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 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

1.1Treatment 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.

1.2Reduction 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.

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 For pediatric patients 2 years to less than 12 years: weight-based dosage, twice daily after at least 5 days of parenteral anticoagulant 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 For pediatric patients aged 2 years to less than 12 years: weight-based dosage, twice daily after previous treatment Pradaxa Oral Pellets 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 ( 2.5 , 2.6 ) Temporarily discontinue PRADAXA before invasive or surgical procedures when possible, then restart promptly

2.1Important 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 .

2.2Recommended

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 .

2.3Dosage 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 and the risk of increased exposure, avoid use of PRADAXA Oral Pellets in these patients. Treat patients with an eGFR > 50 mL/min/1.73 m 2 with the dosage according to Tables 1 and 2 .

2.4Administration

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 .

2.5Converting 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 < 50 mL/min/1.73 m 2 have not been studied.

Avoid use of PRADAXA Oral Pellets in these patients. Because PRADAXA Oral Pellets can increase INR, the INR will better reflect warfarin's effect only after PRADAXA Oral Pellets have been stopped for at least 2 days .

2.6Converting from or to Parenteral Anticoagulants For

pediatric patients currently receiving a parenteral anticoagulant, start PRADAXA Oral Pellets 0 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 pediatric patients currently taking PRADAXA Oral Pellets, wait 12 hours after the last dose before switching to a parenteral anticoagulant .

2.7Discontinuation for Surgery and Other Interventions If

possible, discontinue PRADAXA Oral Pellets before invasive or surgical procedures because of the increased risk of bleeding. For pediatric patients, PRADAXA Oral Pellets should be stopped 24 hours before an elective surgery (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 . If surgery cannot be delayed, there is an increased risk of bleeding . This risk of bleeding should be weighed against the urgency of intervention . 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 . Refer to the idarucizumab prescribing information for additional information. Restart PRADAXA Oral Pellets as soon as medically appropriate.

Bleeding: PRADAXA can cause serious and fatal bleeding Bioprosthetic heart valves: PRADAXA use not recommended Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: PRADAXA use not recommended

5.1Increased Risk of Thrombotic Events

after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including PRADAXA, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA Oral Pellets are discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart PRADAXA Oral Pellets as soon as medically appropriate .

5.2Risk of Bleeding

PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA Oral Pellets in patients with active pathological bleeding . Risk factors for bleeding include the concomitant use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs).

PRADAXA's anticoagulant activity and half-life are increased in patients with renal impairment . Reversal of Anticoagulant Effect Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited . Prothrombin complex concentrates or recombinant Factor VIIa may be considered but their use has not been evaluated in clinical trials. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

In adults, a specific reversal agent (idarucizumab) for PRADAXA is available when reversal of the anticoagulant effect of dabigatran is needed. In pediatric patients, the efficacy and safety of idarucizumab have not been established.

5.3Spinal/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 . To reduce the potential risk of bleeding associated with the concurrent use of PRADAXA and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dabigatran . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), and bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms.

If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

5.4Thromboembolic and Bleeding Events in Patients with Prosthetic

Heart Valves The safety and efficacy of PRADAXA Capsules in adult patients with bileaflet mechanical prosthetic heart valves was evaluated in the RE-ALIGN trial, in which patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than three months prior to enrollment) were randomized to dose-adjusted warfarin or 150 mg, 220 mg, or 300 mg of PRADAXA Capsules twice a day. RE-ALIGN was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) in the PRADAXA treatment arm as compared to the warfarin treatment arm. These bleeding and thromboembolic events were seen both in patients who were initiated on PRADAXA Capsules postoperatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment.

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

5.5Effect of P-gp Inducers and Inhibitors on Dabigatran

Exposure The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided . 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. The concomitant use of PRADAXA Oral Pellets with P-gp-inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.

5.6Increased Risk of Thrombosis in Patients with Triple-Positive

Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including PRADAXA, are 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.

4 CONTRAINDICATIONS PRADAXA is contraindicated in patients with: 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 Active pathological bleeding History of serious hypersensitivity reaction to PRADAXA Mechanical prosthetic heart valve

8.1Pregnancy 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 . 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 . 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 . 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 . 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).

The following clinically significant adverse reactions are described elsewhere in the labeling: Increased Risk of Thrombotic Events after Premature Discontinuation Risk of Bleeding Spinal/Epidural Anesthesia or Puncture Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome The most serious adverse reactions reported with PRADAXA were related to bleeding . Most common adverse reactions (> 15%) are gastrointestinal adverse reactions and bleeding. To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 Fatal bleeding 0 1 Clinically relevant non-major bleeding 2 1 Minor bleeding 33 21 Major and clinically relevant non-major bleeding 6 3 Any bleeding 38 22 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.

6.2Postmarketing 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