Pradaxa

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Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available.

Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran's plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Pradaxa can cause serious side effects. See the "Pradaxa Precautions" section.

Common side effects of Pradaxa include:

• indigestion, upset stomach, or burning
• stomach pain

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Pradaxa. For more information, ask your doctor or pharmacist.

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if Pradaxa is excreted in human breast milk or if it will harm your nursing baby.

Take Pradaxa exactly as prescribed by your doctor.

• Do not take Pradaxa more often than your doctor tells you to.
• You can take Pradaxa with or without food.
• Pradaxa comes in a bottle or in a blister package.
• Only open 1 bottle of Pradaxa at a time. Finish your opened bottle of Pradaxa before opening a new bottle.
• After opening a bottle of Pradaxa, use within 4 months. 
• When it is time for you to take a dose of Pradaxa, only remove your prescribed dose of Pradaxa from your open bottle or blister package.
• Tightly close your bottle of Pradaxa right away after you take your dose.
• Swallow Pradaxa capsules whole. Do not break, chew, or empty the pellets from the capsule.
• 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.
• 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 stroke.
• Do not run out of Pradaxa. Refill your prescription before you run out. If you plan to have surgery, or a medical or a dental procedure, tell your doctor and dentist that you are taking Pradaxa. You may have to stop taking Pradaxa for a short time.
• If you take too much Pradaxa, go to the nearest hospital emergency room or call your doctor.
• Call your healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you.

• Store Pradaxa at room temperature between 59°F to 86°F (15°C to 30°C). After opening the bottle, use Pradaxa within 4 months. Safely throw away any unused Pradaxa after 4 months.
• Keep Pradaxa in the original bottle or blister package to keep it dry (protect the capsules from moisture). Do not put Pradaxa in pill boxes or pill organizers.
• Tightly close your bottle of Pradaxa right away after you take your dose.
• Keep Pradaxa and all medicines out of the reach of children.

Dabigatran etexilate is absorbed after oral administration of dabigatran etexilate mesylate and hydrolyzed to the active moiety, dabigatran, by esterases in plasma and the liver.1 13 7 Dabigatran undergoes conjugation to acyl glucuronides that have similar pharmacologic activity to dabigatran and account for approximately 20% of the total plasma dabigatran concentration.1 11 12 13 The pharmacokinetics of dabigatran are generally described in terms of total plasma dabigatran concentrations, which includes the major acyl glucuronide metabolites.1 11 Dabigatran exhibits linear, dose-dependent pharmacokinetics.1

Absorption

Bioavailability

Absolute bioavailability of dabigatran following oral administration of dabigatran etexilate approximately 3–7%.1

Steady-state expected within 3 days when given 3 times daily.12

Onset

Peak plasma concentration attained approximately 1–2 hours following oral administration.1 11 13 Maximal effects on coagulation assays expected within 2 hours of administration; such effects correlate with peak plasma concentrations.1 11 13

Duration

Effects on anticoagulation assays decline by approximately 50% at 12 hours after administration.11

Food

High-fat meal delays time to peak plasma concentration by 2 hours but does not affect bioavailability.1

Special Populations

When dabigatran was administered 1–3 hours after completing hip arthroplasty, time to peak plasma concentrations was delayed to 6 hours but returned to normal day after surgery.2 12 There was no effect on AUC.2 12

In patients with mild, moderate, or severe renal impairment, AUC estimated to be increased 1.5-, 3.2-, or 6.3-fold respectively; peak plasma concentrations increased 1.1-, 1.7-, or 2.1-fold, respectively.1 14

Distribution

Extent

Not known whether dabigatran distributes into milk.1

Plasma Protein Binding

Approximately 35%.1 13

Elimination

Metabolism

Dabigatran etexilate is a prodrug of dabigatran;2 rapidly absorbed following oral administration and hydrolyzed in the plasma to dabigatran, the active moiety.1 11

Elimination Route

Bioavailable dabigatran excreted principally (80%) in urine as unchanged drug.1 13 Approximately 86% of total dose is eliminated in the feces.1

Half-life

12–17 hours.1 11

Special Populations

In patients with mild, moderate, or severe renal impairment, plasma half-life averages 15, 18, or 28 hours, respectively.1

In patients with moderate hepatic impairment (Child-Pugh class B), large interpatient variability apparent, but no consistent change in exposure or pharmacodynamic response.1 15 41

Storage

Oral

25°C (may be exposed to 15–30°C).1 Store in original package (i.e., bottles or blister pack) to protect from moisture.1

Advise patients about special storage and handling requirements.36 Dispense only in original bottle with desiccant cap to minimize product breakdown from moisture.36 (See Advice to Patients.)

Once bottle is opened, manufacturer recommends that drug be used within 4 months.1 Keep bottle tightly closed.1

Keep out of reach of children.1

• Risk of bleeding.1 Patients should seek emergency medical care if they experience manifestations of serious bleeding (e.g., unusual bruising, including bruises with unknown cause or that enlarge; pink or brown urine; red or black, tarry stool; coughing up blood; vomiting blood; vomitus with the appearance of coffee grounds).1

• Patients should consult healthcare provider for other manifestations of bleeding (e.g., pain, swelling, or discomfort in a joint, headaches, dizziness, weakness, recurrent nose bleeds, unusual bleeding from the gums, prolonged bleeding from a cut, heavier than normal menstrual or vaginal bleeding).1

• Importance of advising patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., back pain, tingling or numbness in lower limbs, muscle weakness, stool or urine incontinence), particularly if they are receiving concomitant NSAIAs, platelet-aggregation inhibitors, or other anticoagulants; importance of immediately contacting a clinician if any of these symptoms occur.1

• Risk of adverse GI reactions.1 Patients should consult healthcare provider if they experience dyspepsia, burning, nausea, abdominal pain/discomfort, epigastric discomfort, or indigestion.1

• Patients should inform healthcare provider that they are taking dabigatran before scheduling any invasive or dental procedure.1

• Importance of informing healthcare provider if patient has had or plans to have a heart valve replacement.1

• Importance of swallowing capsules whole with a full glass of water, without breaking, chewing, or otherwise emptying the contents of the capsule.1 Do not sprinkle contents of capsules on food or into a beverage.1

• Importance of taking dabigatran exactly as prescribed.1 Do not stop taking dabigatran without discussing with prescriber.1

• Instruct patients to take missed dose as soon as remembered but only if it can be taken at least 6 hours prior to next scheduled dose.1

• Importance of informing patient of special storage and handling requirements for drug.1 36 Store only in original container, not in pill boxes or organizers.1 36 Protect from moisture.1 Remove only one capsule from container right before use, then close bottle tightly.1 36 When more than one bottle is dispensed, only open one bottle at a time.1 Do not open or puncture blister on blister package until time of use.36 Per manufacturer, use capsules within 4 months after the bottle is first opened.1 (See Stability.)

• Importance of providing patient a copy of manufacturer’s patient information.1

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In the U.S.

• Pradaxa

Available Dosage Forms:

• Capsule

Therapeutic Class: Anticoagulant

Pharmacologic Class: Dabigatran Etexilate

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Very bad dizziness or passing out.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Feeling confused.
• Feeling very tired or weak.
• Very bad headache.
• Very bad swelling.
• Very bad belly pain.
• Joint pain or swelling.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about Pradaxa, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Pradaxa. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Pradaxa.

Review Date: October 4, 2017

 Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including Pradaxa, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If Pradaxa is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart Pradaxa as soon as medically appropriate [see Dosage and Administration (2.4, 2.5, 2.6)].

 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 (2.2)].

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 (12.2)].

Reversal of Anticoagulant Effect:

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

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

Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited [see Overdosage (10)]. Prothrombin complex concentrates, or recombinant Factor VIIa 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.

 Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

To reduce the potential risk of bleeding associated with the concurrent use of dabigatran and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dabigatran [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently 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. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

 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 (4)].

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

 Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure

The concomitant use of Pradaxa with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3)].

P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology (12.3)]. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.

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

Reduce 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 (7.1) and Use in Specific Populations (8.6)].

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism

Avoid use of Pradaxa and concomitant P-gp inhibitors in patients with CrCl <50 mL/min [see Drug Interactions (7.2) and Use in Specific Populations (8.6)].

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery

Avoid use of Pradaxa and concomitant P-gp inhibitors in patients with CrCl <50 mL/min [see Drug Interactions (7.3) and Use in Specific Populations (8.6)].

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

The concomitant use of Pradaxa with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3)].

P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology (12.3)]. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.

In patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of Pradaxa to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment of Pradaxa. These results should not be extrapolated to other P-gp inhibitors [see Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

The concomitant use of Pradaxa and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided [see Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

 Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism

Avoid use of Pradaxa and P-gp inhibitors in patients with CrCl <50 mL/min [see Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery

In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of Pradaxa and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided [see Warnings and Precautions (5.5), Use in Specific Populations (8.6) and Clinical Pharmacology (12.2, 12.3)].

Pradaxa 75 mg capsules have a white opaque cap imprinted with the Boehringer Ingelheim company symbol and a white opaque body imprinted with “R75”. The color of the imprinting is black. The capsules are supplied in 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 capsules have a light blue opaque cap imprinted with the Boehringer Ingelheim company symbol and a light blue opaque body imprinted with “R110”. The color of the imprinting is black. The capsules are supplied in 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 light blue opaque cap imprinted with the Boehringer Ingelheim company symbol and a white opaque body imprinted with “R150”. The color of the imprinting is 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

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Once opened, the product must be used within 4 months. Keep the bottle tightly closed. Store in the original package to protect from moisture.

Blisters

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store in the original package to protect from moisture.

Keep out of the reach of children.

Applies to dabigatran: oral capsule

Along with its needed effects, dabigatran (the active ingredient contained in Pradaxa) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking dabigatran:

• Acid or sour stomach
• belching
• black, tarry stools
• bloody stools
• constipation
• diarrhea
• heartburn
• indigestion
• nausea
• pain or burning in the throat
• stomach discomfort, upset, burning, or pain
• vomiting
• vomiting of blood or material that looks like coffee grounds

• Cough
• difficulty with swallowing
• dizziness
• fainting or loss of consciousness
• fast heartbeat
• fast or irregular breathing
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• redness of the skin
• skin rash, hives, welts, or itching skin
• tightness in the chest
• trouble breathing
• unusual tiredness or weakness

• Large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs