AMASTAN

The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate.

The empirical formula is

C 34 H 41 N 7 O 5 ⋅ CH 4 O 3 S and the molecular weight is 723.86 (mesylate salt), 627.75 (free base).

The structural formula is

Dabigatran etexilate mesylate is off-white to yellowish powder.

It is freely soluble in methanol and ethanol, practically insoluble in acetone, ethyl acetate and water.

Dabigatran etexilate capsules are supplied in 75 mg, 110 mg, and 150 mg strengths for oral administration.

Each capsule contains dabigatran etexilate mesylate as the active ingredient: 75 mg dabigatran etexilate (equivalent to 86.48 mg dabigatran etexilate mesylate), 110 mg dabigatran etexilate (equivalent to 126.83 mg dabigatran etexilate mesylate) or 150 mg dabigatran etexilate (equivalent to 172.95 mg dabigatran etexilate mesylate) along with the following inactive ingredients: hydroxypropyl cellulose, hypromellose phthalate, pelletized tartaric acid, talc.

The capsule shell is composed of carrageenan, hypromellose, potassium chloride and titanium dioxide.

Additionally, 110 mg and 150 mg capsule shell also contains FD&C Blue No. 2.

The empty hard hypromellose capsule shells are printed with edible black ink containing iron oxide black, potassium hydroxide and shellac. dabigatran-structure.jpg.

• To reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation.

• For the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in adult patients who have been treated with a parenteral anticoagulant for to 10 days.

• To reduce the risk of recurrence of DVT and PE in adult patients who have been previously treated.

• For the prophylaxis of DVT and PE in adult patients who have undergone hip replacement surgery.

• For the treatment of venous thromboembolic events (VTE) in pediatric patients to less than 18 years of age who have been treated with a parenteral anticoagulant for at least 5 days.

• To reduce the risk of recurrence of VTE in pediatric patients to less than 18 years of age who have been previously treated 1.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients Dabigatran etexilate capsules are indicated to reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation. 1.2 Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Dabigatran etexilate capsules are indicated for the treatment of deep venous thrombosis and pulmonary embolism in adult patients who have been treated with a parenteral anticoagulant for to 10 days. 1.3 Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Dabigatran etexilate capsules are indicated to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in adult patients who have been previously treated. 1.4 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult PatientsFollowing Hip Replacement Surgery Dabigatran etexilate capsules are indicated for the prophylaxis of deep vein thrombosis and pulmonary embolism in adult patients who have undergone hip replacement surgery. 1.5 Treatment of Venous Thromboembolic Events in Pediatric Patients Dabigatran etexilate capsules are indicated for the treatment of venous thromboembolic events (VTE) in pediatric patients to less than 18 years of age who have been treated with a parenteral anticoagulant for at least 5 days. 1.6 Reduction in the Risk of Recurrence of Venous Thromboembolic Events in Pediatric Patients Dabigatran etexilate capsules are indicated to reduce the risk of recurrence of VTE in pediatric patients to less than 18 years of age who have been previously treated.

Abduction by catheter of atrial fibrillation Acute stroke Peridural anesthesia Recent history of biopsy Cancer Dehydration Lung embolism Bacterial endocarditis Female likely to be pregnant Hip fracture Gastritis Hypovolaemia Mild to moderate renal impairment Surgical intervention Invasive intervention Digestive malabsorption Esophagitis Surgical emergency patient Patients receiving parenteral anticoagulant reassignment Patients receiving relay therapy with antivitamin K Lumbar puncture Rachianesthesis Gastroesophageal reflux Substitution with parenteral anticoagulant treatment Substitution with antivitamin treatment K Subject at risk of thromboembolic accident Subject at risk of bleeding Subject under 18 Subject less than 50 kg Subject of more than 110 kg Subject over 75 years Antiphospholipid syndrome Thrombopathy Thrombocytopenia Deep thrombophlebitis Serum transaminases > 2 times the normal upper limit Major trauma, recent history Coagulation disorder.

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors.

Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus.

Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties. 12.2 Pharmacodynamics At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, TT, and dTT.

INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.

The aPTT test provides an approximation of dabigatran etexilate’s anticoagulant effect.

The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2.

The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT.

While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of dabigatran etexilate is not precisely known.

In the

RE-LY trial, the median (10 th to 90 th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

Figure 2: Average Time Course for Effects of Dabigatran on aPTT, Following Approved DABIGATRAN Dosing Regimens in Adult Patients with Various Degrees of Renal Impairment Simulations based on PK data from a study in subjects with renal impairment and PK/aPTT relationships derived from the RE-LY study; aPTT prolongation in RE-LY was measured centrally in citrate plasma using PTT Reagent Roche Diagnostics GmbH, Mannheim, Germany.

There may be quantitative differences between various established methods for aPTT assessment.

The degree of anticoagulant activity can also be assessed by the ecarin clotting time (ECT).

This test is a more specific measure of the effect of dabigatran than activated partial thromboplastin time (aPTT).

RE-LY trial, the median (10 th to 90 th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds.

In orthopedic hip surgery patients, maximum aPTT response (E max ) to dabigatran and baseline aPTT were higher shortly after surgery than at later time points (e.g. ≥3 days after surgery).

As in adults, there is a correlation between plasma dabigatran concentrations and the degree of its anticoagulant effect in pediatric patients with venous thromboembolism.

The parameters dTT and

ECT increased in direct linear proportion to the plasma concentration of dabigatran, whereas aPTT prolongation increases in a nonlinear fashion with dabigatran plasma concentrations.

PK/PD relationships for aPTT, ECT, and dTT were observed across age groups of pediatric patients (ages 26 days to < 18 years) and between pediatric and adult patients with venous thromboembolism.

This similarity in

PK/PD relationship suggests that similar exposure-response relationship is expected for dabigatran etexilate treatment across the pediatric age groups and adult patients.

Cardiac Electrophysiology No prolongation of the

QTc interval was observed with dabigatran etexilate at doses up to 600 mg. dabigatran-figure2.jpg 12.3 Pharmacokinetics Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester.

The ester is then hydrolyzed, forming dabigatran, the active moiety.

Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity.

Pharmacokinetics described here refer to the sum of dabigatran and its glucuronides.

Dabigatran displays dose-proportional pharmacokinetics in healthy adult subjects and adult patients in the range of doses from to 400 mg. Given twice daily, dabigatran’s accumulation factor in adults and pediatrics is approximately two.

The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3% to 7%.

Dabigatran etexilate is a substrate of the efflux transporter P-gp.

After oral administration of dabigatran etexilate in healthy volunteers, C max occurs at 1-hour post-administration in the fasted state.

Coadministration of dabigatran etexilate with a high-fat meal delays the time to C max by approximately 2 hours but has no effect on the bioavailability of dabigatran; dabigatran etexilate may be administered with or without food.

The oral bioavailability of dabigatran etexilate increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation based on a single-dose relative bioavailability study.

Dabigatran etexilate capsules should therefore not be broken, chewed, or opened before administration.

Dabigatran etexilate is available in capsules and oral pellets.

The approved indications and intended age groups are not the same.

Oral absorption of dabigatran etexilate is formulation-dependent.

At steady-state, dabigatran etexilate oral pellets show 37% higher relative bioavailability in healthy adults compared to dabigatran etexilate capsules based on a multiple-dose relative bioavailability study.

In addition, the relative bioavailability between the two dosage forms is age-dependent.

The relative bioavailability observed in adults cannot be translated to pediatrics.

Dabigatran is approximately 35% bound to human plasma proteins.

The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3.

The volume of distribution of dabigatran is to 70 L. Elimination Dabigatran is eliminated primarily in the urine.

Renal clearance of dabigatran is 80% of total clearance after intravenous administration.

After oral administration of radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% in feces.

The half-life of dabigatran in healthy adult subjects is to 17 hours.

Population pharmacokinetic simulation shows that the elimination half-life in pediatric patients is to 14 hours.

After oral administration, dabigatran etexilate is converted to dabigatran.

The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to 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 active acyl glucuronides.

Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.

The pharmacokinetics of dabigatran was characterized in two clinical studies (DIVERSITY and Study 2) following multiple doses in pediatric patients from birth to less than 18 years old.

In pediatric patients taking age.

• and weight-adjusted dosages of dabigatran etexilate capsules (aged to 18 years), the observed geometric mean steady-state trough concentration was 97.9 ng/mL (63.7 to 151 ng/mL, 10 th to 90 th percentile) compared to the steady-state geometric mean trough concentration of 59.7 ng/mL (26.3 to 146 ng/mL, 10 th to 90 th percentile) observed in adult patients with DVT/PE.

An open, parallel-group, single-center study compared dabigatran pharmacokinetics in healthy adult subjects and adult patients with mild to moderate renal impairment receiving a single dose of dabigatran etexilate capsules 150 mg. Exposure to dabigatran increases with severity of renal function impairment (Table 10).

Similar findings were observed in the

RE-LY, RE-COVER and RE-NOVATE II trials.

Table 10: Impact of Renal Impairment on Dabigatran Pharmacokinetics Renal Function CrCl (mL/min) Increase in AUC Increase in C max t 1/2 (h) Normal ≥ 80 1x 1x 13 Mild to 80 1.5x 1.1x 15 Moderate to 50 3.2x 1.7x 18 Severe + 15 to 30 6.3x 2.1x 27 + Patients with severe renal impairment were not studied in RE-LY, RE-COVER and RE-NOVATE II.

Dosing recommendations in subjects with severe renal impairment are based on pharmacokinetic modeling.

Administration of dabigatran etexilate capsules in adult patients with moderate hepatic impairment (Child-Pugh B) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics.

A summary of the effect of coadministered drugs on dabigatran exposure in healthy adult subjects is 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-gp Inhibitor or Inducer (rifampicin) Drugs on Peak and Total Exposure to Dabigatran (C max and AUC).

Shown are the Geometric Mean

Ratios (Ratio) and 90% Confidence Interval (90% CI).

The Perpetrator and Dabigatran Etexilate Dosage and Dosage Frequency are given as well as the Time of Perpetrator Dosage in Relation to Dabigatran Etexilate Dosage (Time Difference) Figure 3.2: Effect of Non-P-gp Inhibitor or Inducer, Other Drugs, on Peak and Total Exposure to Dabigatran (C max and AUC).

The Perpetrator and Dabigatran Etexilate Dosage and Dosage Frequency are given as well as the Time of Perpetrator Dosage in Relation to Dabigatran Etexilate Dosage (Time Difference) In RE-LY, dabigatran plasma samples were also collected.

The concomitant use of proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change the trough concentration of dabigatran.

Impact of Dabigatran on Other Drugs In clinical studies exploring CYP3A4, CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alter the pharmacokinetics of amiodarone, atorvastatin, clarithromycin, diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine. dabigatran-fig3-1.jpg dabigatran-fig3-2.jpg.

Dabigatran etexilate

Mechanism of action Dabigatran etexilate is a small molecule in the form of prodrug, which has no pharmacological activity.

After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran, by hydrolysis catalyzed by esterase, in plasma and in the liver.

Dabigatran is a powerful, competitive and reversible direct inhibitor of thrombin and is the main active plasma substance. thrombin (serine protease) allowing the conversion of fibrinogen to fibrin during the cascade of coagulation, its inhibition prevents the formation of clot.

Dabigatran also inhibits free thrombin, fibrin-bound thrombin and platelet aggregation induced by thrombin.

Antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous injection and those of dabigatran etexilate after oral administration have been demonstrated in various animal models of thrombosis in in in in vivo and ex vivo studies in animals.

• Hematocrite (decrease) (Uncommon)
• Liver status (abnormality) (Common)
• Blood globinaemia (decrease) (Common)
• ALT (increase) (Uncommon)
• ASAT (increase) (Uncommon)
• Hyperbilirubinaemia (Uncommon)
• Liver enzymes (increase) (Uncommon)
• Neutropenia Skin haemorrhage (Common)
• Rash (Uncommon)
• Drowsing pleat (Uncommon)
• Pruritus (Uncommon)
• Urticaria (Rare)
• Wound drain (Rare)
• Alopecia Palor Postoperative flow (Uncommon)
• Tumef Edema Post-operative injury (complication)
• Weakness Anemia (Common)
• Haemorrhage (Uncommon)
• Postoperative hematoma (Uncommon)
• Traumatic haemorrhage (Uncommon)
• Post-operative haemorrhage (Uncommon)
• Hematoma (Uncommon)
• Thrombocytopenia (Uncommon)
• Haemorrhage at the incision site (Rare)
• Postoperative anaemia (Rare)
• Post-traumatic haemorrhage Agranulocytosis Hepatic impairment Drug hypersensitivity (Uncommon)
• Hypersensitivity (Uncommon)
• Angioedema (Rare)
• Anaphylactic reaction (Rare)
• Haemorrhage at the catheter site (Rare)
• Injection site haemorrhage (Rare)
• Dysphagia (Uncommon)
• Epistaxis (Common)
• Blood-dyed nasal mucosities (Rare)
• Feeling dizzy Hypoperfusion Blood shock Shock Abdominal pain (Common)
• Gastrointestinal ulcer (Uncommon)
• Esophagitis (Uncommon)
• Nausea (Common)
• Gastroesophageal reflux (Uncommon)
• Gastrointestinal haemorrhage (Common)
• Esophagus Ulcer (Uncommon)
• Dyspepsia (Common)
• Vomiting (Uncommon)
• Haemorrhoidal haemorrhage (Uncommon)
• Diarrhoea (Common)
• Rectorragie (Uncommon)
• Abnormal liver function Lodge syndrome
• Haemarthritis Intracranial haemorrhage (Uncommon)
• Headache Hemoptysis (Uncommon)
• Dyspnoea Bronchospasm Urogenital haemorrhage (Common)
• Haematuria Nephropathy Acute renal impairment.

Accidental overdose may lead to hemorrhagic complications.

In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with dabigatran etexilate, and investigate the source of bleeding.

A specific reversal agent (idarucizumab) is available for adult patients.

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.

• Active pathological bleeding.

• History of a serious hypersensitivity reaction to dabigatran, dabigatran etexilate, or to one of the excipients of the product (e.g., anaphylactic reaction or anaphylactic shock).

• Mechanical prosthetic heart valve.

• History of serious hypersensitivity reaction to dabigatran etexilate capsules.

• Non-valvular Atrial Fibrillation in Adult Patients: o For patients with CrCl >30 mL/min: 150 mg orally, twice daily o For patients with CrCl to 30 mL/min: 75 mg orally, twice daily.

• Treatment of DVT and PE in Adult Patients: o For patients with CrCl >30 mL/min: 150 mg orally, twice daily after to 10 days of parenteral anticoagulation.

• Reduction in the Risk of Recurrence of DVT and PE in Adult Patients: o For patients with CrCl >30 mL/min: 150 mg orally, twice daily after previous treatment.

• Prophylaxis of DVT and PE Following Hip Replacement Surgery in Adult Patients: o For patients with CrCl >30 mL/min: 110 mg orally first day, then 220 mg once daily.

• Treatment of Pediatric VTE: o For pediatric patients: weight-based dosage, twice daily after at least 5 days of parenteral anticoagulant.

• Reduction in the Risk of Recurrence of Pediatric VTE: o For pediatric patients: weight-based dosage, twice daily after previous treatment.

• Dabigatran etexilate capsules are NOT substitutable on a milligram-to-milligram basis with other dabigatran etexilate dosage forms.

• Review recommendations for converting to or from other oral or parenteral anticoagulants.

• Temporarily discontinue dabigatran etexilate capsules before invasive or surgical procedures when possible, then restart promptly 2.1 Important Dosage Information Dabigatran etexilate is available in different dosage forms and not all dosage forms are approved for the same indications and age groups.

In addition, there are differences between the dosage forms with respect to dosing due to differences in bioavailability.

Do not substitute different dosage forms on a milligram-to-milligram basis and do not combine more than one dosage form to achieve the total dose. 2.2 Recommended Dabigatran Etexilate Capsules Dosage for Adults Indication Dosage Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF CrCl >30 mL/min: 150 mg twice daily CrCl to 30 mL/min: 75 mg twice daily CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dosage to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.

CrCl <30 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration Treatment of DVT and PE Reduction in the Risk of 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 use of P-gp inhibitors: Avoid coadministration Prophylaxis of DVT and PE Following Hip Replacement Surgery CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily 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 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily.

For patients with severe renal impairment (CrCl to 30 mL/min), the recommended dosage of dabigatran etexilate capsules are 75 mg twice daily.

Dosing recommendations for patients with a

CrCl <15 mL/min or on dialysis cannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients For patients with CrCl >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily, after to 10 days of parenteral anticoagulation.

CrCl ≤30 mL/min or on dialysis cannot be provided.

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients For patients with CrCl >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily after previous treatment.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery For patients with CrCl >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 110 mg taken orally to 4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for to 35 days.

If dabigatran etexilate capsules is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily.

CrCl ≤30 mL/min or on dialysis cannot be provided. 2.3 Recommended Dabigatran Etexilate Capsules Dosage for Pediatrics Dabigatran etexilate capsules can be used in pediatric patients aged to less than 18 years of age who are able to swallow the capsules whole.

Other age-appropriate pediatric dosage forms of dabigatran etexilate are available for pediatric patients less than 8 years of age.

For the treatment of

VTE in pediatric patients, initiate treatment following treatment with a parenteral anticoagulant for at least 5 days.

For reduction in risk of recurrence of VTE, initiate treatment following previous treatment.

Dabigatran etexilate capsules are dosed orally twice daily, one dose in the morning and one dose in the evening, at approximately the same time every day. The dosing interval should be as close to 12 hours as possible.

The recommended dosage of dabigatran etexilate capsules for the treatment of or reducing the risk of VTE in pediatric patients to less than 18 years of age is based on the patient’s actual weight as shown in Table 1 below.

Administer dabigatran etexilate capsules twice daily.

Adjust the dosage according to actual weight as treatment progresses.

Table 1: Weight-Based Dabigatran Etexilate Capsules Dosage for Pediatric Patients Aged to Less Than 18 Years Actual Weight (kg) Dosage (mg) Number of Capsules Needed 11 kg to less than 16 kg 75 mg twice daily one 75 mg capsule twice daily 16 kg to less than 26 kg 110 mg twice daily one 110 mg capsule twice daily 26 kg to less than 41 kg 150 mg twice daily one 150 mg capsule twice daily or two 75 mg capsules twice daily 41 kg to less than 61 kg 185 mg twice daily one 110 mg capsule plus one 75 mg capsule twice daily 61 kg to less than 81 kg 220 mg twice daily two 110 mg capsule twice daily 81 kg or greater 260 mg twice daily one 150 mg capsule plus one 110 mg capsule twice daily or one 110 mg capsule plus two 75 mg capsules twice daily 2.4 Dosage Adjustments Adult patients with renal impairment Assess renal function prior to initiation of treatment with dabigatran etexilate capsules.

Periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly.

Discontinue dabigatran etexilate capsules in patients who develop acute renal failure while on dabigatran etexilate and consider alternative anticoagulant therapy.

Generally, in adult patients, the extent of anticoagulation does not need to be assessed.

When necessary, use aPTT or ECT, and not INR, to assess for anticoagulant activity in adult patients on dabigatran etexilate capsules.

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation In patients with moderate renal impairment (CrCl to 50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce dabigatran exposure similar to that observed in severe renal impairment.

Reduce the dosage of dabigatran etexilate capsules to 75 mg twice daily.

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism Dosing recommendations for patients with CrCl ≤30 mL/min cannot be provided.

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

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery Dosing recommendations for patients with CrCl ≤30 mL/min or on dialysis cannot be provided.

Pediatric patients with renal impairment

Treatment and reduction in risk of recurrence of VTE in pediatric patients Due to lack of data in pediatric patients with eGFR < 50 mL/min/1.73 m and the risk of increased exposure, avoid use of dabigatran etexilate capsules in these patients.

Prior to the initiation of treatment with dabigatran etexilate capsules, estimate the glomerular filtration rate (eGFR) using the Schwartz formula: eGFR (Schwartz) = (0.413 x height in cm) / serum creatinine in mg/dL.

Treat patients with an eGFR > 50 mL/min/1.73 m with the dosage according to Table 1. 2.5 Administration Dabigatran etexilate capsules should be swallowed whole.

Dabigatran etexilate capsules should be taken with a full glass of water.

Breaking, chewing, or emptying the contents of the capsule can result in increased exposure.

If a dose of dabigatran etexilate capsules are not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose.

The dose of dabigatran etexilate capsules should not be doubled to make up for a missed dose.

Consider administration with food if gastrointestinal distress occurs with dabigatran etexilate capsules. 2.6 Converting from or to Warfarin When converting patients from warfarin therapy to dabigatran etexilate capsules, discontinue warfarin and start dabigatran etexilate capsules when the INR is below 2.

When converting from dabigatran etexilate capsules to warfarin, adjust the starting time of warfarin as follows: Adults For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing dabigatran etexilate capsules.

CrCl to 50 mL/min, start warfarin 2 days before discontinuing dabigatran etexilate capsules.

CrCl to 30 mL/min, start warfarin 1 day before discontinuing dabigatran etexilate capsules.

CrCl <15 mL/min, no recommendations can be made.

• For eGFR ≥ 50 mL/min/1.73 m 2, start warfarin 3 days before discontinuing dabigatran etexilate capsules.

• Pediatric patients with an eGFR < 50 mL/min/1.73 m 2 have not been studied.

Avoid use of dabigatran etexilate capsules in these patients.

Because dabigatran etexilate capsules can increase

INR, the INR will better reflect warfarin’s effect only after dabigatran etexilate capsules has been stopped for at least 2 days. 2.7 Converting from or to Parenteral Anticoagulants For adult and pediatric patients currently receiving a parenteral anticoagulant, start dabigatran etexilate capsules to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin).

For adult patients currently taking d.

Dabigatran etexilate capsules 75 mg are with white opaque cap / white opaque body, size ‘2’ HPMC capsules having imprinting “A” on cap with black ink and “329” on body with black ink, filled with off white to yellowish pellets.

The capsules are supplied in the packages listed: Bottle of 60 capsules with child-resistant closure, NDC 46708-634-60 Carton of 60 capsules (10 x 6 unit-dose blister cards), NDC 46708-634-06 Dabigatran etexilate capsules 110 mg are with light blue opaque cap / light blue opaque body, size ‘1’ HPMC capsules having imprinting “A” on cap with black ink and “192” on body with black ink, filled with off white to yellowish pellets.

The capsules are supplied in the packages listed: Bottle of 60 capsules with child-resistant closure, NDC 46708-635-60 Carton of 60 capsules (10 x 6 unit-dose blister cards), NDC 46708-635-06 Dabigatran etexilate capsules 150 mg are with light blue opaque cap / white opaque body, size ‘0’ HPMC capsules having imprinting “A” on cap with black ink and “316” on body with black ink, filled with off white to yellowish pellets.

The capsules are supplied in the packages listed: Bottle of 60 capsules with child-resistant closure, NDC 46708-636-60 Bottle of 180 capsules with child-resistant closure, NDC 46708-636-45 Carton of 60 capsules (10 x 6 unit-dose blister cards), NDC 46708-636-06 Bottles Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Once opened, the product must be used within 4 months.

Keep the bottle tightly closed.

Store in the original package to protect from moisture.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

The limited available data on dabigatran etexilate use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes.

There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulants.

In pregnant rats treated from implantation until weaning, dabigatran increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition at an exposure 2.6 times the human exposure.

At a similar exposure, dabigatran decreased the number of implantations when rats were treated prior to mating and up to implantation (gestation Day 6).

Dabigatran administered to pregnant rats and rabbits during organogenesis up to exposures and 13 times the human exposure, respectively, did not induce major malformations.

However, the incidence of delayed or irregular ossification of fetal skull bones and vertebrae was increased in the rat.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions.

Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy.

Fetal/Neonatal adverse reaction Use of anticoagulants, including dabigatran etexilate, may increase the risk of bleeding in the fetus and neonate.

Monitor neonates for bleeding.

Labor or delivery

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.

Dabigatran etexilate 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.

Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3 times the human exposure at MRHD of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation (gestation Day 6).

Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition.

Dabigatran administered to pregnant rats and rabbits during organogenesis up to maternally toxic doses of 200 mg/kg (8 and 13 times the human exposure, respectively, at a MRHD of 300 mg/day based on AUC comparisons) did not induce major malformations, but increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat.

Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons).

The safety and effectiveness of dabigatran etexilate capsules for the treatment and the reduction in risk of recurrence of venous thromboembolism have been established in pediatric patients to less than 18 years of age.

Use of dabigatran etexilate capsules for this indication is supported by evidence from adequate and well-controlled studies in pediatric patients.

These studies included an open-label, randomized, parallel-group study and an open-label, single-arm safety study.

Other age-appropriate pediatric dosage forms of dabigatran etexilate are available for pediatric patients less than 8 years of age for these indications.

Safety and effectiveness of dabigatran etexilate capsules have not been established in pediatric patients with non-valvular atrial fibrillation or those who have undergone hip replacement surgery.

Of the total number of patients in the RE-LY study, 82% were and over, while 40% were and over.

The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.