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 mg packet plus one 40 mg packet twice daily 9 kg to less than 11 kg 90 mg one 40 mg packet plus one 50 mg packet twice daily 11 kg to less than 13 kg 110 mg one 110 mg packet twice daily 13 kg to less than 16 kg 140 mg one 30 mg packet plus one 110 mg packet twice daily 16 kg to less than 21 kg 170 mg one 20 mg packet plus one 150 mg packet twice daily 21 kg to less than 41 kg 220 mg two 110 mg packets twice daily 41 kg or greater 260 mg one 110 mg packet plus one 150 mg packet twice daily Evaluation of the extent of anticoagulation in pediatric patients on PRADAXA Oral Pellets may be accomplished using dTT or ECT, and not INR [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] . 2.3 Dosage Adjustments Pediatric Patients with Renal Impairment Assess renal function prior to initiation of treatment with PRADAXA Oral Pellets. 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 PRADAXA Oral Pellets in patients who develop acute renal failure while on PRADAXA Oral Pellets and consider alternative anticoagulant therapy. Prior to the initiation of treatment with PRADAXA Oral Pellets, estimate the glomerular filtration rate (eGFR) using the Schwartz formula, eGFR (Schwartz) = (0.413 × height in cm) / serum creatinine in mg/dL. Due to lack of data in pediatric patients with an eGFR 50 mL/min/1.73 m 2 with the dosage according to Tables 1 and 2 [see Dosage and Administration (2.2) ] . 2.4 Administration PRADAXA Oral Pellets are administered 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. If a dose of PRADAXA Oral Pellets is 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 PRADAXA Oral Pellets should not be doubled to make up for a missed dose. If a partial dose has been taken, a second dose should not be administered at that time. The next dose should be taken as scheduled approximately 12 hours later. The prepared medication should be given before meals to ensure that the patient takes the full dose. PRADAXA Oral Pellets should be administered immediately after mixing or within 30 minutes after mixing. If the PRADAXA dose is not administered within 30 minutes of mixing, the dose should be discarded, and a new dose prepared. PRADAXA Oral Pellets should be administered with only specific soft foods or apple juice. Administration with soft foods PRADAXA Oral Pellets may be mixed with two teaspoons of the following soft foods at room temperature: Mashed carrots Apple sauce Mashed banana Administration with apple juice PRADAXA Oral Pellets may be spooned directly into the patient's mouth and swallowed with apple juice or added to approximately 1-2 ounces of apple juice for drinking. PRADAXA Oral Pellets should not be administered: via syringes or feeding tubes with milk, milk products, or soft foods containing milk products Instruct patients/caregivers to discard the desiccant once the package is opened. See Instructions for Use . 2.5 Converting from or to Warfarin When converting patients from warfarin therapy to PRADAXA Oral Pellets, discontinue warfarin and start PRADAXA Oral Pellets when the INR is below 2.0. When converting from PRADAXA Oral Pellets to warfarin, adjust the starting time of warfarin as follows: For eGFR ≥ 50 mL/min/1.73 m 2 , start warfarin 3 days before discontinuing PRADAXA Oral Pellets. Patients with an eGFR 80 mL/min/1.73 m 2 ) or 2 days before an elective surgery (eGFR 50-80 mL/min/1.73 m 2 ). Pediatric patients with an eGFR < 50 mL/min/1.73 m 2 have not been studied, avoid use of PRADAXA Oral Pellets in these patients. 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . If surgery cannot be delayed, there is an increased risk of bleeding [see Warnings and Precautions (5.2) ] . This risk of bleeding should be weighed against the urgency of intervention [see Warnings and Precautions (5.1 , 5.3) ] . In adults, a specific reversal agent (idarucizumab) is available in case of emergency surgery or urgent procedures when reversal of the anticoagulant effect of dabigatran is needed. Efficacy and safety of idarucizumab have not been established in pediatric patients [see Warnings and Precautions (5.2) ] . Refer to the idarucizumab prescribing information for additional information. Restart PRADAXA Oral Pellets as soon as medically appropriate.

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% (vs 2%), nausea 5% (vs 4%), and diarrhea 5% (vs 1%). Reduction in Risk of Recurrence of VTE in Pediatric Patients The safety of PRADAXA in the reduction in the risk of recurrence of VTE in pediatric patients was studied in one open-label single-arm trial (Study 2). Study 2 enrolled patients who required further anticoagulation due to the presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study and received PRADAXA until the clinical risk factor resolved, or up to a maximum of 12 months. There were 213 pediatric patients treated with PRADAXA, in a similar fashion as in the DIVERSITY trial. Patients had a median age of 14 years (range: 0-18 years), 91% were white, and 55% of patients were male. Patients previously enrolled on DIVERSITY accounted for 43% of patients enrolled on Study 2 (29% from PRADAXA arm and 14% from SOC arm). The median duration of treatment with PRADAXA in Study 2 was 42 weeks (range: 0-56 weeks), with 45% of patients completing the 12-month planned duration, 17% stopping due to resolution of VTE risk factors, 12% stopping due to failure to attain target dabigatran concentration and 6% had an adverse event leading to discontinuation. During the on-treatment period of Study 2, 3 patients (1.4%) had a major bleeding event, 3 patients (1.4%) had a clinically relevant non-major bleeding event, and 44 patients (20%) had a minor bleeding event. The most common drug-related adverse reactions were dyspepsia (5%), epistaxis (3.3%), nausea (3.3%) and menorrhagia (2.8%). The adverse reaction profile in pediatric patients was generally consistent with that of adult patients. Hypersensitivity Reactions in Adult PRADAXA Trials In adult DVT/PE pivotal studies, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in 0.1% of patients receiving PRADAXA Capsules. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of PRADAXA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Agranulocytosis, neutropenia, thrombocytopenia Gastrointestinal Disorders: Esophageal ulcer Immune System Disorders: Angioedema Renal and Urinary Disorders: Anticoagulant-related nephropathy Skin and Subcutaneous Tissue Disorders: Alopecia

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 )

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.