USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding not recommended (8.2). Lactation: Breastfeeding not recommended (8.2). 8.1 Pregnancy. Risk SummaryThe 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 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 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 (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 riskPregnancy 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 previous history of venous thrombosis are at high risk for recurrence during pregnancy.. Fetal/Neonatal adverse reactionUse 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 deliveryAll 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 DataDabigatran has been shown to decrease the number of implantations when male and female rats were treated at 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 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 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 SummaryThere are no data on the presence of dabigatran in human milk, the effects 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 Reproductive Potential. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including PRADAXA should be assessed in females of reproductive potential and those with abnormal uterine bleeding.. 8.4 Pediatric Use. The safety and effectiveness of PRADAXA Oral Pellets for the treatment and the reduction in risk of recurrence of venous thromboembolism have been established in pediatric patients less than 12 years of age. Use of PRADAXA Oral Pellets 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 [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)]. Other age-appropriate pediatric formulations of dabigatran etexilate are available for pediatric patients aged 12 years and older for these indications.Safety and effectiveness of PRADAXA have not been established in pediatric patients with non-valvular atrial fibrillation or those who have undergone hip replacement surgery. 8.5 Geriatric Use. Clinical studies of PRADAXA Oral Pellets did not include patients 65 years of age and older. Information on the use of PRADAXA Capsules in geriatric patients is available in that prescribing information.. 8.6 Renal Impairment. PRADAXA has not been studied in pediatric patients with an eGFR 50 mL/min/1.73m2. Reduced renal function could increase exposure. Dosing recommendations cannot be provided for treatment of these patients. Avoid use of PRADAXA in these patients [see Dosage and Administration (2.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Bleeding: PRADAXA can cause serious and fatal bleeding (5.2)Bioprosthetic heart valves: PRADAXA use not recommended (5.4) Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: PRADAXA use not recommended (5.6). Bleeding: PRADAXA can cause serious and fatal bleeding (5.2). Bioprosthetic heart valves: PRADAXA use not recommended (5.4) Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: PRADAXA use not recommended (5.6). 5.1 Increased 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 reason other than pathological bleeding or completion of course of therapy, consider coverage with another anticoagulant and restart PRADAXA Oral Pellets as soon as medically appropriate [see Dosage and Administration (2.5, 2.6, 2.7)]. 5.2 Risk 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., drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA Oral Pellets in patients with active pathological bleeding [see Dosage and Administration (2.2)]. 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). PRADAXAs anticoagulant activity and half-life are increased in patients with renal impairment [see Clinical Pharmacology (12.2)]. Reversal of Anticoagulant Effect:Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as treatment for bleeding is limited [see Overdosage (10)]. Prothrombin complex concentrates or recombinant Factor VIIa may be considered but their use has not been evaluated in clinical trials. Protamine sulfate and vitamin 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, 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.. 5.3 Spinal/Epidural Anesthesia or Puncture. When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].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 [see Clinical Pharmacology (12.3)]. 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 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.. 5.4 Thromboembolic 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 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 [see Contraindications (4)]. 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 bioprosthetic heart valve, has not been studied and is not recommended.. 5.5 Effect 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 [see Clinical Pharmacology (12.3)].P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology (12.3)]. 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.. 5.6 Increased 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 antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin antagonist therapy.

ADVERSE REACTIONS SECTION.

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)].. 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)] 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 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 PatientsThe safety of PRADAXA in the treatment of VTE in pediatric patients was studied in one phase III trial (DIVERSITY). The DIVERSITY study was randomized, open-label, active-controlled, parallel-group trial comparing PRADAXA with standard of care SOC (vitamin 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 doses of an age-appropriate formulation of PRADAXA (capsules, pellets, or oral solution) twice daily.Patients had median age of 14 years (range: 0-17 years), 92% were white, and half the patients were male (50%). Following at least 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/1.73m2 were excluded from the trial.. BleedingData 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 4. There was no statistically significant difference in the time to first major bleeding event.Table Summary of All Adjudicated Bleeding Events During On-Treatment Period in DIVERSITYPRADAXAN (%)Standard of Care (SOC)N (%)PatientsN=176N=901 Major bleeding event if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L) or more, or leading to transfusion of or more units of whole blood or red cells.Major bleeding event1 (2.3)2 (2.2) Fatal bleeding01 (1.1)Clinically relevant non-major bleeding2 (1.1)1 (1.1)Minor bleeding33 (19)21 (23)Major and clinically relevant non-major bleeding6 (3.4)3 (3.3)Any bleeding38 (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 ReactionsThe 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 PatientsThe 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 enrolled patients who required further anticoagulation due to the presence of clinical risk factor after completing the initial treatment for confirmed VTE (for at least months) or after completing the DIVERSITY study and received PRADAXA until the clinical risk factor resolved, or up to maximum of 12 months. There were 213 pediatric patients treated with PRADAXA, in similar fashion as in the DIVERSITY trial.Patients had 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 (29% from PRADAXA arm and 14% from SOC arm). The median duration of treatment with PRADAXA in Study 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, patients (1.4%) had major bleeding event, patients (1.4%) had clinically relevant non-major bleeding event, and 44 patients (20%) had 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 TrialsIn 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of PRADAXA: angioedema, thrombocytopenia, esophageal ulcer, alopecia, neutropenia, agranulocytosis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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 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.As in adults, there is 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 nonlinear fashion with dabigatran plasma concentrations.Similar 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.. 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 10 mg to 400 mg. Given twice daily, dabigatrans accumulation factor in pediatric patients receiving pellets is 1.5-1.7.. AbsorptionThe absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3% to 7%. Dabigatran etexilate is substrate of the efflux transporter P-gp. After oral administration of dabigatran etexilate in healthy volunteers, Cmax occurs at hour post-administration in the fasted state. Coadministration of PRADAXA with high-fat meal delays the time to Cmax by approximately hours but has no effect on the bioavailability of dabigatran; PRADAXA may be administered with or without food.PRADAXA 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. Dabigatran etexilate oral pellets show 37% higher relative bioavailability in healthy adults compared to dabigatran etexilate capsules. In addition, the relative bioavailability between the two dosage forms is age dependent. The relative bioavailability observed in adult patients cannot be translated to pediatric patients.. DistributionDabigatran 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 50 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 elimination half-life of dabigatran in pediatric patients receiving pellets is approximately to 11 hours.. MetabolismAfter 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 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.. Specific Populations. Pediatric PatientsThe 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 doses of PRADAXA pellets (less than 12 years of age), the observed geometric mean steady-state trough concentration was 54.7 ng/mL (25.9 to 88.3 ng/mL, 10th to 90th percentile) compared to the geometric mean steady-state trough concentration of 59.7 ng/mL (26.3 to 146 ng/mL, 10th to 90th percentile) observed in adult patients with DVT/PE taking PRADAXA capsules.. Renal Impairment An open, parallel-group, single-center study compared dabigatran pharmacokinetics in healthy adult subjects and adult patients with mild to moderate renal impairment receiving single dose of PRADAXA capsules 150 mg. Exposure to dabigatran increases with severity of renal function impairment (Table 5). Similar findings were observed in the RE-LY, RE-COVER and RE-NOVATE II trials.Table Impact of Renal Impairment on Dabigatran PharmacokineticsRenal FunctionCrCl (mL/min)Increase in AUCIncrease in Cmax t1/2 (h)+Patients with severe renal impairment were not studied in RE-LY, RE-COVER and RE-NOVATE II.Normal>= 801x1x13Mild50-801.5x1.1x15Moderate30-503.2x1.7x18Severe+ 15-306.3x2.1x27. Hepatic Impairment Administration of PRADAXA Capsules in adult patients with moderate hepatic impairment (Child-Pugh B) showed large inter-subject variability, but no evidence of consistent change in exposure or pharmacodynamics.. Drug Interactions No clinical drug interaction studies have been conducted in pediatric subjects. summary of the effect of coadministered drugs on dabigatran exposure in adult subjects is shown in Figures and 2.Figure Effect of P-gp Inhibitor or Inducer (rifampicin) Drugs on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose (Time Difference)Figure Effect of Non-P-gp Inhibitor or Inducer, Other Drugs, on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose (Time Difference). Figure 1. Figure 2. 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Treatment of VTE in Pediatric Patients. The DIVERSITY study was conducted to demonstrate the efficacy and safety of PRADAXA compared to standard of care (SOC) for the treatment of venous thromboembolism (VTE) in pediatric patients from birth to less than 18 years of age. The study was designed as an open-label, randomized, parallel-group, non-inferiority study. Patients enrolled were randomized according to 2:1 scheme to either an age-appropriate formulation (capsules, oral pellets, or oral solution) of PRADAXA (doses adjusted for age and weight) after at least days and no longer than 21 days of treatment with parenteral anticoagulant, or to SOC comprised of low molecular weight heparins (LMWH) or vitamin antagonists (VKA) or fondaparinux. For patients on PRADAXA, drug concentration was determined prior to the 7th dose and single titration was permitted to achieve drug target levels of 50-250 ng/ml. Inability to achieve target, after one up-titration, resulted in premature termination of study drug in 12 patients (6.8%).The median treatment duration during the treatment period was 85 days. In total, 267 patients entered the study (leading index VTE was 64% deep vein thrombosis, 10% cerebral venous thrombosis or sinus thrombosis, and 9.0% pulmonary embolism), with 18% of patients having central line-associated thrombosis. The patient population was 49.8% male, 91.8% white, 4.9% Asian, and 1.5% black; 168 patients were 12 to <18 years old, 64 patients to <12 years, and 35 patients were younger than years. The concomitant VTE-related risk factors of patients in this trial among study arms were as follows: inherited thrombophilia disorder (PRADAXA: 20%; SOC: 22%), congenital heart disease (PRADAXA: 12%; SOC: 30%), heart failure (PRADAXA: 3%; SOC: 18%), history of cancer (PRADAXA: 10%; SOC: 1%), CVL insertion (PRADAXA: 23%; SOC: 27%), immobility (PRADAXA: 13%; SOC: 10%) and significant infection (PRADAXA: 15%; SOC: 13%). The number of patients taking concomitant medications with hemostatic effects were similar in both treatment groups (PRADAXA: 15%; SOC: 16%).The efficacy of PRADAXA was established based on composite endpoint of patients with complete thrombus resolution, freedom from recurrent venous thromboembolic event, and freedom from mortality related to venous thromboembolic event (composite primary endpoint). Of the 267 randomized patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients (42.2%) in the SOC group met the criteria for the composite primary endpoint. The corresponding rate difference and 95% CI was -0.038 (-0.161, 0.086) and thus demonstrated non-inferiority of PRADAXA to SOC, since the upper bound of the 95% CI was lower than the predefined non-inferiority margin of 20% (see Table 6).Table Efficacy Results [ITT population] DIVERSITY StudyPRADAXAStandard of Care1 Mantel-Haenszel weighted difference with age group as stratification factorNumber of patients randomized (%)177 (100.0)90 (100.0) Complete thrombus resolution81(45.8)38(42.2) Freedom from recurrent VTE170(96.0)83(92.2) Freedom from mortality related to VTE177(100.0)89(98.9) Composite endpoint met81(45.8)38(42.2) Difference in rate (95% CI)1 -0.038 (-0.161, 0.086) p-value for non-inferiority<0.0001 p-value for superiority0.2739Subgroup analyses showed that there were no outliers in the treatment effect for the subgroups by age, sex, region, and presence of certain risk factors (central venous line, congenital heart disease, malignant disease). For the different age strata, the proportions of patients that met the efficacy endpoint in the PRADAXA and SOC groups, respectively, were 13/22 (59.1%) and 7/13 (53.8%) for patients from birth to 2 years [Rate Difference -0.052; (95%CI: -0.393, 0.288)], 21/43 (48.8%) and 12/21 (57.1%) for patients aged to 12 years [Rate Difference 0.083; (95%CI: -0.176, 0.342)], and 47/112 (42.0%) and 19/56 (33.9%) for patients aged 12 to 18 years [Rate Difference -0.080; (95%CI: -0.234, 0.074)].. 14.2 Reduction in the Risk of Recurrence of VTE in Pediatric Patients. Study was an open-label, single-arm safety study to assess the safety of PRADAXA for the prevention of recurrent VTE in pediatric patients from birth to <18 years. Patients who required further anticoagulation due to the presence of clinical risk factor after completing the initial treatment for confirmed VTE (for at least months) or after completing the DIVERSITY study were included in the study. Eligible patients received age- and weight-adjusted doses of an age-appropriate formulation (capsules or oral pellets) of PRADAXA until the clinical risk factor resolved, or up to maximum of 12 months. The primary endpoints of the study included the recurrence of VTE, major and minor bleeding events, and mortality (overall and related to thrombotic or thromboembolic events) at and 12 months.Of the 214 patients in the study, 162 patients were 12 to <18 years old, 43 patients were to <12 years old, and patients were aged months to <2 years old.The overall probability of being free from recurrence of VTE during the on-treatment period was 0.990 (95% CI: 0.960, 0.997) at months, 0.984 (95% CI: 0.950, 0.995) at months, and 0.984 (95% CI: 0.950, 0.995) at 12 months. The probability of being free from bleeding events during the on-treatment period was 0.849 (95% CI: 0.792, 0.891) at months, 0.785 (95% CI: 0.718, 0.838) at months, and 0.723 (95% CI: 0.645, 0.787) at 12 months. No on-treatment deaths occurred.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of 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 PatientsThe safety of PRADAXA in the treatment of VTE in pediatric patients was studied in one phase III trial (DIVERSITY). The DIVERSITY study was randomized, open-label, active-controlled, parallel-group trial comparing PRADAXA with standard of care SOC (vitamin 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 doses of an age-appropriate formulation of PRADAXA (capsules, pellets, or oral solution) twice daily.Patients had median age of 14 years (range: 0-17 years), 92% were white, and half the patients were male (50%). Following at least 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/1.73m2 were excluded from the trial.. BleedingData 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 4. There was no statistically significant difference in the time to first major bleeding event.Table Summary of All Adjudicated Bleeding Events During On-Treatment Period in DIVERSITYPRADAXAN (%)Standard of Care (SOC)N (%)PatientsN=176N=901 Major bleeding event if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L) or more, or leading to transfusion of or more units of whole blood or red cells.Major bleeding event1 (2.3)2 (2.2) Fatal bleeding01 (1.1)Clinically relevant non-major bleeding2 (1.1)1 (1.1)Minor bleeding33 (19)21 (23)Major and clinically relevant non-major bleeding6 (3.4)3 (3.3)Any bleeding38 (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 ReactionsThe 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 PatientsThe 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 enrolled patients who required further anticoagulation due to the presence of clinical risk factor after completing the initial treatment for confirmed VTE (for at least months) or after completing the DIVERSITY study and received PRADAXA until the clinical risk factor resolved, or up to maximum of 12 months. There were 213 pediatric patients treated with PRADAXA, in similar fashion as in the DIVERSITY trial.Patients had 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 (29% from PRADAXA arm and 14% from SOC arm). The median duration of treatment with PRADAXA in Study 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, patients (1.4%) had major bleeding event, patients (1.4%) had clinically relevant non-major bleeding event, and 44 patients (20%) had 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 TrialsIn 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.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Issued: June 2021 MEDICATION GUIDEPRADAXA (pra dax a)(dabigatran etexilate) Oral PelletsThis Medication Guide is for PRADAXA Oral Pellets. If your child is over years of age and your healthcare provider prescribes PRADAXA Capsules for your child, read the Medication Guide that comes with your medicine.Read this Medication Guide before you start giving PRADAXA Oral Pellets to your child and each time you get refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your childs medical condition or their treatment. What is the most important information should know about PRADAXA Do not stop giving PRADAXA without talking to the healthcare provider who prescribes it for your child. Stopping PRADAXA increases your childs risk of clot forming in their blood.PRADAXA may need to be stopped, if possible, before surgery or medical or dental procedure. Ask the healthcare provider who prescribed PRADAXA for your child when your child should stop taking it. Your healthcare provider will tell you when you may start giving PRADAXA to your child again after their surgery or procedure. If your child has to stop taking PRADAXA, your healthcare provider may prescribe another medicine to help prevent blood clot from forming.PRADAXA can cause bleeding which can be serious, and sometimes lead to death. This is because PRADAXA is blood thinner medicine that lowers the chance of blood clots forming in the body.Your child may have higher risk of bleeding if your child takes PRADAXA and:has kidney problemshas stomach or intestine bleeding that is recent or keeps coming back, or stomach ulcer takes other medicines that increase the risk of bleeding, including:aspirin or aspirin-containing products long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs) medicine that contains warfarin sodiuma medicine that contains heparina medicine that contains clopidogrel bisulfate medicine that contains prasugrel has certain kidney problems and also takes medicine that contains dronedarone or ketoconazole tabletsTell your healthcare provider if your child takes any of these medicines. Ask your healthcare provider or pharmacist if you are not sure if your childs medicine is one listed above.PRADAXA can increase your childs risk of bleeding because it lessens the ability of your childs blood to clot. During treatment with PRADAXA:he or she may bruise more easilyit may take longer for any bleeding to stop Call your healthcare provider or get medical help right away if your child has any of these signs or symptoms of bleeding: unexpected bleeding or bleeding that lasts long time, such as:unusual bleeding from the gumsnose bleeds that happen oftenmenstrual bleeding or vaginal bleeding that is heavier than normal bleeding that is severe or you cannot controlpink or brown urinered or black stools (looks like tar)bruises that happen without known cause or get largercough up blood or blood clotsvomit blood or your vomit looks like coffee groundsunexpected pain, swelling, or joint painheadaches, feeling dizzy or weak Take PRADAXA Oral Pellets exactly as prescribed. Do not stop giving PRADAXA Oral Pellets to your child without first talking to the healthcare provider who prescribes it for your child. Stopping PRADAXA increases your childs risk of clot forming in their blood. Spinal or epidural blood clots (hematoma). People who take blood thinner medicine (anticoagulant) like PRADAXA, and have medicine injected into their spinal and epidural area, or have spinal puncture have risk of forming blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your childs risk of developing spinal or epidural blood clot is higher if:a thin tube called an epidural catheter is placed in your childs back to give them certain medicineyour child takes NSAIDs or medicine to prevent blood from clottingyour child has history of difficult or repeated epidural or spinal puncturesyour child has history of problems with their spine or has had surgery on their spineIf your child takes PRADAXA and receives spinal anesthesia or has spinal puncture, your healthcare provider should watch your child closely for symptoms of spinal or epidural blood clots. Tell your healthcare provider right away if your child has back pain, tingling, numbness, muscle weakness (especially in the legs and feet), loss of control of the bowels or bladder (incontinence).See What are the possible side effects of PRADAXA for more information about side effects.What is PRADAXA Oral PelletsPRADAXA Oral Pellets is prescription medicine that is used to:treat blood clots in children who are age months to less than 12 years of age who have received an injectable medicine to treat their blood clots for at least days. reduce the risk of blood clots happening again in children who are age months to less than 12 years of age who have already been treated for blood clots.Do not give PRADAXA if your child:currently has certain types of abnormal bleeding. Talk to your healthcare provider before giving PRADAXA if your child currently has unusual bleeding.has had serious allergic reaction to any of the ingredients in PRADAXA. See the end of this Medication Guide for complete list of ingredients in PRADAXA. Ask your healthcare provider if you are not sure. has ever had or if there are plans for your child to have valve in their heart replaced with mechanical (artificial) prosthetic heart valve.Before giving PRADAXA to your child, tell your healthcare provider about all of your childs medical conditions, including if they:have kidney problemshave ever had bleeding problemshave ever had stomach ulcershave antiphospholipid syndrome (APS)are pregnant or plan to become pregnant. It is not known if PRADAXA will harm your childs unborn baby.If your child is able to become pregnant, talk with your healthcare provider about your childs risk for severe uterine bleeding during treatment with blood thinner medicines, including PRADAXA.Tell your healthcare provider right away if your child becomes pregnant during treatment with PRADAXA Oral Pellets. are breastfeeding or plan to breastfeed. It is not known if PRADAXA passes into your childs breastmilk. Your child should not breastfeed during treatment with PRADAXA.Tell all of your healthcare providers and dentists that your child is taking PRADAXA. They should talk to the healthcare provider who prescribed PRADAXA for your child before your child has any surgery or medical or dental procedure. Tell your healthcare provider about all the medicines your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Some of your childs other medicines may affect the way PRADAXA works. Certain medicines may increase your childs risk of bleeding. See What is the most important information should know about PRADAXA Especially tell your healthcare provider if your child takes medicine that contains rifampin.Know the medicines your child takes. Keep list of them and show it to your healthcare provider and pharmacist when your child gets new medicine.How should give PRADAXASee the detailed Instructions for Use that comes with PRADAXA Oral Pellets for information about the right way to prepare and give your child dose of PRADAXA Oral Pellets.Your healthcare provider will decide how long your child should take PRADAXA Oral Pellets. Do not stop giving your child PRADAXA Oral Pellets without first talking with your healthcare provider. Stopping PRADAXA Oral Pellets may increase your childs risk of forming blood clots. Give PRADAXA Oral Pellets exactly as prescribed by your healthcare provider. Check with your healthcare provider if you are not sure.Your healthcare provider will prescribe the correct dose of PRADAXA Oral Pellets for your child. Your healthcare provider will change your childs dose as they grow, and as needed during treatment. Give PRADAXA Oral Pellets times day, dose in the morning and dose in the evening. The doses should be given as close as possible to every 12 hours, and at about the same time every day.Give PRADAXA Oral Pellets before meals to help ensure that your child takes the full dose.You can mix PRADAXA Oral Pellets with apple juice or the following soft foods at room temperature:Baby rice cereal, prepared with waterMashed carrotsApple sauceMashed bananasDo not mix PRADAXA Oral Pellets with any food or liquid other than the ones listed above.Do not mix PRADAXA Oral Pellets with milk or with foods that contain milk.Give PRADAXA Oral Pellets right away or within 30 minutes after mixing. Do not give PRADAXA Oral Pellets if they have been in contact with the soft food or apple juice for more than 30 minutes.Do not give PRADAXA Oral Pellets using syringe or through feeding tube.Do not run out of PRADAXA Oral Pellets. Refill your childs prescription before you run out. If you plan for your child to have surgery, or medical or dental procedure, tell your healthcare provider and dentist that your child is taking PRADAXA Oral Pellets. Your child may have to stop taking PRADAXA Oral Pellets for short time. See What is the most important information should know about PRADAXA If your child only takes part of their dose, do not give another dose at that time. Give your child their next dose at the regular scheduled time, about 12 hours later.If your child misses dose of PRADAXA Oral Pellets, give it as soon as you remember. If your childs next dose is less than hours away, skip the missed dose. Do not give your child double dose of PRADAXA Oral Pellets to make up for missed dose.If your child takes too much PRADAXA Oral Pellets, go to the nearest hospital emergency room or call your healthcare provider right away.Call your healthcare provider right away if your child falls or injures himself, especially if your child hits his head. Your healthcare provider may need to check your child.PRADAXA Oral Pellets come in an aluminum bag that contains packets of the Oral Pellets used to prepare your childs dose of medicine. After opening the aluminum bag, the packets of PRADAXA Oral Pellets must be used within months. See How should store PRADAXA Oral Pellets What are the possible side effects of PRADAXA PRADAXA can cause serious side effects. See What is the most important information should know about PRADAXA Allergic Reactions. Some adults taking PRADAXA capsules have developed symptoms of an allergic reaction.Call your healthcare provider if your child gets symptoms of an allergic reaction, such as: hivesrashitchingGet medical help right away if your child gets any of the following symptoms of serious allergic reaction with PRADAXA Oral Pellets:chest pain or chest tightnessswelling of the face or tonguetrouble breathing or wheezingfeeling dizzy or faintCommon side effects of PRADAXA in children include: indigestion, upset stomach, burningnausea, vomiting, or diarrhea stomach-area (abdominal) pain or discomfortCall your healthcare provider if your child develops any of the signs and symptoms of stomach and intestine problems listed above.Tell your healthcare provider if your child has any side effect that bothers them or that does not go away.These are not all of the possible side effects of PRADAXA. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store PRADAXA Oral PelletsStore PRADAXA Oral Pellets at room temperature 68F to 77F (20C to 25C). After opening the aluminum bag that contains the packets of Oral Pellets, PRADAXA Oral Pellets must be used within months. Safely throw away any unused PRADAXA Oral Pellets after months.Keep PRADAXA Oral Pellets packets in the original aluminum bag to keep them dry (protect the packets from moisture). Do not open packets of PRADAXA Oral Pellets until you are ready to use them.Throw away any PRADAXA Oral Pellets that have not been given within 30 minutes after the Oral Pellets come into contact with apple juice or soft food.Keep PRADAXA and all medicines out of the reach of children.General information about the safe and effective use of PRADAXAMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use PRADAXA for condition for which it was not prescribed. Do not give PRADAXA to other people, even if they have the same symptoms that your child has. It may harm them.This Medication Guide summarizes the most important information about PRADAXA. If you would like more information, talk with your childs healthcare provider. You can ask your childs pharmacist or healthcare provider for information about PRADAXA that is written for health professionals.What are the ingredients in PRADAXAActive ingredient: dabigatran etexilate mesylate Inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USAFor more information about PRADAXA Oral Pellets, call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257.Copyright (C) 2021 Boehringer Ingelheim Pharmaceuticals, Inc.ALL RIGHTS RESERVEDCOL8834AF252021. PRADAXA can cause bleeding which can be serious, and sometimes lead to death. This is because PRADAXA is blood thinner medicine that lowers the chance of blood clots forming in the body.. Your child may have higher risk of bleeding if your child takes PRADAXA and:has kidney problemshas stomach or intestine bleeding that is recent or keeps coming back, or stomach ulcer takes other medicines that increase the risk of bleeding, including:aspirin or aspirin-containing products long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs) medicine that contains warfarin sodiuma medicine that contains heparina medicine that contains clopidogrel bisulfate medicine that contains prasugrel has certain kidney problems and also takes medicine that contains dronedarone or ketoconazole tabletsTell your healthcare provider if your child takes any of these medicines. Ask your healthcare provider or pharmacist if you are not sure if your childs medicine is one listed above.. has kidney problems. has stomach or intestine bleeding that is recent or keeps coming back, or stomach ulcer takes other medicines that increase the risk of bleeding, including:aspirin or aspirin-containing products long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs) medicine that contains warfarin sodiuma medicine that contains heparina medicine that contains clopidogrel bisulfate medicine that contains prasugrel aspirin or aspirin-containing products long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs) a medicine that contains warfarin sodium. medicine that contains heparin. medicine that contains clopidogrel bisulfate a medicine that contains prasugrel has certain kidney problems and also takes medicine that contains dronedarone or ketoconazole tablets. PRADAXA can increase your childs risk of bleeding because it lessens the ability of your childs blood to clot. During treatment with PRADAXA:he or she may bruise more easilyit may take longer for any bleeding to stop Call your healthcare provider or get medical help right away if your child has any of these signs or symptoms of bleeding: unexpected bleeding or bleeding that lasts long time, such as:unusual bleeding from the gumsnose bleeds that happen oftenmenstrual bleeding or vaginal bleeding that is heavier than normal bleeding that is severe or you cannot controlpink or brown urinered or black stools (looks like tar)bruises that happen without known cause or get largercough up blood or blood clotsvomit blood or your vomit looks like coffee groundsunexpected pain, swelling, or joint painheadaches, feeling dizzy or weak Take PRADAXA Oral Pellets exactly as prescribed. Do not stop giving PRADAXA Oral Pellets to your child without first talking to the healthcare provider who prescribes it for your child. Stopping PRADAXA increases your childs risk of clot forming in their blood. he or she may bruise more easily. it may take longer for any bleeding to stop. unexpected bleeding or bleeding that lasts long time, such as:unusual bleeding from the gumsnose bleeds that happen oftenmenstrual bleeding or vaginal bleeding that is heavier than normal unusual bleeding from the gums. nose bleeds that happen often. menstrual bleeding or vaginal bleeding that is heavier than normal. bleeding that is severe or you cannot control. pink or brown urine. red or black stools (looks like tar). bruises that happen without known cause or get larger. cough up blood or blood clots. vomit blood or your vomit looks like coffee grounds. unexpected pain, swelling, or joint pain. headaches, feeling dizzy or weak. Spinal or epidural blood clots (hematoma). People who take blood thinner medicine (anticoagulant) like PRADAXA, and have medicine injected into their spinal and epidural area, or have spinal puncture have risk of forming blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your childs risk of developing spinal or epidural blood clot is higher if:a thin tube called an epidural catheter is placed in your childs back to give them certain medicineyour child takes NSAIDs or medicine to prevent blood from clottingyour child has history of difficult or repeated epidural or spinal puncturesyour child has history of problems with their spine or has had surgery on their spineIf your child takes PRADAXA and receives spinal anesthesia or has spinal puncture, your healthcare provider should watch your child closely for symptoms of spinal or epidural blood clots. Tell your healthcare provider right away if your child has back pain, tingling, numbness, muscle weakness (especially in the legs and feet), loss of control of the bowels or bladder (incontinence).. thin tube called an epidural catheter is placed in your childs back to give them certain medicine. your child takes NSAIDs or medicine to prevent blood from clotting. your child has history of difficult or repeated epidural or spinal punctures. your child has history of problems with their spine or has had surgery on their spine. treat blood clots in children who are age months to less than 12 years of age who have received an injectable medicine to treat their blood clots for at least days. reduce the risk of blood clots happening again in children who are age months to less than 12 years of age who have already been treated for blood clots.. currently has certain types of abnormal bleeding. Talk to your healthcare provider before giving PRADAXA if your child currently has unusual bleeding.. has had serious allergic reaction to any of the ingredients in PRADAXA. See the end of this Medication Guide for complete list of ingredients in PRADAXA. Ask your healthcare provider if you are not sure. has ever had or if there are plans for your child to have valve in their heart replaced with mechanical (artificial) prosthetic heart valve.. have kidney problems. have ever had bleeding problems. have ever had stomach ulcers. have antiphospholipid syndrome (APS). are pregnant or plan to become pregnant. It is not known if PRADAXA will harm your childs unborn baby.If your child is able to become pregnant, talk with your healthcare provider about your childs risk for severe uterine bleeding during treatment with blood thinner medicines, including PRADAXA.Tell your healthcare provider right away if your child becomes pregnant during treatment with PRADAXA Oral Pellets. If your child is able to become pregnant, talk with your healthcare provider about your childs risk for severe uterine bleeding during treatment with blood thinner medicines, including PRADAXA.. Tell your healthcare provider right away if your child becomes pregnant during treatment with PRADAXA Oral Pellets. are breastfeeding or plan to breastfeed. It is not known if PRADAXA passes into your childs breastmilk. Your child should not breastfeed during treatment with PRADAXA.. See the detailed Instructions for Use that comes with PRADAXA Oral Pellets for information about the right way to prepare and give your child dose of PRADAXA Oral Pellets.. Your healthcare provider will decide how long your child should take PRADAXA Oral Pellets. Do not stop giving your child PRADAXA Oral Pellets without first talking with your healthcare provider. Stopping PRADAXA Oral Pellets may increase your childs risk of forming blood clots. Give PRADAXA Oral Pellets exactly as prescribed by your healthcare provider. Check with your healthcare provider if you are not sure.. Your healthcare provider will prescribe the correct dose of PRADAXA Oral Pellets for your child. Your healthcare provider will change your childs dose as they grow, and as needed during treatment. Give PRADAXA Oral Pellets times day, dose in the morning and dose in the evening. The doses should be given as close as possible to every 12 hours, and at about the same time every day.. Give PRADAXA Oral Pellets before meals to help ensure that your child takes the full dose.. You can mix PRADAXA Oral Pellets with apple juice or the following soft foods at room temperature:. Baby rice cereal, prepared with water. Mashed carrots. Apple sauce. Mashed bananas. Do not mix PRADAXA Oral Pellets with any food or liquid other than the ones listed above.. Do not mix PRADAXA Oral Pellets with milk or with foods that contain milk.. Give PRADAXA Oral Pellets right away or within 30 minutes after mixing. Do not give PRADAXA Oral Pellets if they have been in contact with the soft food or apple juice for more than 30 minutes.. Do not give PRADAXA Oral Pellets using syringe or through feeding tube.. Do not run out of PRADAXA Oral Pellets. Refill your childs prescription before you run out. If you plan for your child to have surgery, or medical or dental procedure, tell your healthcare provider and dentist that your child is taking PRADAXA Oral Pellets. Your child may have to stop taking PRADAXA Oral Pellets for short time. See What is the most important information should know about PRADAXA If your child only takes part of their dose, do not give another dose at that time. Give your child their next dose at the regular scheduled time, about 12 hours later.. If your child misses dose of PRADAXA Oral Pellets, give it as soon as you remember. If your childs next dose is less than hours away, skip the missed dose. Do not give your child double dose of PRADAXA Oral Pellets to make up for missed dose.. If your child takes too much PRADAXA Oral Pellets, go to the nearest hospital emergency room or call your healthcare provider right away.. Call your healthcare provider right away if your child falls or injures himself, especially if your child hits his head. Your healthcare provider may need to check your child.. PRADAXA Oral Pellets come in an aluminum bag that contains packets of the Oral Pellets used to prepare your childs dose of medicine. After opening the aluminum bag, the packets of PRADAXA Oral Pellets must be used within months. See How should store PRADAXA Oral Pellets Allergic Reactions. Some adults taking PRADAXA capsules have developed symptoms of an allergic reaction.Call your healthcare provider if your child gets symptoms of an allergic reaction, such as: Call your healthcare provider if your child gets symptoms of an allergic reaction, such as: hives. rash. itching. Get medical help right away if your child gets any of the following symptoms of serious allergic reaction with PRADAXA Oral Pellets:. chest pain or chest tightness. swelling of the face or tongue. trouble breathing or wheezing. feeling dizzy or faint. indigestion, upset stomach, burning. nausea, vomiting, or diarrhea stomach-area (abdominal) pain or discomfort. Store PRADAXA Oral Pellets at room temperature 68F to 77F (20C to 25C). After opening the aluminum bag that contains the packets of Oral Pellets, PRADAXA Oral Pellets must be used within months. Safely throw away any unused PRADAXA Oral Pellets after months.. Keep PRADAXA Oral Pellets packets in the original aluminum bag to keep them dry (protect the packets from moisture). Do not open packets of PRADAXA Oral Pellets until you are ready to use them.. Throw away any PRADAXA Oral Pellets that have not been given within 30 minutes after the Oral Pellets come into contact with apple juice or soft food.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Treatment of Pediatric Venous Thromboembolic Events (VTE):For pediatric patients aged months to less than years: age- and weight-based dosage, twice daily after at least days of parenteral anticoagulant (2.2)For pediatric patients years to less than 12 years: weight-based dosage, twice daily after at least days of parenteral anticoagulant (2.2)Reduction in the Risk of Recurrence of Pediatric VTE:For pediatric patients aged months to less than years: age- and weight-based dosage, twice daily after previous treatment (2.2)For pediatric patients aged years to less than 12 years: weight-based dosage, twice daily after previous treatment (2.2)Pradaxa Oral Pellets are NOT substitutable on milligram-to-milligram basis with other dabigatran etexilate dosage formsReview 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) Treatment of Pediatric Venous Thromboembolic Events (VTE):For pediatric patients aged months to less than years: age- and weight-based dosage, twice daily after at least days of parenteral anticoagulant (2.2)For pediatric patients years to less than 12 years: weight-based dosage, twice daily after at least days of parenteral anticoagulant (2.2). For pediatric patients aged months to less than years: age- and weight-based dosage, twice daily after at least days of parenteral anticoagulant (2.2). For pediatric patients years to less than 12 years: weight-based dosage, twice daily after at least days of parenteral anticoagulant (2.2). Reduction in the Risk of Recurrence of Pediatric VTE:For pediatric patients aged months to less than years: age- and weight-based dosage, twice daily after previous treatment (2.2)For pediatric patients aged years to less than 12 years: weight-based dosage, twice daily after previous treatment (2.2). For pediatric patients aged months to less than years: age- and weight-based dosage, twice daily after previous treatment (2.2). For pediatric patients aged years to less than 12 years: weight-based dosage, twice daily after previous treatment (2.2). Pradaxa Oral Pellets are NOT substitutable on 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 (2.7) 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 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 Dose for Pediatric Patients PRADAXA Oral Pellets can be used in pediatric patients aged 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 parenteral anticoagulant for at least days. For reduction in risk of recurrence of VTE, treatment should be initiated following previous treatment.The recommended dose of PRADAXA Oral Pellets is based on the patients age and actual weight as shown in the tables below. PRADAXA Oral Pellets is administered twice daily. Adjust the dose according to age and actual weight as treatment progresses.Table Age- and Weight-Based Dosing for PRADAXA Oral Pellets for Pediatric Patients less than Years OldActual Weight (kg)Age (in months)Dose (mg) twice dailyNumber of Packets Needed3 kg to less than kg3 to less than months30 mgone 30 mg packet twice daily4 kg to less than kg3 to less than 10 months40 mgone 40 mg packet twice daily5 kg to less than kg3 to less than months40 mgone 40 mg packet twice daily5 to less than 24 months50 mgone 50 mg packet twice daily7 kg to less than kg3 to less than months50 mgone 50 mg packet twice daily4 to less than months60 mgtwo 30 mg packets twice daily9 to less than 24 months70 mgone 30 mg packet plus one 40 mg packet twice daily9 kg to less than 11 kg5 to less than months60 mgtwo 30 mg packets twice daily6 to less than 11 months80 mgtwo 40 mg packets twice daily11 to less than 24 months90 mgone 40 mg packet plus one 50 mg packet twice daily11 kg to less than 13 kg8 to less than 18 months100 mgtwo 50 mg packets twice daily18 to less than 24 months110 mgone 110 mg packet twice daily13 kg to less than 16 kg10 to less than 11 months100 mgtwo 50 mg packets twice daily11 to less than 24 months140 mgone 30 mg packet plus one 110 mg packet twice daily16 kg to less than 21 kg12 to less than 24 months140 mgone 30 mg packet plus one 110 mg packet twice daily21 kg to less than 26 kg18 to less than 24 months180 mgone 30 mg packet plus one 150 mg packet twice dailyTable Weight-Based Dosing for PRADAXA Oral Pellets for Pediatric Patients between Years to less than 12 Years OldActual Weight (kg)Dose (mg) twice dailyNumber of Packets Needed7 kg to less than kg70 mgone 30 mg packet plus one 40 mg packet twice daily9 kg to less than 11 kg90 mgone 40 mg packet plus one 50 mg packet twice daily11 kg to less than 13 kg110 mgone 110 mg packet twice daily13 kg to less than 16 kg140 mgone 30 mg packet plus one 110 mg packet twice daily16 kg to less than 21 kg170 mgone 20 mg packet plus one 150 mg packet twice daily21 kg to less than 41 kg220 mgtwo 110 mg packets twice daily41 kg or greater260 mgone 110 mg packets plus one 150 mg packet twice dailyEvaluation 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 ImpairmentAssess 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 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/1.73m2 and the risk of increased exposure, avoid use of PRADAXA Oral Pellets in these patients. Treat patients with an eGFR 50 mL/min/1.73m2 with the dose according to Tables and [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 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 hours before the next scheduled dose. The dose of PRADAXA Oral Pellets should not be doubled to make up for missed dose.If partial dose has been taken, 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 new dose prepared.PRADAXA Oral Pellets should be administered with only specific soft foods or apple juice.. Administration with soft foodsPRADAXA Oral Pellets may be mixed with two teaspoons of the following soft foods at room temperature: Baby rice cereal, prepared with water Mashed carrots Apple sauce Mashed banana. Baby rice cereal, prepared with water. Mashed carrots. Apple sauce. Mashed banana. Administration with apple juicePRADAXA Oral Pellets may be spooned directly into the patients 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 productsSee Instructions for Use.. via syringes or feeding tubes. with milk, milk products, or soft foods containing milk products. 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/1.73m2, start warfarin days before discontinuing PRADAXA Oral Pellets.Patients with an eGFR <50 mL/min/1.73m2 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 warfarins effect only after PRADAXA Oral Pellets have been stopped for at least days [see Clinical Pharmacology (12.2)]. For eGFR >=50 mL/min/1.73m2, start warfarin days before discontinuing PRADAXA Oral Pellets.. Patients with an eGFR <50 mL/min/1.73m2 have not been studied. Avoid use of PRADAXA Oral Pellets in these patients.. 2.6 Converting from or to Parenteral Anticoagulants For pediatric patients currently receiving parenteral anticoagulant, start PRADAXA Oral Pellets to hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of 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 parenteral anticoagulant [see Clinical Pharmacology (12.3)].. 2.7 Discontinuation 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/1.73m2) or days before an elective surgery (eGFR 50-80 mL/min/1.73m2). Pediatric patients with an eGFR 50 mL/min/1.73m2 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 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, 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and Instruction for Use).. Instructions for Patients Tell patients or their caregivers to take or administer PRADAXA Oral Pellets exactly as prescribed. Tell patients or their caregivers to remove desiccant from the aluminum bag and throw away. Remind patients or their caregivers not to discontinue PRADAXA Oral Pellets without talking to the healthcare provider who prescribed it. Provide the following instructions on administration to the patients or caregivers: Take the prescribed dose of PRADAXA Oral Pellets twice day, approximately 12 hours apart; PRADAXA Oral Pellets may be sprinkled on baby rice cereal prepared with water, mashed carrots, apple sauce, or mashed banana, or may be taken with approximately 1-2 ounces of apple juice; PRADAXA Oral Pellets should not be mixed with milk or with foods that contain milk; Once the Oral Pellets are mixed with the soft food or apple juice, the patient should take the dose within 30 minutes; If dose of PRADAXA Oral Pellets is not taken at the scheduled time, the dose should be skipped if it cannot be taken at least hours before the next scheduled dose. The dose of PRADAXA Oral Pellets should not be doubled to make up for missed dose. [see Boxed Warning, and Dosage and Administration (2.2, 2.4)]. Tell patients or their caregivers to take or administer PRADAXA Oral Pellets exactly as prescribed.. Tell patients or their caregivers to remove desiccant from the aluminum bag and throw away.. Remind patients or their caregivers not to discontinue PRADAXA Oral Pellets without talking to the healthcare provider who prescribed it.. Provide the following instructions on administration to the patients or caregivers: Take the prescribed dose of PRADAXA Oral Pellets twice day, approximately 12 hours apart; PRADAXA Oral Pellets may be sprinkled on baby rice cereal prepared with water, mashed carrots, apple sauce, or mashed banana, or may be taken with approximately 1-2 ounces of apple juice; PRADAXA Oral Pellets should not be mixed with milk or with foods that contain milk; Once the Oral Pellets are mixed with the soft food or apple juice, the patient should take the dose within 30 minutes; If dose of PRADAXA Oral Pellets is not taken at the scheduled time, the dose should be skipped if it cannot be taken at least hours before the next scheduled dose. The dose of PRADAXA Oral Pellets should not be doubled to make up for missed dose. Take the prescribed dose of PRADAXA Oral Pellets twice day, approximately 12 hours apart;. PRADAXA Oral Pellets may be sprinkled on baby rice cereal prepared with water, mashed carrots, apple sauce, or mashed banana, or may be taken with approximately 1-2 ounces of apple juice;. PRADAXA Oral Pellets should not be mixed with milk or with foods that contain milk;. Once the Oral Pellets are mixed with the soft food or apple juice, the patient should take the dose within 30 minutes;. If dose of PRADAXA Oral Pellets is not taken at the scheduled time, the dose should be skipped if it cannot be taken at least hours before the next scheduled dose. The dose of PRADAXA Oral Pellets should not be doubled to make up for missed dose.. BleedingInform patients or their caregivers that they may bleed more easily, may bleed longer, and should call their healthcare provider for any signs or symptoms of bleeding [see Warnings and Precautions (5.2)].Instruct patients or their caregivers to seek emergency care right away if they have any of the following, which may be sign or symptom of serious bleeding: Unusual bruising (bruises that appear without known cause or that get bigger) Pink or brown urine Red or black, tarry stools Coughing up blood Vomiting blood, or vomit that looks like coffee groundsInstruct patients or their caregivers to call their healthcare provider or to get prompt medical attention if they experience any signs or symptoms of bleeding: Pain, swelling or discomfort in joint Headaches, dizziness, or weakness Reoccurring nose bleeds Unusual bleeding from gums Bleeding from cut that takes long time to stop Menstrual bleeding or vaginal bleeding that is heavier than normalIf patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients or their caregivers to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient or their caregivers to contact his or her physician immediately [see Boxed Warning].. Unusual bruising (bruises that appear without known cause or that get bigger). Pink or brown urine. Red or black, tarry stools. Coughing up blood. Vomiting blood, or vomit that looks like coffee grounds. Pain, swelling or discomfort in joint. Headaches, dizziness, or weakness. Reoccurring nose bleeds. Unusual bleeding from gums. Bleeding from cut that takes long time to stop. Menstrual bleeding or vaginal bleeding that is heavier than normal. Gastrointestinal Adverse Reactions Instruct patients or their caregivers to call their healthcare provider if they experience any signs or symptoms of dyspepsia or gastritis: Dyspepsia (upset stomach), burning, or nausea Abdominal pain or discomfort Epigastric discomfort, GERD (gastric indigestion)[see Adverse Reactions (6.1)] Dyspepsia (upset stomach), burning, or nausea. Abdominal pain or discomfort. Epigastric discomfort, GERD (gastric indigestion). Invasive or Surgical Procedures Instruct patients or their caregivers to inform their healthcare provider that they are taking PRADAXA before any invasive procedure (including dental procedures) is scheduled [see Dosage and Administration (2.7)].. Concomitant MedicationsAsk patients or their caregivers to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so the patients healthcare provider knows about other treatments that may affect bleeding risk (e.g., aspirin or NSAIDs) or dabigatran exposure (e.g., dronedarone or systemic ketoconazole) [see Warnings and Precautions (5.2, 5.5)].. Prosthetic Heart Valves Instruct patients or their caregivers to inform their healthcare provider if they will have or have had surgery to place prosthetic heart valve [see Warnings and Precautions (5.4)].. Allergic ReactionsAdvise caregivers that some adults taking PRADAXA have developed symptoms of an allergic reaction. Advise caregivers to inform their childs healthcare provider if their child develops symptoms of an allergic reaction, such as hives, rash, or itching. Advise caregivers to seek emergency medical attention for their child if they develop chest pain or tightness, swelling of the face or tongue, trouble breathing or wheezing, or feeling dizzy or faint.. Pregnancy Advise patients to inform their healthcare provider immediately if they become pregnant or intend to become pregnant during treatment with PRADAXA [see Use in Specific Populations (8.1)].. Lactation Advise patients not to breastfeed if they are taking PRADAXA [see Use in Specific Populations (8.2)].

INSTRUCTIONS FOR USE SECTION.

Instructions for UsePRADAXA (pra dax a)(dabigatran etexilate)Oral Pellets. Read the Medication Guide and this Instructions for Use that come with PRADAXA Oral Pellets for the most important information you need to know before giving PRADAXA Oral Pellets to your child for the first time, and each time you get refill. The information may have changed. This Instructions for Use does not take the place of talking to your healthcare provider about your childs medical condition or treatment.Your healthcare provider should tell you the amount (dose) of PRADAXA Oral Pellets to give your child. Your childs dose of PRADAXA Oral Pellets will change as they grow.Important InformationPRADAXA Oral Pellets can be used in children as soon as they are able to swallow soft foodDo not open the packets of PRADAXA Oral Pellets until you are ready to use themGive PRADAXA Oral Pellets either with soft foods or apple juiceDo not give PRADAXA Oral Pellets using syringes or through feeding tubesDo not mix PRADAXA Oral Pellets with milk or soft foods containing milk productsGive your child the prepared dose of PRADAXA Oral Pellets before meals to help ensure that your child takes the full doseGive PRADAXA Oral Pellets to your child right away or within 30 minutes after mixingDo not give PRADAXA Oral Pellets if they have been in contact with the food or apple juice for more than 30 minutesIf your child does not take all of the mixed PRADAXA Oral Pellets, do not give another dose at that time. Give the next scheduled dose about 12 hours later.If 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 hours before the next scheduled dose. The dose of PRADAXA Oral Pellets should not be doubled to make up for missed dose.Instructions are provided below for preparing and giving dose of PRADAXA Oral Pellets with soft foods and preparing and giving dose of PRADAXA Oral Pellets with apple juice.How to prepare and give dose of PRADAXA Oral Pellets with soft foods:The food should be at room temperature before mixing with the pellets. Use only one of the following soft foods:Baby rice cereal, prepared with waterMashed carrotsApple sauce (for administration with apple juice see below)Mashed bananaDo not mix with milk, milk products, or soft foods containing milk products.Step - Prepare cup or bowlPlace teaspoons of the soft food into small cup or bowl.Step - Collect PRADAXA Oral Pellets packet(s)Open the silver aluminum bag by cutting at the top with scissors. The aluminum bag contains 60 silver-colored packets of PRADAXA Oral Pellets and desiccant.Remove desiccant from aluminum bag and throw away.Do not open or eat the desiccant.Remove the prescribed number of PRADAXA Oral Pellets packets from the aluminum bag.Leave the unused packets of PRADAXA Oral Pellets in the aluminum bag.Step - Open the PRADAXA Oral Pellets packet(s)Tap the packet of Oral Pellets on flat surface to ensure that the contents settle to the bottom.Keep the packet of Oral Pellets in an upright position and open the packet by cutting at the top with scissors.Step - Add the PRADAXA Oral Pellets to soft foodEmpty the entire packet into the small cup or bowl containing the soft food.Repeat Steps and if more than one packet is needed.Throw away the empty packets in your household trash.Step - Stir the soft food to mix with the PRADAXA Oral PelletsStir the pellets into the soft food with spoon to mix well.Step - Give the soft food and oral pellet mixtureGive the soft food and oral pellet mixture to your child right away.Make sure that your child eats all of the soft food and oral pellet mixture.How to prepare and give dose of PRADAXA Oral Pellets with apple juice:Step - Pour about to ounces of apple juice into clean drinking cup. Step - Collect PRADAXA Oral Pellets packet(s) Open the silver aluminum bag by cutting at the top with scissors. The aluminum bag includes 60 silver-colored packets of pellets and desiccant.Remove desiccant from aluminum bag and throw away.Do not open or eat the desiccant. Remove the prescribed number of PRADAXA Oral Pellets packets from the aluminum bag.Leave the unused packets of PRADAXA Oral Pellets in the aluminum bag.Step - Open PRADAXA Oral Pellets packet(s)Tap the packet on flat surface to make sure that the contents settle to the bottom.Keep the packet in an upright position and open the packet by cutting at the top with scissors.Step - Mix the PRADAXA Oral Pellets with apple juiceSpoon the PRADAXA Oral Pellets from the packet into your childs mouth. Offer your child as much apple juice as needed to swallow the PRADAXA Oral Pellets. Make sure all of the PRADAXA Oral Pellets are swallowed. OR Mix the PRADAXA Oral Pellets in small amount of apple juice that your child is likely to drink completely. Make sure all of the PRADAXA Oral Pellets are swallowed. If any of the PRADAXA Oral Pellets stick to the cup, add little more apple juice and give it to your child. Repeat until no PRADAXA Oral Pellets remain in the cup.Storing PRADAXA Oral PelletsStore at room temperature from 68F to 77F (20C to 25C).Keep PRADAXA Oral Pellets packets in the aluminum bag until you are ready to use them. Do not open PRADAXA Oral Pellets packets until you are ready to use them.Use the PRADAXA Oral Pellets within months of opening the aluminum bag.Keep PRADAXA Oral Pellets and all medicines out of the reach of children.For more information about PRADAXA Oral Pellets, call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257.Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USACopyright (C) 2021 Boehringer Ingelheim Pharmaceuticals, Inc.ALL RIGHTS RESERVEDCOL8834AF252021This Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: June 2021. PRADAXA Oral Pellets can be used in children as soon as they are able to swallow soft food. Do not open the packets of PRADAXA Oral Pellets until you are ready to use them. Give PRADAXA Oral Pellets either with soft foods or apple juice. Do not give PRADAXA Oral Pellets using syringes or through feeding tubes. Do not mix PRADAXA Oral Pellets with milk or soft foods containing milk products. Give your child the prepared dose of PRADAXA Oral Pellets before meals to help ensure that your child takes the full dose. Give PRADAXA Oral Pellets to your child right away or within 30 minutes after mixing. Do not give PRADAXA Oral Pellets if they have been in contact with the food or apple juice for more than 30 minutes. If your child does not take all of the mixed PRADAXA Oral Pellets, do not give another dose at that time. Give the next scheduled dose about 12 hours later.. If 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 hours before the next scheduled dose. The dose of PRADAXA Oral Pellets should not be doubled to make up for missed dose.. Baby rice cereal, prepared with water. Mashed carrots. Apple sauce (for administration with apple juice see below). Mashed banana. Place teaspoons of the soft food into small cup or bowl.. Open the silver aluminum bag by cutting at the top with scissors. The aluminum bag contains 60 silver-colored packets of PRADAXA Oral Pellets and desiccant.. Remove desiccant from aluminum bag and throw away.. Do not open or eat the desiccant.. Remove the prescribed number of PRADAXA Oral Pellets packets from the aluminum bag.. Leave the unused packets of PRADAXA Oral Pellets in the aluminum bag.. Tap the packet of Oral Pellets on flat surface to ensure that the contents settle to the bottom.. Keep the packet of Oral Pellets in an upright position and open the packet by cutting at the top with scissors.. Empty the entire packet into the small cup or bowl containing the soft food.. Repeat Steps and if more than one packet is needed.. Throw away the empty packets in your household trash.. Stir the pellets into the soft food with spoon to mix well.. Give the soft food and oral pellet mixture to your child right away.. Make sure that your child eats all of the soft food and oral pellet mixture.. Open the silver aluminum bag by cutting at the top with scissors. The aluminum bag includes 60 silver-colored packets of pellets and desiccant.. Remove desiccant from aluminum bag and throw away.. Do not open or eat the desiccant.. Remove the prescribed number of PRADAXA Oral Pellets packets from the aluminum bag.. Leave the unused packets of PRADAXA Oral Pellets in the aluminum bag.. Tap the packet on flat surface to make sure that the contents settle to the bottom.. Keep the packet in an upright position and open the packet by cutting at the top with scissors.. Spoon the PRADAXA Oral Pellets from the packet into your childs mouth. Offer your child as much apple juice as needed to swallow the PRADAXA Oral Pellets. Make sure all of the PRADAXA Oral Pellets are swallowed. OR Mix the PRADAXA Oral Pellets in small amount of apple juice that your child is likely to drink completely. Make sure all of the PRADAXA Oral Pellets are swallowed. If any of the PRADAXA Oral Pellets stick to the cup, add little more apple juice and give it to your child. Repeat until no PRADAXA Oral Pellets remain in the cup.. Store at room temperature from 68F to 77F (20C to 25C).. Keep PRADAXA Oral Pellets packets in the aluminum bag until you are ready to use them. Do not open PRADAXA Oral Pellets packets until you are ready to use them.. Use the PRADAXA Oral Pellets within months of opening the aluminum bag.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

PHARMACOKINETICS SECTION.

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 10 mg to 400 mg. Given twice daily, dabigatrans accumulation factor in pediatric patients receiving pellets is 1.5-1.7.. AbsorptionThe absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3% to 7%. Dabigatran etexilate is substrate of the efflux transporter P-gp. After oral administration of dabigatran etexilate in healthy volunteers, Cmax occurs at hour post-administration in the fasted state. Coadministration of PRADAXA with high-fat meal delays the time to Cmax by approximately hours but has no effect on the bioavailability of dabigatran; PRADAXA may be administered with or without food.PRADAXA 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. Dabigatran etexilate oral pellets show 37% higher relative bioavailability in healthy adults compared to dabigatran etexilate capsules. In addition, the relative bioavailability between the two dosage forms is age dependent. The relative bioavailability observed in adult patients cannot be translated to pediatric patients.. DistributionDabigatran 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 50 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 elimination half-life of dabigatran in pediatric patients receiving pellets is approximately to 11 hours.. MetabolismAfter 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 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.. Specific Populations. Pediatric PatientsThe 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 doses of PRADAXA pellets (less than 12 years of age), the observed geometric mean steady-state trough concentration was 54.7 ng/mL (25.9 to 88.3 ng/mL, 10th to 90th percentile) compared to the geometric mean steady-state trough concentration of 59.7 ng/mL (26.3 to 146 ng/mL, 10th to 90th percentile) observed in adult patients with DVT/PE taking PRADAXA capsules.. Renal Impairment An open, parallel-group, single-center study compared dabigatran pharmacokinetics in healthy adult subjects and adult patients with mild to moderate renal impairment receiving single dose of PRADAXA capsules 150 mg. Exposure to dabigatran increases with severity of renal function impairment (Table 5). Similar findings were observed in the RE-LY, RE-COVER and RE-NOVATE II trials.Table Impact of Renal Impairment on Dabigatran PharmacokineticsRenal FunctionCrCl (mL/min)Increase in AUCIncrease in Cmax t1/2 (h)+Patients with severe renal impairment were not studied in RE-LY, RE-COVER and RE-NOVATE II.Normal>= 801x1x13Mild50-801.5x1.1x15Moderate30-503.2x1.7x18Severe+ 15-306.3x2.1x27. Hepatic Impairment Administration of PRADAXA Capsules in adult patients with moderate hepatic impairment (Child-Pugh B) showed large inter-subject variability, but no evidence of consistent change in exposure or pharmacodynamics.. Drug Interactions No clinical drug interaction studies have been conducted in pediatric subjects. summary of the effect of coadministered drugs on dabigatran exposure in adult subjects is shown in Figures and 2.Figure Effect of P-gp Inhibitor or Inducer (rifampicin) Drugs on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose (Time Difference)Figure Effect of Non-P-gp Inhibitor or Inducer, Other Drugs, on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose (Time Difference). Figure 1. Figure 2. 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.