ed.

globin 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). pradaxa's 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 a 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 k are not expected to affect the anticoagulant activity of dabigatran. consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. in adults, a specific reversal agent (idarucizumab) for pradaxa is available when reversal of the anticoagulant effect of dabigatran is needed. in pediatric patients, the efficacy and safety of idarucizumab have not been established. 5.3 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 a sufficiently low anticoagulant effect in each patient is not known. should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), and bowel and/or bladder dysfunction. instruct patients to immediately report if they experience any of the above signs or symptoms. if signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae. 5.4 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 a day. re-align was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) in the pradaxa treatment arm as compared to the warfarin treatment arm. these bleeding and thromboembolic events were seen both in patients who were initiated on pradaxa capsules postoperatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment. therefore, the use of pradaxa is contraindicated in all patients with mechanical prosthetic valves [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 a 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 i antibodies]), treatment with doacs has been associated with increased rates of recurrent thrombotic events compared with vitamin k antagonist therapy.

cedures when possible, then restart promptly ( 2.7 ) 2.1 important dosage information dabigatran etexilate is available in different dosage forms and not all dosage forms are approved for the same indications and age groups. in addition, there are differences between the dosage forms with respect to dosing due to differences in bioavailability. do not substitute different dosage forms (for example, capsules) for oral pellets on a milligram-to-milligram basis and do not combine more than one dosage form to achieve the total dose [see clinical pharmacology (12.3) ] . 2.2 recommended pradaxa oral pellets dose for pediatric patients pradaxa oral pellets can be used in pediatric patients aged 3 months to less than 12 years as soon as they are able to swallow soft food. for the treatment of vte in pediatric patients, treatment should be initiated following treatment with a parenteral anticoagulant for at least 5 days. for reduction in risk of recurrence of vte, treatment should be initiated following previous treatment. the recommended dose of pradaxa oral pellets is based on the patient's age and actual weight as shown in the tables below. pradaxa oral pellets is administered twice daily. adjust the dose according to age and actual weight as treatment progresses. table 1 age- and weight-based dosing for pradaxa oral pellets for pediatric patients less than 2 years old actual weight (kg) age (in months) dose (mg) twice daily number of packets needed 3 kg to less than 4 kg 3 to less than 6 months 30 mg one 30 mg packet twice daily 4 kg to less than 5 kg 3 to less than 10 months 40 mg one 40 mg packet twice daily 5 kg to less than 7 kg 3 to less than 5 months 40 mg one 40 mg packet twice daily 5 to less than 24 months 50 mg one 50 mg packet twice daily 7 kg to less than 9 kg 3 to less than 4 months 50 mg one 50 mg packet twice daily 4 to less than 9 months 60 mg two 30 mg packets twice daily 9 to less than 24 months 70 mg one 30 mg packet plus one 40 mg packet twice daily 9 kg to less than 11 kg 5 to less than 6 months 60 mg two 30 mg packets twice daily 6 to less than 11 months 80 mg two 40 mg packets twice daily 11 to less than 24 months 90 mg one 40 mg packet plus one 50 mg packet twice daily 11 kg to less than 13 kg 8 to less than 18 months 100 mg two 50 mg packets twice daily 18 to less than 24 months 110 mg one 110 mg packet twice daily 13 kg to less than 16 kg 10 to less than 11 months 100 mg two 50 mg packets twice daily 11 to less than 24 months 140 mg one 30 mg packet plus one 110 mg packet twice daily 16 kg to less than 21 kg 12 to less than 24 months 140 mg one 30 mg packet plus one 110 mg packet twice daily 21 kg to less than 26 kg 18 to less than 24 months 180 mg one 30 mg packet plus one 150 mg packet twice daily table 2 weight-based dosing for pradaxa oral pellets for pediatric patients between 2 years to less than 12 years old actual weight (kg) dose (mg) twice daily number of packets needed 7 kg to less than 9 kg 70 mg one 30 mg packet plus one 40 mg packet twice daily 9 kg to less than 11 kg 90 mg one 40 mg packet plus one 50 mg packet twice daily 11 kg to less than 13 kg 110 mg one 110 mg packet twice daily 13 kg to less than 16 kg 140 mg one 30 mg packet plus one 110 mg packet twice daily 16 kg to less than 21 kg 170 mg one 20 mg packet plus one 150 mg packet twice daily 21 kg to less than 41 kg 220 mg two 110 mg packets twice daily 41 kg or greater 260 mg one 110 mg packet plus one 150 mg packet twice daily evaluation of the extent of anticoagulation in pediatric patients on pradaxa oral pellets may be accomplished using dtt or ect, and not inr [see warnings and precautions (5.2) and clinical pharmacology (12.2) ] . 2.3 dosage adjustments pediatric patients with renal impairment assess renal function prior to initiation of treatment with pradaxa oral pellets. periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly. discontinue pradaxa oral pellets in patients who develop acute renal failure while on pradaxa oral pellets and consider alternative anticoagulant therapy. prior to the initiation of treatment with pradaxa oral pellets, estimate the glomerular filtration rate (egfr) using the schwartz formula, egfr (schwartz) = (0.413 × height in cm) / serum creatinine in mg/dl. due to lack of data in pediatric patients with an egfr < 50 ml/min/1.73m 2 and the risk of increased exposure, avoid use of pradaxa oral pellets in these patients. treat patients with an egfr > 50 ml/min/1.73m 2 with the dose according to tables 1 and 2 [see dosage and administration (2.2) ] . 2.4 administration pradaxa oral pellets are administered twice daily, one dose in the morning and one dose in the evening, at approximately the same time every day. the dosing interval should be as close to 12 hours as possible. if a dose of pradaxa oral pellets is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. the dose of pradaxa oral pellets should not be doubled to make up for a missed dose. if a partial dose has been taken, a second dose should not be administered at that time. the next dose should be taken as scheduled approximately 12 hours later. the prepared medication should be given before meals to ensure that the patient takes the full dose. pradaxa oral pellets should be administered immediately after mixing or within 30 minutes after mixing. if the pradaxa dose is not administered within 30 minutes of mixing, the dose should be discarded, and a new dose prepared. pradaxa oral pellets should be administered with only specific soft foods or apple juice. administration with soft foods pradaxa oral pellets may be mixed with two teaspoons of the following soft foods at room temperature: mashed carrots apple sauce mashed banana administration with apple juice pradaxa oral pellets may be spooned directly into the patient's mouth and swallowed with apple juice or added to approximately 1-2 ounces of apple juice for drinking. pradaxa oral pellets should not be administered: via syringes or feeding tubes with milk, milk products, or soft foods containing milk products instruct patients/caregivers to discard the desiccant once the package is opened. see instructions for use . 2.5 converting from or to warfarin when converting patients from warfarin therapy to pradaxa oral pellets, discontinue warfarin and start pradaxa oral pellets when the inr is below 2.0. when converting from pradaxa oral pellets to warfarin, adjust the starting time of warfarin as follows: for egfr ≥50 ml/min/1.73m 2 , start warfarin 3 days before discontinuing pradaxa oral pellets. patients with an egfr <50 ml/min/1.73m 2 have not been studied. avoid use of pradaxa oral pellets in these patients. because pradaxa oral pellets can increase inr, the inr will better reflect warfarin's effect only after pradaxa oral pellets have been stopped for at least 2 days [see clinical pharmacology (12.2) ]. 2.6 converting from or to parenteral anticoagulants for pediatric patients currently receiving a parenteral anticoagulant, start pradaxa oral pellets 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin). for pediatric patients currently taking pradaxa oral pellets, wait 12 hours after the last dose before switching to a parenteral anticoagulant [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/1.73m 2 ) or 2 days before an elective surgery (egfr 50-80 ml/min/1.73m 2 ). pediatric patients with an egfr < 50 ml/min/1.73m 2 have not been studied, avoid use of pradaxa oral pellets in these patients. consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required [see use in specific populations (8.6) and clinical pharmacology (12.3) ] . if surgery cannot be delayed, there is an increased risk of bleeding [see warnings and precautions (5.2) ] . this risk of bleeding should be weighed against the urgency of intervention [see warnings and precautions (5.1 , 5.3) ] . in adults, a specific reversal agent (idarucizumab) is available in case of emergency surgery or urgent procedures when reversal of the anticoagulant effect of dabigatran is needed. efficacy and safety of idarucizumab have not been established in pediatric patients [see warnings and precautions (5.2) ] . refer to the idarucizumab prescribing information for additional information. restart pradaxa oral pellets as soon as medically appropriate.

nce because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. pediatric trials treatment of vte in pediatric patients the safety of pradaxa in the treatment of vte in pediatric patients was studied in one phase iii trial (diversity). the diversity study was a randomized, open-label, active-controlled, parallel-group trial comparing pradaxa with standard of care – soc (vitamin k antagonists, low molecular weight heparin, or fondaparinux). there were 266 pediatric patients who received study treatment, 176 patients treated with pradaxa and 90 patients treated with soc. patients on pradaxa received age- and weight-adjusted doses of an age-appropriate formulation of pradaxa (capsules, pellets, or oral solution) twice daily. patients had a median age of 14 years (range: 0-17 years), 92% were white, and half the patients were male (50%). following at least 5 days of parenteral anticoagulant therapy, the median duration of treatment with pradaxa was 85 days (range: 1-105). patients with estimated glomerular filtration rate (egfr) < 50 ml/min/1.73m 2 were excluded from the trial. bleeding data on adjudicated major bleeding, clinically relevant non-major (crnm) bleeding, and minor bleeding events for the pradaxa group and the soc group in the diversity study are reported in table 3. there was no statistically significant difference in the time to first major bleeding event. table 3 summary of all adjudicated bleeding events during on-treatment period in diversity pradaxa n (%) standard of care (soc) n (%) patients n=176 n=90 1 major bleeding event if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dl (1.24 mmol/l) or more, or leading to transfusion of 2 or more units of whole blood or red cells. major bleeding event 1 4 (2.3) 2 (2.2) fatal bleeding 0 1 (1.1) clinically relevant non-major bleeding 2 (1.1) 1 (1.1) minor bleeding 33 (19) 21 (23) major and clinically relevant non-major bleeding 6 (3.4) 3 (3.3) any bleeding 38 (22) 22 (24) site-specific bleeding rates were comparable between the two arms, with the exception of the rate of any gastrointestinal bleeds (5.7% in pradaxa arm vs 1.8% in soc arm). gastrointestinal adverse reactions the incidence of gastrointestinal adverse reactions for patients on pradaxa and soc was 32% and 12%, respectively, with the following occurring in ≥5% of patients taking pradaxa: dyspepsia (including term gastro-esophageal reflux disease, gastric ph decreased and esophagitis) in 9% (vs 2%), upper abdominal pain in 5% (vs 1%), vomiting in 8% (vs 2%), nausea 5% (vs 4%), and diarrhea 5% (vs 1%). reduction in risk of recurrence of vte in pediatric patients the safety of pradaxa in the reduction in the risk of recurrence of vte in pediatric patients was studied in one open-label single-arm trial (study 2). study 2 enrolled patients who required further anticoagulation due to the presence of a clinical risk factor after completing the initial treatment for confirmed vte (for at least 3 months) or after completing the diversity study and received pradaxa until the clinical risk factor resolved, or up to a maximum of 12 months. there were 213 pediatric patients treated with pradaxa, in a similar fashion as in the diversity trial. patients had a median age of 14 years (range: 0-18 years), 91% were white, and 55% of patients were male. patients previously enrolled on diversity accounted for 43% of patients enrolled on study 2 (29% from pradaxa arm and 14% from soc arm). the median duration of treatment with pradaxa in study 2 was 42 weeks (range: 0-56 weeks), with 45% of patients completing the 12-month planned duration, 17% stopping due to resolution of vte risk factors, 12% stopping due to failure to attain target dabigatran concentration and 6% had an adverse event leading to discontinuation. during the on-treatment period of study 2, 3 patients (1.4%) had a major bleeding event, 3 patients (1.4%) had a clinically relevant non-major bleeding event, and 44 patients (20%) had a minor bleeding event. the most common drug-related adverse reactions were dyspepsia (5%), epistaxis (3.3%), nausea (3.3%) and menorrhagia (2.8%). the adverse reaction profile in pediatric patients was generally consistent with that of adult patients. hypersensitivity reactions in adult pradaxa trials in adult dvt/pe pivotal studies, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in 0.1% of patients receiving pradaxa capsules. 6.2 postmarketing experience the following adverse reactions have been identified during post approval use of pradaxa. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. the following adverse reactions have been identified during post approval use of pradaxa: angioedema, thrombocytopenia, esophageal ulcer, alopecia, neutropenia, agranulocytosis.

malformations. however, the incidence of delayed or irregular ossification of fetal skull bones and vertebrae was increased in the rat (see data ) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. fetal/neonatal adverse reaction use of anticoagulants, including pradaxa, may increase the risk of bleeding in the fetus and neonate. monitor neonates for bleeding [see warnings and precautions (5.2) ]. labor or delivery all patients receiving anticoagulants, including pregnant women, are at risk for bleeding. pradaxa use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. consider discontinuation or use of shorter acting anticoagulant as delivery approaches [see warnings and precautions (5.2 , 5.3) ] . data animal data dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at mrhd of 300 mg/day based on area under the curve [auc] comparisons) prior to mating and up to implantation (gestation day 6). treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. dabigatran administered to pregnant rats and rabbits during organogenesis up to maternally toxic doses of 200 mg/kg (8 and 13 times the human exposure, respectively, at a mrhd of 300 mg/day based on auc comparisons) did not induce major malformations, but increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat. death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation day 7) to weaning (lactation day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at mrhd of 300 mg/day based on auc comparisons). 8.2 lactation risk summary there are 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/1.73m 2 . 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) ].

etal skull bones and vertebrae was increased in the rat (see data ) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. fetal/neonatal adverse reaction use of anticoagulants, including pradaxa, may increase the risk of bleeding in the fetus and neonate. monitor neonates for bleeding [see warnings and precautions (5.2) ]. labor or delivery all patients receiving anticoagulants, including pregnant women, are at risk for bleeding. pradaxa use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. consider discontinuation or use of shorter acting anticoagulant as delivery approaches [see warnings and precautions (5.2 , 5.3) ] . data animal data dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at mrhd of 300 mg/day based on area under the curve [auc] comparisons) prior to mating and up to implantation (gestation day 6). treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. dabigatran administered to pregnant rats and rabbits during organogenesis up to maternally toxic doses of 200 mg/kg (8 and 13 times the human exposure, respectively, at a mrhd of 300 mg/day based on auc comparisons) did not induce major malformations, but increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat. death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation day 7) to weaning (lactation day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at mrhd of 300 mg/day based on auc comparisons).

creases in a 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, dabigatran's accumulation factor in pediatric patients receiving pellets is 1.5-1.7. absorption the absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3% to 7%. dabigatran etexilate is a substrate of the efflux transporter p-gp. after oral administration of dabigatran etexilate in healthy volunteers, c max occurs at 1 hour post-administration in the fasted state. coadministration of pradaxa with a high-fat meal delays the time to c max by approximately 2 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. distribution dabigatran is approximately 35% bound to human plasma proteins. the red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. the volume of distribution of dabigatran is 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 9 to 11 hours. metabolism after oral administration, dabigatran etexilate is converted to dabigatran. the cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. dabigatran is not a substrate, inhibitor, or inducer of cyp450 enzymes. dabigatran is subject to conjugation, forming pharmacologically active acyl glucuronides. four positional isomers, 1-o, 2-o, 3-o, and 4-o-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma. specific populations pediatric patients the pharmacokinetics of dabigatran was characterized in two clinical studies (diversity and study 2) following multiple doses in pediatric patients from birth to less than 18 years old. in pediatric patients taking age- and weight-adjusted 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, 10 th to 90 th percentile) compared to the geometric mean steady-state trough concentration of 59.7 ng/ml (26.3 to 146 ng/ml, 10 th to 90 th percentile) observed in adult patients with dvt/pe 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 a single dose of pradaxa capsules 150 mg. exposure to dabigatran increases with severity of renal function impairment (table 4). similar findings were observed in the re-ly, re-cover and re-novate ii trials. table 4 impact of renal impairment on dabigatran pharmacokinetics renal function crcl (ml/min) increase in auc increase in c max t 1/2 (h) + patients with severe renal impairment were not studied in re-ly, re-cover and re-novate ii. normal ≥ 80 1× 1× 13 mild 50-80 1.5× 1.1× 15 moderate 30-50 3.2× 1.7× 18 severe + 15-30 6.3× 2.1× 27 hepatic impairment administration of pradaxa capsules in adult patients with moderate hepatic impairment (child-pugh b) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics. drug interactions no clinical drug interaction studies have been conducted in pediatric subjects. a summary of the effect of coadministered drugs on dabigatran exposure in adult subjects is shown in figures 1 and 2. figure 1 effect of p-gp inhibitor or inducer (rifampicin) drugs on peak and total exposure to dabigatran (c max and auc). shown are the geometric mean ratios (ratio) and 90% confidence interval (90% ci). the perpetrator and dabigatran etexilate dose and dosing frequency are given as well as the time of perpetrator dosing in relation to dabigatran etexilate dose (time difference) figure 2 effect of non-p-gp inhibitor or inducer, other drugs, on peak and total exposure to dabigatran (c max and auc). shown are the geometric mean ratios (ratio) and 90% confidence interval (90% ci). the perpetrator and dabigatran etexilate 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.

of pradaxa with a high-fat meal delays the time to c max by approximately 2 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. distribution dabigatran is approximately 35% bound to human plasma proteins. the red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. the volume of distribution of dabigatran is 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 9 to 11 hours. metabolism after oral administration, dabigatran etexilate is converted to dabigatran. the cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. dabigatran is not a substrate, inhibitor, or inducer of cyp450 enzymes. dabigatran is subject to conjugation, forming pharmacologically active acyl glucuronides. four positional isomers, 1-o, 2-o, 3-o, and 4-o-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma. specific populations pediatric patients the pharmacokinetics of dabigatran was characterized in two clinical studies (diversity and study 2) following multiple doses in pediatric patients from birth to less than 18 years old. in pediatric patients taking age- and weight-adjusted 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, 10 th to 90 th percentile) compared to the geometric mean steady-state trough concentration of 59.7 ng/ml (26.3 to 146 ng/ml, 10 th to 90 th percentile) observed in adult patients with dvt/pe 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 a single dose of pradaxa capsules 150 mg. exposure to dabigatran increases with severity of renal function impairment (table 4). similar findings were observed in the re-ly, re-cover and re-novate ii trials. table 4 impact of renal impairment on dabigatran pharmacokinetics renal function crcl (ml/min) increase in auc increase in c max t 1/2 (h) + patients with severe renal impairment were not studied in re-ly, re-cover and re-novate ii. normal ≥ 80 1× 1× 13 mild 50-80 1.5× 1.1× 15 moderate 30-50 3.2× 1.7× 18 severe + 15-30 6.3× 2.1× 27 hepatic impairment administration of pradaxa capsules in adult patients with moderate hepatic impairment (child-pugh b) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics. drug interactions no clinical drug interaction studies have been conducted in pediatric subjects. a summary of the effect of coadministered drugs on dabigatran exposure in adult subjects is shown in figures 1 and 2. figure 1 effect of p-gp inhibitor or inducer (rifampicin) drugs on peak and total exposure to dabigatran (c max and auc). shown are the geometric mean ratios (ratio) and 90% confidence interval (90% ci). the perpetrator and dabigatran etexilate dose and dosing frequency are given as well as the time of perpetrator dosing in relation to dabigatran etexilate dose (time difference) figure 2 effect of non-p-gp inhibitor or inducer, other drugs, on peak and total exposure to dabigatran (c max and auc). shown are the geometric mean ratios (ratio) and 90% confidence interval (90% ci). the perpetrator and dabigatran etexilate 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.

decreased in females receiving 70 mg/kg, or 3 times the human exposure at mrhd based on auc comparisons.

iving 70 mg/kg, or 3 times the human exposure at mrhd based on auc comparisons.

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 a 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 2 to <12 years, and 35 patients were younger than 2 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 was similar in both treatment groups (pradaxa: 15%; soc: 16%). the efficacy of pradaxa was established based on a 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 5 ). table 5 efficacy results [itt population] diversity study pradaxa standard of care 1 mantel-haenszel weighted difference with age group as stratification factor number of patients randomized (%) 177 (100.0) 90 (100.0) complete thrombus resolution 81 (45.8) 38 (42.2) freedom from recurrent vte 170 (96.0) 83 (92.2) freedom from mortality related to vte 177 (100.0) 89 (98.9) composite endpoint met 81 (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 superiority 0.2739 subgroup 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 3 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 2 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 2 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 a clinical risk factor after completing the initial treatment for confirmed vte (for at least 3 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 a 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 6 and 12 months. of the 214 patients in the study, 162 patients were 12 to <18 years old, 43 patients were 2 to <12 years old, and 9 patients were aged 6 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 3 months, 0.984 (95% ci: 0.950, 0.995) at 6 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 3 months, 0.785 (95% ci: 0.718, 0.838) at 6 months, and 0.723 (95% ci: 0.645, 0.787) at 12 months. no on-treatment deaths occurred.

pellets within 6 months of opening the aluminum bag containing the packets.

ient should take the dose within 30 minutes; if a dose of pradaxa oral pellets is not taken at the scheduled time, the dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. the dose of pradaxa oral pellets should not be doubled to make up for a missed dose. [see boxed warning , and dosage and administration (2.2 , 2.4) ] bleeding inform 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 a 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 grounds instruct 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 a joint headaches, dizziness, or weakness reoccurring nose bleeds unusual bleeding from gums bleeding from a cut that takes a long time to stop menstrual bleeding or vaginal bleeding that is heavier than normal if 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 ] . 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) ] 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 medications ask 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 patient's 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 a prosthetic heart valve [see warnings and precautions (5.4) ] . allergic reactions advise caregivers that some adults taking pradaxa have developed symptoms of an allergic reaction. advise caregivers to inform their child's 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) ] .