dabigatran (Rx)

Brand and Other Names:Pradaxa
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

capsule

  • 75mg
  • 110mg
  • 150mg

Stroke Prophylaxis With Atrial Fibrillation

Prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation

CrCl >30 mL/min: 150 mg PO BID

CrCl 15-30 mL/min: 75 mg PO BID

CrCl <15 mL/min or dialysis: No data available; not recommended

Dosage modifications (atrial fibrillation)

  • Renal impairment and coadministration with P-gp inhibitors
    • CrCl 30-50 mL/min and coadministration with dronedarone or systemic ketoconazole: Reduce dose to 75 mg BID (dose adjustment is not necessary when coadministered with other P-gp inhibitors)
    • CrCl <30 mL/min with concomitant use of any P-gp inhibitor: Avoid coadministration

AHA/ACC/HRS guidelines for atrial fibrillation

  • Class 1: For patients with AF or atrial flutter <48-hour duration and with high risk of stroke, IV heparin or LMWH, or administration of a factor Xa or direct thrombin inhibitor, is recommended as soon as possible before or immediately after cardioversion, followed by long-term anticoagulation therapy
  • Class IIa: For patients with AF or atrial flutter of ≥48-hr, or when the duration of AF is unknown, anticoagulation with warfarin (INR 2-3), a factor Xa inhibitor, or direct thrombin inhibitor is recommended for at least 3 weeks prior to and 4 weeks after cardioversion
  • Class IIb: For patients with AF or atrial flutter <48-hour duration who are at low thromboembolic risk, anticoagulation (IV heparin, LMWH, or a new oral anticoagulant) or no antithrombotic therapy may be considered for cardioversion, without the need for postcardioversion oral anticoagulation
  • For patients with nonvalvular AF unable to maintain a therapeutic INR level with warfarin, use of a direct thrombin or factor Xa inhibitor
  • Not recommended in patients with AF and end-stage CKD or on hemodialysis because of the lack of evidence from clinical trials regarding the balance of risks and benefits; warfarin or apixaban recommended
  • Circulation July 9, 2019

DVT or PE Treatment

Indicated for treatment of deep vein thrombosis (DVT) and pulmonary embolus (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days

Also indicated to reduce the risk of recurrence of DVT and PE in patients who have been previously treated

CrCl >30 mL/min: 150 mg PO BID

CrCl ≤30 mL/min or on dialysis: Dosage recommendations cannot be provided

CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration

DVT or PE Prophylaxis

Indicated for the prophylaxis of DVT and PE following hip replacement surgery

CrCl >30 mL/min: 110 mg PO 1-4 hr after surgery and after hemostasis has been achieved on first day, then 220 mg taken qDay for 28-35 days

If dabigatran is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg qDay

CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided

CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration

Dosing Considerations

Different dosage forms

  • Available in different dosage forms (ie, capsules for adults or children aged 8 to <18 years, oral pellets for children aged 3 months to <12 years) and not all dosage forms are approved for the same indications and age groups
  • Additionally, there are differences between dosage forms with respect to dosing owing different bioavailability
  • Do not substitute different dosage forms (for example, capsules) for oral pellets on a milligram-to-milligram basis and do not combine more than 1 dosage form to achieve the total dose

Converting to dabigatran from warfarin or parenteral anticoagulants

  • Converting from warfarin: Discontinue warfarin and initiate dabigatran when INR <2.0
  • Converting from parenteral anticoagulant: Give dabigatran 0-2 hours before time for next dose of the parenteral drug that was to have been administered or initiate at time of discontinuing continuous IV heparin

Converting from dabigatran to warfarin or parenteral anticoagulants

  • CrCl ≥50 mL/min: Start warfarin 3 days before discontinuing dabigatran
  • CrCl 30-50 mL/min: Start warfarin 2 days before discontinuing dabigatran
  • CrCl 15-30 mL/min: Start warfarin 1 day before discontinuing dabigatran
  • CrCl <15 mL/min: No recommendations can be made
  • Converting to parenteral anticoagulant: Wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after last dabigatran dose before initiating parenteral anticoagulant

Discontinuation for surgery and other interventions

  • If possible, discontinue dabigatran 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding
  • Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required
  • If surgery cannot be delayed, there is increased risk of bleeding; this risk of bleeding should be weighed against urgency of intervention; use a specific reversal agent (idarucizumab) in case of emergency surgery or urgent procedures when reversal of anticoagulant effect of dabigatran is needed; refer to idarucizumab prescribing information for additional information
  • Restart dabigatran capsules as soon as medically appropriate

Dosage Forms & Strengths

capsule

  • 75mg, 110mg, 150mg

oral pellets

  • 20mg, 30mg, 40mg
  • 50mg, 110mg, 150mg

VTE Treatment or Prevention

Indicated for treatment of venous thromboembolic events (VTE) in pediatric patients aged >3 months to <18 years who have been treated with a parenteral anticoagulant for at least 5 days

Also indicated to reduce risk of recurrent VTEs in pediatric patients aged 3 months to <18 years who have been previously treated

<3 months: Safety and efficacy not established

3 months to <2 years (oral pellets)

  • Adjust dose according to age and actual weight as treatment progresses
  • 3 to <4 kg (3 to <6 months): 30 mg PO BID
  • 4 to <5 kg (3 to <10 months): 40 mg PO BID
  • 5 to <7 kg (3 to <5 months): 40 mg PO BID
  • 5 to <7 kg (5 to <24 months): 50 mg PO BID
  • 7 kg to <9 kg (3 to <4 months): 50 mg PO BID
  • 7 kg to <9 kg (4 to <9 months): 60 mg PO BID
  • 7 kg to <9 kg (9 to <24 months): 70 mg PO BID
  • 9 kg to <11 kg (5 to <6 months): 60 mg PO BID
  • 9 kg to <11 kg (6 to <11 months): 80 mg PO BID
  • 9 kg to <11 kg (11 to <24 months): 90 mg PO BID
  • 11 to <13 kg (8 to <18 months): 100 mg PO BID
  • 11 to <13 kg (18 to <24 months): 110 mg PO BID
  • 13 to <16 kg (10 to <11 months): 100 mg PO BID
  • 13 to <16 kg (11 to <24 months): 140 mg PO BID
  • 16 kg to <21 kg (12 to <24 months): 140 mg PO BID
  • 21 kg to <26 kg (18 to <24 months): 180 mg PO BID

2 to <12 years (oral pellets)

  • 7 to <9 kg: 70 mg PO BID
  • 9 to <11 kg: 90 mg PO BID
  • 11 to <13 kg: 110 mg PO BID
  • 13 to <16 kg: 140 mg PO BID
  • 16 to <21 kg: 170 mg PO BID
  • 21 to <41 kg: 220 mg PO BID
  • >41 kg: 260 mg PO BID

8 to <18 years (capsules)

  • May use for older children or adolescents who can swallow the capsule whole
  • Dosage based on actual weight
  • 11 to <16 kg: 75 mg PO BID
  • 16 to <26 kg: 110 mg PO BID
  • 26 to <41 kg: 150 mg PO BID
  • 41 to <61 kg: 185 mg PO BID
  • 61 to <81 kg: 220 mg PO BID
  • >81 kg: 260 mg PO BID

Dosage Modifications

Renal impairment (pellets or capsules)

  • eGFR >50 mL/min/1.73 m2: No dosage adjustment required
  • eGFR <50 mL/min/1.73 m2: Avoid use owing to lack of pediatric data

Dosing Considerations

Different dosage forms

  • Available in different dosage forms (ie, capsules for adults or children aged 8 to <18 years, oral pellets for children aged 3 months to <12 years) and not all dosage forms are approved for the same indications and age groups
  • Additionally, there are differences between dosage forms with respect to dosing owing different bioavailability
  • Do not substitute different dosage forms (for example, capsules) for oral pellets on a milligram-to-milligram basis and do not combine more than 1 dosage form to achieve the total dose

Converting to dabigatran from warfarin or parenteral anticoagulants

  • Converting from warfarin: Discontinue warfarin and initiate dabigatran when INR <2.0
  • Converting from parenteral anticoagulant: Give dabigatran 0-2 hours before time for next dose of the parenteral drug that was to have been administered or initiate at time of discontinuing continuous IV heparin

Converting from dabigatran to warfarin or parenteral anticoagulants

  • eGFR ≥50 mL/min/1.73 m2: Start warfarin 3 days before discontinuing dabigatran capsules
  • eGFR <50 mL/min/1.73 m2: Not studied; avoid dabigatran capsules/pellets in these patients
  • Wait 12 hr after last dose of oral pellets or capsule before switching to parenteral anticoagulant

Discontinuation for surgery and other interventions

  • Discontinue dabigatran pellets/capsules 24 hr before an elective surgery (eGFR >80 mL/min/1.73 m2) or 2 days before an elective surgery (eGFR 50-80 mL/min/1.73 m2)
  • Pediatric patients with an eGFR <50 mL/min/1.73 m2 have not been studied; avoid use of dabigatran pellets/ capsules in these patients

Increases risk of bleeding; bleeding can be significant and sometimes fatal; risk for bleeding or stroke increases with age >75 years

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Interactions

Interaction Checker

and dabigatran

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Adults

            • Dyspepsia and gastritis (35%; compared with warfarin [24%])
            • Any bleed (16.6%; compared with warfarin [18.4%])

            Pediatrics

            • GI adverse effects (32%; compared with standard of care [SOC] with warfarin, LMWH, or fondaparinux [12%])
            • Any bleeding (22%; SOC 24%)
            • Minor bleeding (19%; SOC 23%)

            1-10%

            Adults

            • Major bleed (3.47%/y; compared with warfarin [3.58%/y])
            • GI bleed (1.59%/y; compared with warfarin [1.51%/y])

            Pediatrics

            • Major and clinically relevant nonmajor bleeding (3.4%; SOC 3.3%)
            • Major bleeding (2.3%; SOC 2.2%)
            • Clinically relevant nonmajor bleeding (1.1%; SOC 1.1%)

            <1%

            Adults

            • Intracranial hemorrhage (0.22%/y; compared with warfarin [0.77%/y])
            • Hypersensitivity, including urticaria, rash, pruritus (<0.1%)

            Postmarketing Reports

            Adults

            • Angioedema
            • Neutropenia
            • Agranulocytosis
            • Esophageal ulcers
            • Thrombocytopenia
            • Alopecia
            • Vomiting
            • Nausea
            • Diarrhea
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            Warnings

            Black Box Warnings

            Premature discontinuation

            • Premature discontinuation of any oral anticoagulant, including dabigatran, increases the risk of thrombotic events
            • If dabigatran must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant

            Spinal/epidural hematoma

            • Epidural or spinal hematomas may occur in patients who are receiving neuraxial anesthesia or undergoing spinal puncture
            • These hematomas may result in long-term or permanent paralysis
            • Monitor patients frequently for signs and symptoms of neurological impairment; if neurological compromise is noted, urgent treatment is necessary
            • Consider the benefits and risks before neuraxial intervention in patients who are anticoagulated or to be anticoagulated
            • Factors that can increase risk include:
              • Indwelling epidural catheters
              • Coadministration with other drugs that affect hemostasis (eg, NSAIDs, platelet inhibitors, other anticoagulants)
              • History of traumatic or repeated epidural or spinal punctures
              • History of spinal deformity or spinal surgery
              • Optimal timing is unknown between dabigatran administration and neuraxial procedures

            Contraindications

            Hypersensitivity to drug or excipients

            Active pathologic bleeding

            Mechanical prosthetic heart valves

            • Significantly more thromboembolic events (eg, valve thrombosis, stroke, TIAs, MI) observed with dabigatran than with warfarin
            • Excessive major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) observed with dabigatran, compared with warfarin
            • These bleeding and thromboembolic events, seen in the RE-ALIGN study (Am Heart J, June 2012), were observed in patients who were started on dabigatran postoperatively within 3 days after mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than 3 months prior to enrollment in the study; this clinical trial was terminated early because of these events

            Cautions

            Premature discontinuation of oral anticoagulants (other than pathological bleeding) in the absence of adequate alternative anticoagulation increases risk of thrombotic events

            Direct-acting oral anticoagulants (DOACs) not recommended for use in patients with triple-positive antiphospholipid syndrome (APS); for patients with APS (especially those who are triple-positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy

            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
            • Consider dabigatran pharmacokinetic profile; placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known

            Coadministration with P-gp inducers and inhibitors

            • P-gp inducers (eg, rifampin) reduce exposure to dabigatran and should generally be avoided
            • P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran
            • 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
            • Concomitant use of dabigatran capsules with P-gp-inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran
            • DVT/PE treatment/prevention, renal impairment, and P-gp inhibitors: Avoid coadministration if CrCl <50 mL/min
            • VTE in pediatric patients: Not studied, but P-gp inhibitors may increase dabigatran exposure
            • AF treatment, renal impairment, and P-gp inhibitors
              • CrCl 30-50 mL/min and P-gp inhibitors dronedarone or ketoconazole: Consider reducing the dose (see Dosage Modifications)
              • CrCl 30-50 mL/min: Use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment, however, these results should not be extrapolated to other P-gp inhibitors
              • CrCl <30 mL/min: Avoid coadministration with all P-gp inhibitors

            Reversing anticoagulant effect

            • Idarucizumab is commercially available for reversal of the anticoagulant effect of dabigatran in adults for surgery/urgent procedures, or life-threatening or uncontrolled bleeding
            • Can be dialyzed (protein binding is low, with the removal of about 60% of drug over 2-3 hr); however, the amount of data supporting this approach is limited
            • Activated prothrombin complex concentrates, recombinant factor VIIa, or concentrates of coagulation factors II, IX, or X may be considered, but their use has not been evaluated in clinical trials
            • Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran
            • Consider administration of platelet concentrates in cases in which thrombocytopenia is present or long-acting antiplatelet drugs have been used
            • Efficacy and safety of idarucizumab not established in pediatric patients
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            Pregnancy & Lactation

            Pregnancy

            Limited available data on use in pregnant females are insufficient to determine drug-associated risks for adverse developmental outcomes; there are risks to mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in mother and fetus associated with use of anticoagulants

            Clinical considerations

            • Pregnancy confers an increased risk for thromboembolism that is higher for females with underlying thromboembolic disease and certain high-risk pregnancy conditions; published data describe that women with previous history of venous thrombosis are at high risk for recurrence during pregnancy
            • Use of anticoagulants, may increase risk of bleeding in fetus and neonate; monitor neonates for bleeding

            Labor or delivery

            • All patients receiving anticoagulants, including pregnant women, are at risk for bleeding; use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas; consider discontinuation or use of shorter acting anticoagulant as delivery approaches

            Females of reproductive potential

            • Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician
            • The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants should be assessed in females of reproductive potential and those with abnormal uterine bleeding

            Lactation

            There are no data on presence of dabigatran in human milk, effects on breastfed child, or on milk production; drug and/or its metabolites were present in rat milk; breastfeeding is not recommended during therapy

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Prevents thrombus development through direct, competitive inhibition of thrombin (thrombin enables fibrinogen conversion to fibrin during the coagulation cascade)

            Inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation

            Absorption

            Peak plasma time: 1 hr (fasting); ~2 hr (high-fat meal)

            Bioavailability

            • Intact oral capsule: 3-7%; oral bioavailability increases by 75% when pellets are taken without the capsule shell
            • Oral pellets: 37% higher relative bioavailability in healthy adults compared to dabigatran capsules
            • Relative bioavailability between the 2 dosage forms is age dependent; relative bioavailability observed in adults cannot be translated to pediatric patients

            Distribution

            Protein bound: 35%

            Vd: 50-70 L

            Metabolism

            Prodrug dabigatran etexilate is converted to dabigatran

            Substrate of efflux transporter P-gp

            Not a substrate, inhibitor, or inducer of CYP450 enzymes

            Elimination

            Half-life

            • Pellets: 9-11 hr
            • Capsule
              • Normal renal function: 12-17 hr
              • Mild to moderate renal impairment: 14-17 hr
              • Severe renal impairment: 28 hr

            Renal clerance: 80% of total clearance after IV administration

            Excretion: 7% urine; 86% feces

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            Administration

            Oral Pellet Preparation

            Administer only with specific soft foods or apple juice

            Soft food preparation

            • Mix with 2 teaspoons of following foods at room temperature
            • Baby rice cereal prepared with water
            • Mashed carrots
            • Applesauce
            • Mashed banana

            Oral Administration

            Oral capsules

            • For adults and children aged 8 years to <18 years
            • Swallow capsule whole (do not chew, crush, or break); do not open capsules and empty the pellets from the capsule
            • Missed dose
              • If dose missed, take as soon as possible on same day
              • Skip missed dose if unable to take at least 6 hr before next scheduled dose; do not double dose to make up for a missed dose

            Oral pellets

            • For pediatric patients aged 3 months to <12 years as soon as they are able to swallow soft food
            • Administered twice daily, 1 dose in the morning and 1 dose in the evening, at approximately the same time every day; dosing interval should be as close to 12 hr as possible
            • Give prepared medication before meals to ensure patient takes the full dose
            • Administer immediately after mixing or within 30 minutes after mixing; discard if not administered within 30 minutes of mixing and prepare a new dose
            • Administration with apple juice: Spoon oral pellets directly into patient’s mouth and swallow with apple juice or added to ~1-2 ounces of apple juice for drinking
            • Do not administer pellets
              • Via syringes or feeding tubes
              • With milk, milk products, or soft foods containing mild products
            • Missed or partial dose
              • If dose missed, take as soon as possible on the same day
              • Skip missed dose if unable to take at least 6 hr before next scheduled dose; do not double dose to make up for a missed dose
              • If partial dose taken, do not administer a second dose at that time; administer next dose as scheduled ~12 hr later

            Storage

            Store at room temperature of 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

            Capsules: Store in original container; once bottle is opened, capsules are stable for only 4 months

            Pellets: Store in original package to protect from moisture; do not open the packets until ready for use; use within 6 months of opening the aluminum bag containing the packets

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            Images

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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