Pradaxa

1 INDICATIONS AND USAGE PRADAXA Oral Pellets are a direct thrombin inhibitor indicated: For the treatment of venous thromboembolic events (VTE) in pediatric patients aged 3 months to less than 12 years of age who have been treated with a parenteral anticoagulant for at least 5 days ( 1.1 ) To reduce the risk of recurrence of VTE in pediatric patients aged 3 months to less than 12 years of age who have been previously treated ( 1.2 ) 1.1 Treatment of Venous Thromboembolic Events in Pediatric Patients PRADAXA Oral Pellets are indicated for the treatment of venous thromboembolic events (VTE) in pediatric patients aged 3 months to less than 12 years of age who have been treated with a parenteral anticoagulant for at least 5 days. 1.2 Reduction in the Risk of Recurrence of Venous Thromboembolic Events in Pediatric Patients PRADAXA Oral Pellets are indicated to reduce the risk of recurrence of VTE in pediatric patients aged 3 months to less than 12 years of age who have been previously treated.

2 DOSAGE AND ADMINISTRATION Treatment of Pediatric Venous Thromboembolic Events (VTE): For pediatric patients aged 3 months to less than 2 years: age- and weight-based dosage, twice daily after at least 5 days of parenteral anticoagulant ( 2.2 ) For pediatric patients 2 years to less than 12 years: weight-based dosage, twice daily after at least 5 days of parenteral anticoagulant ( 2.2 ) Reduction in the Risk of Recurrence of Pediatric VTE: For pediatric patients aged 3 months to less than 2 years: age- and weight-based dosage, twice daily after previous treatment ( 2.2 ) For pediatric patients aged 2 years to less than 12 years: weight-based dosage, twice daily after previous treatment ( 2.2 ) Pradaxa Oral Pellets are NOT substitutable on a milligram-to-milligram basis with other dabigatran etexilate dosage forms ( 2.1 ) Review recommendations for converting to or from other oral or parenteral anticoagulants ( 2.5 , 2.6 ) Temporarily discontinue PRADAXA before invasive or surgical procedures when possible, then restart promptly ( 2.7 ) 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 (for example, capsules) for oral pellets on a milligram-to-milligram basis and do not combine more than one dosage form to achieve the total dose [see Clinical Pharmacology (12.3) ] . 2.2 Recommended PRADAXA Oral Pellets Dosage for Pediatric Patients PRADAXA Oral Pellets can be used in pediatric patients aged 3 months to less than 12 years as soon as they are able to swallow soft food. For the treatment of VTE in pediatric patients, treatment should be initiated following treatment with a parenteral anticoagulant for at least 5 days. For reduction in risk of recurrence of VTE, treatment should be initiated following previous treatment. The recommended dosage of PRADAXA Oral Pellets is based on the patient's age and actual weight as shown in the tables below. PRADAXA Oral Pellets is administered twice daily. Adjust the dosage according to age and actual weight as treatment progresses. Table 1 Age- and Weight-Based Dosage for PRADAXA Oral Pellets for Pediatric Patients less than 2 Years Old Actual Weight (kg) Age (in months) Dosage (mg) twice daily Number of Packets Needed 3 kg to less than 4 kg 3 to less than 6 months 30 mg one 30 mg packet twice daily 4 kg to less than 5 kg 3 to less than 10 months 40 mg one 40 mg packet twice daily 5 kg to less than 7 kg 3 to less than 5 months 40 mg one 40 mg packet twice daily 5 to less than 24 months 50 mg one 50 mg packet twice daily 7 kg to less than 9 kg 3 to less than 4 months 50 mg one 50 mg packet twice daily 4 to less than 9 months 60 mg two 30 mg packets twice daily 9 to less than 24 months 70 mg one 30 mg packet plus one 40 mg packet twice daily 9 kg to less than 11 kg 5 to less than 6 months 60 mg two 30 mg packets twice daily 6 to less than 11 months 80 mg two 40 mg packets twice daily 11 to less than 24 months 90 mg one 40 mg packet plus one 50 mg packet twice daily 11 kg to less than 13 kg 8 to less than 18 months 100 mg two 50 mg packets twice daily 18 to less than 24 months 110 mg one 110 mg packet twice daily 13 kg to less than 16 kg 10 to less than 11 months 100 mg two 50 mg packets twice daily 11 to less than 24 months 140 mg one 30 mg packet plus one 110 mg packet twice daily 16 kg to less than 21 kg 12 to less than 24 months 140 mg one 30 mg packet plus one 110 mg packet twice daily 21 kg to less than 26 kg 18 to less than 24 months 180 mg one 30 mg packet plus one 150 mg packet twice daily Table 2 Weight-Based Dosage for PRADAXA Oral Pellets for Pediatric Patients between 2 Years to less than 12 Years Old Actual Weight (kg) Dosage (mg) twice daily Number of Packets Needed 7 kg to less than 9 kg 70 mg one 30 …

3 DOSAGE FORMS AND STRENGTHS PRADAXA Oral Pellets are available in the following strengths: 20 mg yellowish pellets in a packet 30 mg yellowish pellets in a packet 40 mg yellowish pellets in a packet 50 mg yellowish pellets in a packet 110 mg yellowish pellets in a packet 150 mg yellowish pellets in a packet Oral pellets: 20 mg, 30 mg, 40 mg, 50 mg, 110 mg, 150 mg per packet ( 3 )

4 CONTRAINDICATIONS PRADAXA is contraindicated in patients with: Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] 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) [see Adverse Reactions (6.1) ] Mechanical prosthetic heart valve [see Warnings and Precautions (5.4) ] Active pathological bleeding ( 4 ) History of serious hypersensitivity reaction to PRADAXA ( 4 ) Mechanical prosthetic heart valve ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Increased Risk of Thrombotic Events after Premature Discontinuation [see Warnings and Precautions (5.1) ] Risk of Bleeding [see Warnings and Precautions (5.2) ] Spinal/Epidural Anesthesia or Puncture [see Warnings and Precautions (5.3) ] Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves [see Warnings and Precautions (5.4) ] Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome [see Warnings and Precautions (5.6) ] The most serious adverse reactions reported with PRADAXA were related to bleeding [see Warnings and Precautions (5.2) ] . Most common adverse reactions (> 15%) are gastrointestinal adverse reactions and bleeding. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pediatric Trials Treatment of VTE in Pediatric Patients The safety of PRADAXA in the treatment of VTE in pediatric patients was studied in one phase III trial (DIVERSITY). The DIVERSITY study was a randomized, open-label, active-controlled, parallel-group trial comparing PRADAXA with standard of care – SOC (vitamin K antagonists, low molecular weight heparin, or fondaparinux). There were 266 pediatric patients who received study treatment, 176 patients treated with PRADAXA and 90 patients treated with SOC. Patients on PRADAXA received age- and weight-adjusted dosages of an age-appropriate formulation of PRADAXA (capsules, pellets, or oral solution) twice daily. Patients had a median age of 14 years (range: 0-17 years), 92% were white, and half the patients were male (50%). Following at least 5 days of parenteral anticoagulant therapy, the median duration of treatment with PRADAXA was 85 days (range: 1-105). Patients with estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m 2 were excluded from the trial. Bleeding Data on adjudicated major bleeding, clinically relevant non-major (CRNM) bleeding, and minor bleeding events for the PRADAXA group and the SOC group in the DIVERSITY study are reported in Table 3. There was no statistically significant difference in the time to first major bleeding event. Table 3 Summary of All Adjudicated Bleeding Events During On-Treatment Period in DIVERSITY PRADAXA N (%) Standard of Care (SOC) N (%) Patients N=176 N=90 1 Major bleeding event if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells. Major bleeding event 1 4 (2.3) 2 (2.2) Fatal bleeding 0 1 (1.1) Clinically relevant non-major bleeding 2 (1.1) 1 (1.1) Minor bleeding 33 (19) 21 (23) Major and clinically relevant non-major bleeding 6 (3.4) 3 (3.3) Any bleeding 38 (22) 22 (24) Site-specific bleeding rates were comparable between the two arms, with the exception of the rate of any gastrointestinal bleeds (5.7% in PRADAXA arm vs 1.8% in SOC arm). Gastrointestinal Adverse Reactions The incidence of gastrointestinal adverse reactions for patients on PRADAXA and SOC was 32% and 12%, respectively, with the following occurring in ≥ 5% of patients taking PRADAXA: dyspepsia (including term gastro-esophageal reflux disease, gastric pH decreased and esophagitis) in 9% (vs 2%), upper abdominal pain in 5% (vs 1%), vomiting in 8% …

7 DRUG INTERACTIONS The concomitant use of PRADAXA with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran [see Warnings and Precautions (5.5) ] . P-gp inducers: Avoid coadministration with PRADAXA ( 5.5 ) The concomitant use of PRADAXA with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran ( 5.5 , 7 )

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended ( 8.2 ) 8.1 Pregnancy Risk Summary The limited available data on PRADAXA 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 (see Clinical Considerations ) . 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 8 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 (see Data ) . 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 2-4% and 15-20%, respectively. Clinical Considerations 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 PRADAXA, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding [see Warnings and Precautions (5.2) ]. Labor or delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. PRADAXA 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 [see Warnings and Precautions (5.2 , 5.3) ] . Data Animal Data Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at 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). 8.2 Lactation Risk Summary There are insufficient data to assess the presence of dabigatran in human milk. There are no data on the effects of dabigatran on the breastfed child or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with PRADAXA. 8.3 Females and Males of Repr …

12.1 Mechanism of Action 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.

11 DESCRIPTION PRADAXA Oral Pellets contain dabigatran etexilate mesylate, a direct thrombin inhibitor. The chemical name of dabigatran etexilate mesylate 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 and it has a molecular formula of C 34 H 41 N 7 O 5 ∙ CH 4 O 3 S and molecular weight of 723.86 for the mesylate salt and 627.75 for the free base. The structural formula is: Dabigatran etexilate mesylate is a yellow-white to yellow powder. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol. A saturated solution in pure water has a solubility of 1.8 mg/mL. Each packet of PRADAXA Oral Pellets contains 20 mg, 30 mg, 40 mg, 50 mg, 110 mg, or 150 mg dabigatran etexilate (equivalent to 23.06 mg, 34.59 mg, 46.12 mg, 57.65 mg, 126.83 mg, or 172.95 mg dabigatran etexilate mesylate) along with the following inactive ingredients: acacia, dimethicone, hydroxypropyl cellulose, hypromellose, talc, and tartaric acid. Chemical Structure

10 OVERDOSAGE 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 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 [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ].

16 HOW SUPPLIED/STORAGE AND HANDLING PRADAXA Oral Pellets are yellowish in a silver-colored, child-resistant packet. The packets are placed in an aluminum bag with a desiccant. PRADAXA Oral Pellets are supplied as follows: Strength Package NDC 20 mg unit of use carton with 1 aluminum bag containing 60 packets 0597-0425-78 30 mg unit of use carton with 1 aluminum bag containing 60 packets 0597-0430-18 40 mg unit of use carton with 1 aluminum bag containing 60 packets 0597-0435-96 50 mg unit of use carton with 1 aluminum bag containing 60 packets 0597-0440-53 110 mg unit of use carton with 1 aluminum bag containing 60 packets 0597-0445-87 150 mg unit of use carton with 1 aluminum bag containing 60 packets 0597-0450-16 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) [see USP Controlled Room Temperature]. Store in the original package to protect from moisture. Do not open the packets until ready for use. Use the PRADAXA Oral Pellets within 6 months of opening the aluminum bag containing the packets.