, or opened before administration.

Distribution

Dabigatranis approximately 35% bound to human plasma proteins. The red bloodcell to plasma partitioning of dabigatran measured as total radioactivityis less than 0.3. The volume of distribution of dabigatran is 50 to70 L. Dabigatran pharmacokinetics are dose proportional after singledoses of 10 to 400 mg. Given twice daily, dabigatran’s accumulationfactor is approximately two.

Elimination

Dabigatranis eliminated primarily in the urine. Renal clearance of dabigatranis 80% of total clearance after intravenous administration. Afteroral administration of radiolabeled dabigatran, 7% of radioactivityis recovered in urine and 86% in feces. The half-life of dabigatranin healthy subjects is 12 to 17 hours.

Metabolism

After oraladministration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysisto the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically activeacyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronideexist, and each accounts for less than 10% of total dabigatran inplasma.

Renal Impairment

An open,parallel-group single-center study compared dabigatran pharmacokineticsin healthy subjects and patients with mild to moderate renal impairmentreceiving a single dose of Pradaxa 150 mg. Exposure to dabigatranincreases with severity of renal function impairment (Table 8). Similarfindings were observed in the RE-LY, RE-COVER and RE-NOVATE II trials.

+Patientswith severe renal impairment were not studied in RE-LY, RE-COVER andRE-NOVATE II. Dosing recommendations in subjects with severe renalimpairment are based on pharmacokinetic modeling .
Renal Function	CrCl (mL/min)	Increase inAUC	Increase inCmax	t1/2 (h)
Normal	≥ 80	1x	1x	13
Mild	50-80	1.5x	1.1x	15
Moderate	30-50	3.2x	1.7x	18
Severe+	15-30	6.3x	2.1x	27

Hepatic Impairment

Administrationof Pradaxa in patients with moderate hepatic impairment (Child-PughB) showed a large inter-subject variability, but no evidence of aconsistent change in exposure or pharmacodynamics.

Drug Interactions

A summary of the effect of coadministered drugs on dabigatran exposureis shown in Figures 3.1 and 3.2.

In the orthopedic hip surgery patients,limited clinical data with P-gp inhibitors is available.

Figure 3.1 Effect of P-gpInhibitor or Inducer (rifampicin) Drugs on Peak and Total Exposureto Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios(Ratio) and 90% Confidence Interval (90% CI). The Perpetrator andDabigatran Etexilate Dose and Dosing Frequency are given as well asthe Time of Perpetrator Dosing in Relation to Dabigatran EtexilateDose (Time Difference)

Figure 3.2 Effect of Non-P-gp Inhibitoror Inducer, Other Drugs, on Peak and Total Exposure to Dabigatran(Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90%Confidence Interval (90% CI). The Perpetrator and Dabigatran EtexilateDose and Dosing Frequency are given as well as the Time of PerpetratorDosing in Relation to Dabigatran Etexilate Dose (Time Difference)

Figure 3.1 Figure 3.2 In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, anddigoxin did not appreciably change the trough concentration of dabigatran.

Impact of Dabigatran onOther Drugs

In clinical studies exploring CYP3A4,CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alterthe 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 administeredby oral gavage to mice and rats for up to 2 years. The highest dosestested (200 mg/kg/day) in mice and rats were approximately 3.6 and6 times, respectively, the human exposure at MRHD of 300 mg/day basedon AUC comparisons.

Dabigatranwas not mutagenic in in vitro tests, including bacterialreversion tests, mouse lymphoma assay and chromosomal aberration assayin human lymphocytes, and the in vivo micronucleusassay in rats.

In the rat fertilitystudy with oral gavage doses of 15, 70, and 200 mg/kg, males weretreated for 29 days prior to mating, during mating up to scheduledtermination, and females were treated 15 days prior to mating throughgestation Day 6. No adverse effects on male or female fertility wereobserved at 200 mg/kg or 9 to 12 times the human exposure at MRHDof 300 mg/day based on AUC comparisons. However, the number of implantationsdecreased in females receiving 70 mg/kg, or 3 times the human exposureat MRHD based on AUC comparisons.

14  CLINICAL STUDIES

14.1 Reduction of Riskof Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation

The clinical evidence for the efficacy ofPRADAXA was derived from RE-LY, a multi-center, multi-national, randomizedparallel group trial comparing two blinded doses of Pradaxa (110 mgtwice daily and 150 mg twice daily) with open-label warfarin (dosedto target INR of 2 to 3) in patients with non-valvular, persistent,paroxysmal, or permanent atrial fibrillation and one or more of thefollowing additional risk factors:

• Previous stroke, transient ischemic attack (TIA), or systemicembolism
• Left ventricular ejection fraction <40%
• Symptomatic heart failure, ≥ New York Heart AssociationClass 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 studywas to determine if Pradaxa was non-inferior to warfarin in reducingthe occurrence of the composite endpoint, stroke (ischemic and hemorrhagic)and systemic embolism. The study was designed to ensure that PRADAXApreserved more than 50% of warfarin’s effect as established by previousrandomized, placebo-controlled trials of warfarin in atrial fibrillation. Statistical superiority was also analyzed.

A total of 18,113 patients were randomized and followedfor a median of 2 years. The patients’ mean age was 71.5 years andthe mean CHADS₂ score was 2.1. The patientpopulation 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 monthstotal lifetime exposure to a VKA. Thirty-two percent of the populationhad never been exposed to a VKA. Concomitant diseases of patientsin 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 intherapeutic range (INR 2 to 3) was 64%.

Relative to warfarin and to Pradaxa 110 mg twice daily,PRADAXA 150 mg twice daily significantly reduced the primary compositeendpoint of stroke and systemic embolism.

* Randomized ITT
	Pradaxa 150 mg twice daily	Pradaxa 110 mg twice daily	Warfarin
Patients randomized	6076	6015	6022
Patients (%) with events	135 (2.2%)	183 (3%)	203 (3.4%)
Hazard ratio vs. warfarin (95%CI)	0.65 (0.52, 0.81)	0.89 (0.73, 1.09)
P-value for superiority	0.0001	0.27
Hazard ratio vs. Pradaxa 110mg (95% CI)	0.72 (0.58, 0.91)
P-value for superiority	0.005

Figure 4 Kaplan-Meier CurveEstimate of Time to First Stroke or Systemic Embolism

The contributions of the components of the compositeendpoint, including stroke by subtype, are shown in Table 10. Thetreatment effect was primarily a reduction in stroke. Pradaxa 150mg twice daily was superior in reducing ischemic and hemorrhagic strokesrelative to warfarin.

	Pradaxa 150 mg twice daily	Warfarin	Hazard ratiovs. warfarin (95% CI)
Patients randomized	6076	6022
Stroke	123	187	0.64 (0.51, 0.81)
Ischemic stroke	104	134	0.76 (0.59, 0.98)
Hemorrhagic stroke	12	45	0.26 (0.14, 0.49)
Systemic embolism	13	21	0.61 (0.30, 1.21)

In the RE-LY trial, therate of all-cause mortality was lower on dabigatran 150 mg than onwarfarin (3.6% per year versus 4.1% per year). The rate of vasculardeath was lower on dabigatran 150 mg compared to warfarin (2.3% peryear versus 2.7% per year). Non-vascular death rates were similarin the treatment arms.

The efficacyof Pradaxa 150 mg twice daily was generally consistent across majorsubgroups.

Figure 5 Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics*

* Randomized ITT

Note: The figureabove presents effects in various subgroups all of which are baselinecharacteristics and all of which were pre-specified. The 95% confidencelimits that are shown do not take into account how many comparisonswere made, nor do they reflect the effect of a particular factor afteradjustment for all other factors. Apparent homogeneity or heterogeneityamong groups should not be over-interpreted.

In RE-LY, a higher rate of clinical myocardial infarctionwas reported in patients who received Pradaxa (0.7 per 100 patient-yearsfor 150 mg dose) than in those who received warfarin (0.6).

Figure 4 Figure 5

14.2 Treatment and Reductionin the Risk of Recurrence of Deep Venous Thrombosis and PulmonaryEmbolism

Inthe randomized, parallel group, double-blind trials, RE-COVER andRE-COVER II, patients with deep vein thrombosis and pulmonary embolismreceived Pradaxa 150 mg twice daily or warfarin (dosed to target INRof 2 to 3) following initial treatment with an approved parenteralanticoagulant for 5-10 days.

In RE-COVER, the median treatment durationduring the oral only treatment period was 174 days. A total of 2539patients (30.9% patients with symptomatic PE with or without DVT and68.9% with symptomatic DVT only) were treated with a mean age of 54.7years. The patient population was 58.4% male, 94.8% white, 2.6% Asian,and 2.6% black. The concomitant diseases of patients in this trialincluded hypertension (35.9%), diabetes mellitus (8.3%), coronaryartery disease (6.5%), active cancer (4.8%), and gastric or duodenalulcer (4.4%). Concomitant medications included agents acting on renin-angiotensinsystem (25.2%), vasodilators (28.4%), serum lipid-reducing agents(18.2%), NSAIDs (21%), beta-blockers (14.8%), calcium channel blockers(8.5%), ASA (8.6%), and platelet inhibitors excluding ASA (0.6%). Patients randomized to warfarin had a mean percentage of time inthe INR target range of 2.0 to 3.0 of 60% in RE-COVER study.

In RE-COVER II, the median treatmentduration during the oral only treatment period was 174 days. A totalof 2568 patients (31.8% patients with symptomatic PE with or withoutDVT and 68.1% with symptomatic DVT only) were treated with a meanage of 54.9 years. The patient population was 60.6% male, 77.6% white,20.9% Asian, and 1.5% black. The concomitant diseases of patientsin this trial included hypertension (35.1%), diabetes mellitus (9.8%),coronary artery disease (7.1%), active cancer (3.9%), and gastricor duodenal ulcer (3.8%). Concomitant medications included agentsacting on renin-angiotensin system (24.2%), vasodilators (28.6%),serum lipid-reducing agents (20.0%), NSAIDs (22.3%), beta-blockers(14.8%), calcium channel blockers (10.8%), ASA (9.8%), and plateletinhibitors excluding ASA (0.8%). Patients randomized to warfarinhad a mean percentage of time in the INR target range of 2.0 to 3.0of 57% in RE-COVER II study.

In studies RE-COVER and RE-COVER II, theprotocol specified non-inferiority margin (2.75) for the hazard ratiowas derived based on the upper limit of the 95% confidence intervalof the historical warfarin effect. Pradaxa was demonstrated to benon-inferior to warfarin (dosed to target INR of 2 to 3) (Table 11)based on the primary composite endpoint (fatal PE or symptomatic non-fatalPE and/or DVT) and retains at least 66.9% (RE-COVER) and 63.9% (RE-COVERII) of the historical warfarin effect, respectively.

aModified ITT analysespopulation consists of all randomized patients who received at leastone dose of study medication. bNumber of patients with one or more event. cNumber of events. For patients with multiple eventseach event is counted independently.
		Pradaxa 150mg twice daily N (%)	Warfarin N(%)	Hazard ratio vs. warfarin (95% CI)
RE-COVER		N=1274	N=1265
Primary CompositeEndpointb		34 (2.7)	32 (2.5)	1.05 (0.65, 1.70)
	Fatal PEc	1 (0.1)	3 (0.2)
	Symptomatic non-fatal PEc	16 (1.3)	8 (0.6)
	Symptomatic recurrent DVTc	17 (1.3)	23 (1.8)
RE-COVER II		N=1279	N=1289
Primary CompositeEndpointb		34 (2.7)	30 (2.3)	1.13 (0.69, 1.85)
	Fatal PEc	3 (0.2)	0
	Symptomatic non-fatal PEc	9 (0.7)	15 (1.2)
	Symptomatic recurrent DVTc	30 (2.3)	17 (1.3)

In the randomized, parallelgroup, double-blind, pivotal trial, RE-MEDY, patients received PRADAXA150 mg twice daily or warfarin (dosed to target INR of 2 to 3) following3 to 12 months of treatment with anticoagulation therapy for an acuteVTE. The median treatment duration during the treatment period was534 days. A total of 2856 patients were treated with a mean age of54.6 years. The patient population was 61% male, and 90.1% white,7.9% Asian and 2.0% black. The concomitant diseases of patients inthis trial included hypertension (38.6%), diabetes mellitus (9.0%),coronary artery disease (7.2%), active cancer (4.2%), and gastricor duodenal ulcer (3.8%). Concomitant medications included agentsacting on renin-angiotensin system (27.9%), vasodilators (26.7%),serum lipid reducing agents (20.6%), NSAIDs (18.3%), beta-blockers(16.3%), calcium channel blockers (11.1%), aspirin (7.7%), and plateletinhibitors excluding ASA (0.9%). Patients randomized to warfarinhad a mean percentage of time in the INR target range of 2.0 to 3.0of 62% in the study.

In study RE-MEDY, the protocol specified non-inferiority margin (2.85)for the hazard ratio was derived based on the point estimate of thehistorical warfarin effect. Pradaxa was demonstrated to be non-inferiorto warfarin (dosed to target INR of 2 to 3) (Table 12) based on theprimary composite endpoint (fatal PE or symptomatic non-fatal PE and/orDVT) and retains at least 63.0% of the historical warfarin effect. If the non-inferiority margin was derived based on the 50% retentionof the upper limit of the 95% confidence interval, Pradaxa was demonstratedto retain at least 33.4% of the historical warfarin effect based onthe composite primary endpoint.

aModified ITT analysespopulation consists of all randomized patients who received at leastone dose of study medication. bNumber of patients with one or more event. cNumber of events. For patients with multiple eventseach event is counted independently.
		Pradaxa 150mg twice daily N=1430 N (%)	Warfarin N=1426 N (%)	Hazard ratio vs. warfarin (95% CI)
Primary CompositeEndpointb		26 (1.8)	18 (1.3)	1.44 (0.78, 2.64)
	Fatal PEc	1 (0.07)	1 (0.07)
	Symptomatic non-fatal PEc	10 (0.7)	5 (0.4)
	Symptomatic recurrent DVTc	17 (1.2)	13 (0.9)

In a randomized, parallelgroup, double-blind, pivotal trial, RE-SONATE, patients received PRADAXA150 mg twice daily or placebo following 6 to 18 months of treatmentwith anticoagulation therapy for an acute VTE. The median treatmentduration was 182 days. A total of 1343 patients were treated witha mean age of 55.8 years. The patient population was 55.5% male,89.0% white, 9.3% Asian, and 1.7% black. The concomitant diseasesof patients in this trial included hypertension (38.8%), diabetesmellitus (8.0%), coronary artery disease (6.0%), history of cancer(6.0%), gastric or duodenal ulcer (4.5%), and heart failure (4.6%). Concomitant medications included agents acting on renin-angiotensinsystem (28.7%), vasodilators (19.4%), beta-blockers (18.5%), serumlipid reducing agents (17.9%), NSAIDs (12.1%), calcium channel blockers(8.9%), aspirin (8.3%), and platelet inhibitors excluding ASA (0.7%). Based on the outcome of the primary composite endpoint (fatal PE,unexplained death, or symptomatic non-fatal PE and/or DVT), PRADAXAwas superior to placebo (Table 13).

aModified ITT analysespopulation consists of all randomized patients who received at leastone dose of study medication. bNumber of patients with one or more events. cNumber of events. For patients with multiple eventseach event is counted independently.
		Pradaxa 150mg twice daily N=681 N (%)	Placebo N=662 N (%)	Hazard ratio vs. placebo (95% CI)
Primary CompositeEndpointb		3 (0.4)	37 (5.6)	0.08 (0.02, 0.25) p-value <0.0001
	Fatal PE and unexplained deathc	0	2 (0.3)
	Symptomatic non-fatal PEc	1 (0.1)	14 (2.1)
	Symptomatic recurrent DVTc	2 (0.3)	23 (3.5)

14.3 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism FollowingHip Replacement Surgery

In the randomized, parallel group, double-blind,non-inferiority trials, RE-NOVATE and RE-NOVATE II patients receivedPRADAXA 75 mg orally 1-4 hours after surgery followed by 150 mg daily(RE-NOVATE), Pradaxa 110 mg orally 1-4 hours after surgery followedby 220 mg daily (RE-NOVATE and RE-NOVATE II) or subcutaneous enoxaparin40 mg once daily initiated the evening before surgery (RE-NOVATE andRE-NOVATE II) for the prophylaxis of deep vein thrombosis and pulmonaryembolism in patients who have undergone hip replacement surgery.

Overall, in RE-NOVATE and RE-NOVATEII, the median treatment duration was 33 days for Pradaxa and 33 daysfor enoxaparin. A total of 5428 patients were treated with a meanage of 63.2 years. The patient population was 45.3% male, 96.1% white,3.6% Asian, and 0.4 % black. The concomitant diseases of patientsin these trials included hypertension (46.1%), venous insufficiency(15.4%), coronary artery disease (8.2%), diabetes mellitus (7.9%),reduced renal function (5.3%), heart failure (3.4%), gastric or duodenalulcer (3.0%), VTE (2.7%), and malignancy (0.1%). Concomitant medicationsincluded cardiac therapy (69.7%), NSAIDs (68%), vasoprotectives (29.7%),agents acting on renin-angiotensin system (29.1%), beta-blockers (21.5%),diuretics (20.8%), lipid modifying agents (18.2%), any antithrombin/anticoagulant(16.0%), calcium channel blockers (13.6%), low molecular weight heparin(7.8%), aspirin (7.0%), platelet inhibitors excluding ASA (6.9%),other antihypertensives (6.7%), and peripheral vasodilators (2.6%).

For efficacy evaluation allpatients were to have bilateral venography of the lower extremitiesat 3 days after last dose of study drug unless an endpoint event hadoccurred earlier in the study. In the primary efficacy analysis,PRADAXA 110 mg orally 1-4 hours after surgery followed by 220 mg dailywas non-inferior to enoxaparin 40 mg once daily in a composite endpointof confirmed VTE (proximal or distal DVT on venogram, confirmed symptomaticDVT, or confirmed PE) and all cause death during the treatment period(Tables 14 and 15). In the studies 2628 (76.5%) patients in RE-NOVATEand 1572 (78.9%) patients in RE-NOVATE II had evaluable venogramsat study completion.

aFull Analysis Set (FAS):The FAS included all randomized patients who received at least onesubcutaneous injection or one oral dose of study medication, underwentsurgery and subjects for whom the presence or absence of an efficacyoutcome at the end of the study was known, i.e., an evaluable negativevenogram for both distal and proximal DVT in both legs or any of thefollowing: positive venography in one or both legs, or confirmed symptomaticDVT, PE, or death during the treatment period. bVTE is defined as proximal DVT and PE
	Pradaxa 220 mg N (%)	Enoxaparin N (%)
Number of Patientsa	N=880	N= 897
Primary Composite Endpoint	53 (6.0)	60 (6.7)
Risk difference (%) vs. enoxaparin(95% CI)	-0.7 (-2.9, 1.6)
Number of Patients	N=909	N=917
Composite endpoint of majorVTEb and VTE related mortality	28 (3.1)	36 (3.9)
Number of Patients	N=905	N=914
Proximal DVT	23 (2.5)	33 (3.6)
Number of Patients	N=874	N=894
Total DVT	46 (5.3)	57 (6.4)
Number of Patients	N=1137	N=1142
Symptomatic DVT	6 (0.5)	1 (0.1)
PE	5 (0.4)	3 (0.3)
Death	3 (0.3)	0

aFull Analysis Set (FAS):The FAS included all randomized patients who received at least onesubcutaneous injection or one oral dose of study medication, underwentsurgery and subjects for whom the presence or absence of an efficacyoutcome at the end of the study was known, i.e., an evaluable negativevenogram for both distal and proximal DVT in both legs or any of thefollowing: positive venography in one or both legs, or confirmed symptomaticDVT, PE, or death during the treatment period. bVTE is defined as proximal DVT and PE
	Pradaxa 220 mg N (%)	Enoxaparin N (%)
Number of Patientsa	N=792	N= 786
Primary Composite Endpoint	61 (7.7)	69 (8.8)
Risk difference (%) vs. enoxaparin(95% CI)	-1.1 (-3.8, 1.6)
Number of Patients	N=805	N=795
Composite endpoint of majorVTEb and VTE related mortality	18 (2.2)	33 (4.2)
Number of Patients	N=804	N=793
Proximal DVT	17 (2.1)	31 (3.9)
Number of Patients	N=791	N=784
Total DVT	60 (7.6)	67 (8.5)
Number of Patients	N=1001	N=992
Symptomatic DVT	0	4 (0.4)
PE	1 (0.1)	2 (0.2)
Death	0	1 (0.1)

16  HOW SUPPLIED/STORAGEAND HANDLING

PRADAXA75 mg capsules have a white opaque cap imprinted with the BoehringerIngelheim company symbol and a white opaque body imprinted with “R75”. The color of the imprinting is black. The capsules are suppliedin the packages listed:

• NDC 0597-0355-09 Unit of use bottle of 60 capsules
• NDC 0597-0355-56 Blister package containing 60 capsules(10 x 6 capsule blister cards)

Pradaxa 110 mg capsuleshave a light blue opaque cap imprinted with the Boehringer Ingelheimcompany symbol and a light blue opaque body imprinted with “R110”. The color of the imprinting is black. The capsules are suppliedin the packages listed:

• NDC 0597-0108-54 Unit of use bottle of 60 capsules
• NDC 0597-0108-60 Blister package containing 60 capsules(10 x 6 capsule blister cards)

Pradaxa 150 mg capsules have a lightblue opaque cap imprinted with the Boehringer Ingelheim company symboland a white opaque body imprinted with “R150”. The color of the imprintingis black. The capsules are supplied in the packages listed:

• NDC 0597-0360-55 Unit of use bottle of 60 capsules
• NDC 0597-0360-82 Blister package containing 60 capsules(10 x 6 capsule blister cards)

Bottles

Storeat 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Once opened, the product mustbe used within 4 months. Keep the bottle tightly closed. Store inthe original package to protect from moisture.

Blisters

Store at 25°C (77°F); excursions permittedto 15° to 30°C (59° to 86°F). Store in the original package to protect from moisture.

Keep out of the reach of children.

17  PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patientlabeling.

17.1 Instructions forPatients

• Tell patients to take Pradaxa exactly as prescribed.
• Remind patients not to discontinue Pradaxa without talkingto 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, instructthem to open only one bottle at a time.
• Instruct patient to remove only one capsule from the openedbottle at the time of use. The bottle should be immediately and tightlyclosed.
• Advise patients not to chew or break the capsules beforeswallowing them and not to open the capsules and take the pelletsalone.
• Advise patients that the capsule should be taken with afull glass of water.

17.2 Bleeding

Inform patients that they may bleed moreeasily, may bleed longer, and should call their health care providerfor any signs or symptoms of bleeding.

Instruct patients to seek emergency care right awayif they have any of the following, which may be a sign or symptomof serious bleeding:

• Unusual bruising
• Pink or brown urine
• Red or black, tarry stools
• Coughing up blood
• Vomiting blood, or vomit that looks like coffee grounds

Instruct patients to call their healthcare provider or to get prompt medical attention if they experienceany 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 thannormal

If patients have had neuraxialanesthesia or spinal puncture, and particularly, if they are takingconcomitant NSAIDs or platelet inhibitors, advise patients to watchfor signs and symptoms of spinal or epidural hematoma, such as backpain, tingling, numbness (especially in the lower limbs), muscle weakness,and stool or urine incontinence. If any of these symptoms occur, advisethe patient to contact his or her physician immediately .

17.3 GastrointestinalAdverse Reactions

Instructpatients to call their health care provider if they experience anysigns or symptoms of dyspepsia or gastritis:

• Dyspepsia (upset stomach), burning, or nausea
• Abdominal pain or discomfort
• Epigastric discomfort, GERD (gastric indigestion)

17.4 Invasive or SurgicalProcedures

Instructpatients to inform their health care provider that they are takingPRADAXA before any invasive procedure is scheduled.

17.5 Concomitant Medications

Ask patients to list all prescription medications,over-the-counter medications, or dietary supplements they are takingor plan to take so their health care provider knows about other treatmentsthat may affect bleeding risk (e.g., aspirin or NSAIDs) or dabigatranexposure (e.g., dronedarone or systemic ketoconazole).

17.6 Prosthetic HeartValves

Instruct patientsto inform their health care provider if they will have or have hadsurgery to place a prosthetic heart valve.

Distributed by:

Boehringer Ingelheim Pharmaceuticals, Inc.

Ridgefield,CT 06877 USA

Copyright 2017 BoehringerIngelheim Pharmaceuticals, Inc.

ALL RIGHTS RESERVED

IT5060AIG262017

MEDICATION GUIDE Pradaxa (pra dax a) (dabigatranetexilate mesylate) capsules
Read this MedicationGuide before you start taking Pradaxa and each time you get a refill. There may be new information. This Medication Guide does not takethe place of talking with your doctor about your medical conditionor your treatment.
What is themost important information I should know about Pradaxa? For people taking Pradaxa for atrial fibrillation: People with atrial fibrillation (a type of irregularheartbeat) are at an increased risk of forming a blood clot in theheart, which can travel to the brain, causing a stroke, or to otherparts of the body. Pradaxa lowers your chance of having a stroke byhelping to prevent clots from forming. If you stop taking Pradaxa,you may have increased risk of forming a clot in your blood. Do not stop taking Pradaxa without talking tothe doctor who prescribes it for you. Stopping Pradaxa increases yourrisk of having a stroke. Pradaxa mayneed to be stopped, if possible, prior to surgery or a medical ordental procedure. Ask the doctor who prescribed Pradaxa for you whenyou should stop taking it. Your doctor will tell you when you maystart taking Pradaxa again after your surgery or procedure. If youhave to stop taking Pradaxa, your doctor may prescribe another medicineto help prevent a blood clot from forming. Pradaxa can cause bleeding which can be serious, and sometimeslead to death. This is because Pradaxa is a blood thinner medicinethat lowers the chance of blood clots forming in your body. You may have a higher risk of bleeding if you takePRADAXA and: are over 75 years old have kidney problems have stomach or intestine bleeding that is recent or keepscoming back, or you have a stomach ulcer take other medicines that increase your risk of bleeding,including: aspirin or aspirin containing products long-term (chronic) use of non-steroidal anti-inflammatorydrugs (NSAIDs) warfarin sodium (Coumadin®, Jantoven®) a medicine that contains heparin clopidogrel bisulfate (Plavix®) prasugrel (Effient®) have certain kidney problems and also take the medicinesdronedarone (Multaq®) or ketoconazole tablets(Nizoral®). Tell your doctorif you take any of these medicines. Ask your doctor or pharmacistif you are not sure if your medicine is one listed above. Pradaxa can increase your risk of bleeding because it lessensthe ability of your blood to clot. While you take Pradaxa: you may bruise more easily it may take longer for any bleeding to stop Call your doctor or get medical help right away if youhave any of these signs or symptoms of bleeding: unexpected bleeding or bleeding that lasts a long time,such as: unusual bleeding from the gums nose bleeds that happen often menstrual bleeding or vaginal bleeding that is heavier thannormal bleeding that is severe or you cannot control pink or brown urine red or black stools (looks like tar) bruises that happen without a known cause or get larger cough up blood or blood clots vomit blood or your vomit looks like “coffee grounds” unexpected pain, swelling, or joint pain headaches, feeling dizzy or weak Take Pradaxa exactly as prescribed. Do not stop takingPRADAXA without first talking to the doctor who prescribes it foryou. Stopping Pradaxa may increase your risk of a stroke. Pradaxa may need to be stopped, if possible, for one or more daysbefore any surgery, or medical or dental procedure. If you need tostop taking Pradaxa for any reason, talk to the doctorwho prescribed Pradaxa for you to find out when you should stop takingit. Your doctor will tell you when to start taking Pradaxa again afteryour surgery or procedure. Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant) like Pradaxa,and have medicine injected into their spinal and epidural area, orhave a spinal puncture have a risk of forming a blood clot that cancause long-term or permanent loss of the ability to move (paralysis).Your risk of developing a spinal or epidural blood clot is higherif: a thin tube called an epidural catheter is placed in yourback to give you certain medicine. you take NSAIDs or a medicine to prevent blood from clotting you have a history of difficult or repeated epidural orspinal punctures you have a history of problems with your spine or have hadsurgery on your spine. If you take Pradaxa and receive spinal anesthesia or have aspinal puncture, your doctor should watch you closely for symptomsof spinal or epidural blood clots. Tell your doctor right away ifyou have back pain, tingling, numbness, muscle weakness (especiallyin your legs and feet), loss of control of the bowels or bladder (incontinence). See “What are the possible side effects of Pradaxa?”for more information about side effects.
What is Pradaxa? Pradaxa is a prescription blood thinner medicine thatlowers the chance of blood clots forming in your body. Pradaxa isused to: reduce the risk of stroke and blood clots in people whohave a medical condition called atrial fibrillation. With atrial fibrillation,part of the heart does not beat the way it should. This can leadto blood clots forming and increase your risk of a stroke. treat blood clots in the veins of your legs (deep vein thrombosis)or lungs (pulmonary embolism) and reduce the risk of them occurringagain. to help prevent blood clots in the legs and lungs of peoplewho have just had hip replacement surgery. Pradaxa is not for use in people with artificial (prosthetic)heart valves. It is not known if Pradaxa is safe and worksin children.
Who shouldnot take Pradaxa? currently have certain types of abnormal bleeding. Talkto your doctor before taking Pradaxa if you currently have unusualbleeding. have had a serious allergic reaction to Pradaxa. Ask yourdoctor if you are not sure. have ever had or plan to have a valve in your heart replaced
What shouldI tell my doctor before taking Pradaxa? have kidney problems have ever had bleeding problems have ever had stomach ulcers have any other medical condition are pregnant or plan to become pregnant. It is not knownif Pradaxa will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not knownif Pradaxa passes into your breast milk. Tell all of your doctors and dentists that you are taking Pradaxa. They should talk to the doctor who prescribed Pradaxa for you, beforeyou have any surgery, or a medical or dental procedure. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbalsupplements. Some of your other medicines may affect theway Pradaxa works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know aboutPRADAXA?” Especially tell your doctor if you take: rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®) Know the medicines you take. Keep a list of themand show it to your doctor and pharmacist when you get a new medicine.
Your doctor will decide how long you should take Pradaxa. Do not stop taking Pradaxa without first talking with your doctor. Stopping Pradaxa may increase your risk of having a stroke or formingblood clots. Take Pradaxa exactly as prescribed by your doctor. Take Pradaxa capsules twice a day (approximately every 12hours). If you miss a dose of Pradaxa, take it as soon as you remember. If your next dose is less than 6 hours away, skip the missed dose. Do not take two doses of Pradaxa at the same time. Swallow Pradaxa capsules whole. Do not break, chew, or emptythe pellets from the capsule. You can take Pradaxa with or without food. You should take Pradaxa with a full glass of water. Do not run out of Pradaxa. Refill your prescription beforeyou run out. If you plan to have surgery, or a medical or a dentalprocedure, tell your doctor and dentist that you are taking Pradaxa. You may have to stop taking Pradaxa for a short time. See “What isthe most important information I should know about Pradaxa?”. If you take too much Pradaxa, go to the nearest hospitalemergency room or call your doctor. Call your doctor or healthcare provider right away if youfall or injure yourself, especially if you hit your head. Your doctoror healthcare provider may need to check you. Pradaxa comes in a bottle or in a blister package. Only open 1 bottle of Pradaxa at a time. Finish your openedbottle of Pradaxa before opening a new bottle. After opening a bottle of Pradaxa, use within 4 months. See “How should I store Pradaxa?” When it is time for you to take a dose of Pradaxa, onlyremove your prescribed dose of Pradaxa from your open bottle or blisterpackage. Tightly close your bottle of Pradaxa right away after youtake your dose.
What are the possibleside effects of Pradaxa? See “What is the most important information I should knowabout Pradaxa?” Allergic Reactions. In some people, Pradaxa can cause symptomsof an allergic reaction, including hives, rash, and itching. Tellyour doctor or get medical help right away if you get any of the followingsymptoms of a serious allergic reaction with Pradaxa:
chest pain or chest tightness swelling of your face or tongue	trouble breathing or wheezing feeling dizzy or faint
Common side effectsof Pradaxa include: indigestion, upset stomach, or burning stomach pain Tell your doctor if you have any side effect that bothers youor that does not go away. These are not all of the possibleside effects of Pradaxa. For more information, ask your doctor orpharmacist. Call your doctor for medical advice about sideeffects. You may report side effects to FDA at 1-800-FDA-1088.
Store Pradaxa at room temperature 68°F to 77°F (20°C to25°C). After opening the bottle, use Pradaxa within 4 months. Safelythrow away any unused Pradaxa after 4 months. Keep Pradaxa in the original bottle or blister packageto keep it dry (protect the capsules from moisture). Do not put PRADAXAin pill boxes or pill organizers. Tightly close your bottle of Pradaxa right away afteryou take your dose. Keep Pradaxa and all medicines out of the reach of children.
General informationabout the safe and effective use of Pradaxa Medicinesare sometimes prescribed for purposes other than those listed in aMedication Guide. Do not use Pradaxa for a condition for which itwas not prescribed. Do not give Pradaxa to other people, even if theyhave the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important informationabout Pradaxa. If you would like more information, talk with yourdoctor. You can ask your pharmacist or doctor for information aboutPRADAXA that is written for health professionals. For moreinformation, go to www.pradaxa.com or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257or (TTY) 1-800-459-9906, or scan here to go to www.pradaxa.com.
What are theingredients in Pradaxa? Active ingredient: dabigatranetexilate mesylate Inactive ingredients: acacia, dimethicone,hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. Thecapsule shell is composed of carrageenan, hypromellose, potassiumchloride, titanium dioxide, black edible ink, and FD&C Blue No.2 (150 mg and 110 mg capsules only). Distributedby: Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT 06877USA The brands listed above are trademarksof their respective owners and are not trademarks of Boehringer IngelheimPharmaceuticals, Inc. The owners of these brands are not affiliatedwith and do not endorse Boehringer Ingelheim Pharmaceuticals, Inc.,or its products. Copyright 2017 BoehringerIngelheim Pharmaceuticals, Inc. ALL RIGHTS RESERVED IT5060AIG262017

This Medication Guidehas been approved by the U.S. Food and Drug Administration.                                                     Revised:July 2017

pradaxa-qrcode Pradaxa (dabigatran etexilate mesylate)

75 mg capsules

NDC 0597-0149-54

Pradaxa (dabigatran etexilate mesylate) capsules

PRADAXA(dabigatran etexilate mesylate)

75 mg capsules

NDC 0597-0149-60

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Pradaxa (dabigatran etexilate mesylate)

75 mg capsules

NDC 0597-0149-54

PRADAXA(dabigatran etexilate mesylate)

110 mg capsules

NDC 0597-0108-54

carton-110mg PRADAXA(dabigatran etexilate mesylate)

110mg capsules

NDC 0597-0108-60

pradaxa-carton-0108-60 Pradaxa (dabigatranetexilate mesylate)

110 mg capsules

NDC 0597-0108-54

Pradaxa (dabigatran etexilate mesylate)

150 mg capsules

NDC 0597-0135-54

NDC 0597-0135-54 carton

Pradaxa (dabigatran etexilate mesylate)

150 mg capsules

NDC 0597-0135-60

Pradaxa 150 Carton

Pradaxa (dabigatran etexilate mesylate)

150 mg capsules

NDC 0597-0135-12

NDC 0597-0135-12 carton

Pradaxa (dabigatran etexilate mesylate)

150 mg capsules

NDC 0597-0135-54

PRADAXA(dabigatran etexilate mesylate)

75 mg capsules

NDC 0597-0355-09

carton-035509 PRADAXA(dabigatran etexilate mesylate)

75 mg capsules

NDC 0597-0355-56

carton-035556 PRADAXA(dabigatran etexilate mesylate)

150 mg capsules

NDC 0597-0360-42

carton-036042 PRADAXA(dabigatran etexilate mesylate)

150 mg capsules

NDC 0597-0360-55

carton-036055 PRADAXA(dabigatran etexilate mesylate)

150 mg capsules

NDC 0597-0360-82

carton-036082 PRADAXA(dabigatran etexilate mesylate)

75 mg capsules

NDC 0597-0355-09

PRADAXA(dabigatran etexilate mesylate)

150 mg capsules

NDC 0597-0360-55

Pradaxa pharmaceutical active ingredients containing related brand and generic drugs:

• Dabigatran Etexilate Mesylate

Pradaxa available forms, composition, doses:

• Capsules; Oral; Dabigatran Etexilate Mesylate 110 mg
• Capsules; Oral; Dabigatran Etexilate Mesylate 150 mg
• Capsules; Oral; Dabigatran Etexilate Mesylate 75 mg

Pradaxa destination | category:

• Human:
• Direct thrombin inhibitors

Pradaxa Anatomical Therapeutic Chemical codes:

• B01AE07 - Dabigatran Etexilate

Pradaxa pharmaceutical companies:

• Boehringer Ingelheim
• DKSH
• Metro Drug Distribution
• Zuellig Pharma

References

1. Dailymed."PRADAXA (DABIGATRAN ETEXILATE MESYLATE) CAPSULE [BOEHRINGER INGELHEIM PHARMACEUTICALS INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. "Dabigatran etexilate". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
3. "Dabigatran etexilate". http://www.drugbank.ca/drugs/DB0669... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Pradaxa?

Depending on the reaction of the Pradaxa after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Pradaxa not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Pradaxa addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Pradaxa, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Pradaxa consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology