CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Idarucizumab is specific reversal agent for dabigatran.It is humanized monoclonal antibody fragment (Fab) that binds todabigatran and its acylglucuronide metabolites with higher affinitythan the binding affinity of dabigatran to thrombin, neutralizingtheir anticoagulant effect.. 12.2 Pharmacodynamics. In healthy subjects aged 45 to 64 years,the plasma concentrations of unbound dabigatran were reduced to belowthe lower limit of quantification immediately after the administrationof g idarucizumab. Subjects diluted thrombin time (dTT), ECT, aPTT,thrombin time (TT), and activated clotting time (ACT) parameters returnedto baseline levels (see Figure and Figure 5). This reduction ofdabigatran plasma concentration was observed over the entire observationperiod of at least 24 hours. Similar findings were also observed inelderly subjects (aged 65 to 80 years) as well as subjects with mildand moderate renal impairment [see Clinical Pharmacology (12.3)].In limited number of patients, re-distributionof dabigatran from the periphery to plasma led to re-elevation ofdTT, ECT, aPTT, and TT [see Warnings and Precautions (5.2)]. Re-dosing with 2.5 idarucizumab in healthysubjects aged 45-64 years at months after first infusion revealedno differences in safety and no indication of allergic reactions [see Clinical Pharmacology (12.3)].No changesin the pharmacokinetics or pharmacodynamics of dabigatran were notedupon re-initiation 24 hours after the administration of idarucizumab [see Dosage and Administration (2.4)].Thrombin Generation ParametersIdarucizumab alone has shown no procoagulant effect measuredas endogenous thrombin potential (ETP).Cardiac ElectrophysiologyClinical trials with idarucizumab in healthy subjectsmeasured heart rate and electrocardiogram (ECG) parameters (waveformmorphology, wave duration, and PR, QRS, QT, and QTc intervals).There were no clinically relevant abnormal findings related to ECG.Drug InteractionsIn vitro Assessment of Drug InteractionsInvitro data suggest that the inhibition of dabigatran by idarucizumabis not affected by coagulation factor concentrates [3- or 4-factorprothrombin complex concentrates (PCCs), activated PCC, or recombinantFactor VIIa].Assessment of Drug Interactions in Animal StudiesThe potential effect of the binding of idarucizumab to dabigatranin the presence of volume replacement agents (e.g., crystalloids,colloids, and retransfusion of washed red blood cells) was investigatedin swine. The results of this study suggest that neutralization ofdabigatran anticoagulant activity is not influenced by 50% hemodilutionwith routinely used volume replacement strategies.. figure-4. figure-5. 12.3 Pharmacokinetics. There were no obvious differences in the idarucizumab plasma concentration time profiles when idarucizumab was administered alone or after pretreatment with dabigatran. dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine was observed.DistributionIdarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of 5 dose, the geometric mean volume of distribution at steady state (Vss) was 8.9 (geometric coefficient of variation (gCV 24.8%)).EliminationIdarucizumab was rapidly eliminated with total clearance of 47.0 mL/min (gCV 18.4%), an initial half-life of 47 minutes (gCV 11.4%), and terminal half-life of 10.3 (gCV 18.9%). After intravenous administration of g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within collection period of hours and less than 1% in the following 18 hours. The remaining part of the dose is assumed to be eliminated via protein catabolism, mainly in the kidney.MetabolismSeveral pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve biodegradation of the antibody to smaller molecules, i.e., small peptides or amino acids which are then reabsorbed and incorporated in the general protein synthesis.Specific PopulationsAge, Sex, Race and Body WeightAge, sex, race (Caucasian vs Asian) and body weight had no clinically important effect on systemic exposure of idarucizumab based on population pharmacokinetic analyses which included data from 220 volunteers and 486 patients.Patients with Renal ImpairmentIdarucizumab has been studied in 12 subjects with mild renal impairment (creatinine clearance [CrCl] 60 to <90 mL/min, by Cockcroft-Gault equation) and subjects with moderate impairment (CrCl30 to <60 mL/min). Compared to healthy subjects, the total clearance was reduced, leading to an increase in idarucizumabs area under the curve (AUC) by 43.5% and 83.5% in mild and moderate renal impairment, respectively. No dose adjustment is required in renally impaired patients.Based on pharmacokinetic data from 347 patients with varying degrees of renal function (median CrCl 21 to 99 mL/min) it is estimated that mean idarucizumab exposure (AUC0-24h) increased by 38%, 90%, and 146% in patients with mild renal impairment (CrCl 50 to <80 mL/min), moderate renal impairment (CrCl 30 to <50 mL/min) and severe renal impairment (CrCl to <30 mL/min), respectively. Since dabigatran is also excreted primarily via the kidneys, increases in the exposure to dabigatran are also seen with worsening renal function.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Thesafety and effectiveness of PRAXBIND was investigated in three randomizedplacebo-controlled healthy volunteer trials, Trials 1321.1, 1321.2and 1321.5 (NCT01688830, NCT01955720, NCT02028780), and in RE-VERSEAD (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial(NCT02104947), single cohort case series trial with dabigatran-treatedpatients who have life-threatening or uncontrolled bleeding, or whorequire emergency surgery or urgent procedure.Healthy VolunteersTrials 1321.1, 1321.2 and 1321.5 in total of 283 subjects assessedthe safety, dose-response, and effect of idarucizumab on reducingunbound dabigatran and coagulation parameters. Of the 283 subjects,224 received at least one dose of idarucizumab. These trials included19 females and 30 subjects aged 65 years or older (overall mean age36 years).The tablesbelow summarize the idarucizumab effect on coagulation parametersdTT, aPTT, ECT, TT, and ACT over time for 14 subjects treated in Trial1321.2. Fourteen subjects received dabigatran 220 mg orally twicedaily for three days and an additional single 220 mg dose of dabigatranon day four, two hours before receiving idarucizumab. Idarucizumabwas administered as one g intravenous infusion over five minutes.Table shows the results of the idarucizumab treatment group andTable shows the results of the placebo treatment group.Table Change in Coagulation Parameters in 14 Dabigatran-exposedSubjects Treated with g IdarucizumabClotting Assay(Mean and Standard Deviation)Pre-Idarucizumab(N=14)End ofinfusion of Idarucizumab(N=14)24 hoursafterIdarucizumab(N=14)dTT [s]66.6 (12.0)32.1 (1.38)33.0 (1.69)aPTT [s]67.8 (14.5)29.2 (4.74)31.9 (5.71)ECT [s]122 (42.2)34.7 (1.92)38.8 (2.86)TT [s]127 (62.6)12.5 (0.786)19.3 (5.14)ACT [s]236 (47.6)116 (7.71)140 (10.1)Table Change in Coagulation Parameters in 14 Dabigatran-exposedSubjects Treated with PlaceboClotting Assay(Mean and Standard Deviation)Pre-Placebo(N=14)End ofinfusion of Placebo(N=14)24 hoursafterPlacebo(N=14)dTT [s]64.7 (9.82)65.3 (12.1)36.1 (2.48)aPTT [s]65.2 (14.0)66.5 (13.2)37.0 (7.10)ECT [s]117 (29.8)122 (32.9)44.7 (5.39)TT [s]132 (35.4)147 (46.7)39.5 (11.8)ACT [s]219 (44.7)216 (50.5)148 (15.1)The effect of idarucizumabon reducing unbound dabigatran in healthy volunteers is summarizedin section 12.2, Pharmacodynamics.RE-VERSE AD Patient ExperienceIn RE-VERSE AD, g idarucizumab was administered topatients treated with dabigatran who presented with dabigatran-relatedlife-threatening or uncontrolled bleeding (Group A) or who requiredemergency surgery or urgent procedures (Group B). The primary endpointwas the maximum percentage reversal of the pharmacodynamic anticoagulanteffect of dabigatran within hours after the administration of idarucizumab,based on central laboratory determination of dTT or ECT.RE-VERSE AD included data for503 patients: 301 patients with serious bleeding (Group A) and 202requiring an urgent procedure (Group B). Approximately half of thepatients in each group were male. The median age was 78 years andthe median creatinine clearance was 53 mL/min. Approximately 62% ofpatients in Group and 62% of patients in Group had been treatedwith dabigatran 110 mg BID.Reversal was evaluable only for those patientsshowing prolonged coagulation times prior to idarucizumab treatment.Among the evaluable patients, the median maximum reversal of the pharmacodynamicanticoagulant effect of dabigatran as measured by ECT, aPTT or dTTin the first hours after administration of g idarucizumab was100%, with most patients achieving complete reversal as measured byECT (82%), aPTT (93%) or dTT (99%). Reversal of the pharmacodynamicseffects was evident immediately after administration. Results forGroups and were similar. In limited number of patients, between12 and 24 hours after administration of g idarucizumab, elevatedcoagulation parameters (e.g., aPTT or ECT) have been observed. Eightpatients were treated with more than g idarucizumab due to rebleeding,a second emergency procedure and/or bleeding after an emergency surgicalprocedure. ECT measures over the 24-hour observation time are shownin Figure 6.Activated partial thromboplastin time (aPTT) showed similar resultsto ECT (see Figure 7).. figure-6. figure-7.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Thefollowing serious adverse reactions are described in more detail elsewherein the labeling:Thromboembolic Risk [see Warnings and Precautions(5.1)] Hypersensitivity Reactions [see Warnings and Precautions(5.3)] Risks of Serious Adverse Reactions in Patients with HereditaryFructose Intolerance due to Sorbitol Excipient [see Warningsand Precautions (5.4)] Thromboembolic Risk [see Warnings and Precautions(5.1)] Hypersensitivity Reactions [see Warnings and Precautions(5.3)] Risks of Serious Adverse Reactions in Patients with HereditaryFructose Intolerance due to Sorbitol Excipient [see Warningsand Precautions (5.4)] In healthy volunteers, the most frequently reported adversereactions in >=5% of subjects treated with idarucizumab was headache.(6.1)In patients, the most frequently reported adverse reactionsin >=5% of patients treated with idarucizumab were constipation andnausea. (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.. In healthy volunteers, the most frequently reported adversereactions in >=5% of subjects treated with idarucizumab was headache.(6.1). In patients, the most frequently reported adverse reactionsin >=5% of patients treated with idarucizumab were constipation andnausea. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction 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 clinical practice.In three healthy volunteer clinical trials, 224 subjects were treated with idarucizumab. In these trials, during the treatment period, the overall frequency of adverse events was similar between idarucizumab-treated subjects (55/224, 25%) and placebo-treated subjects (26/105, 25%). Among those subjects treated with idarucizumab, adverse reactions reported in >=5% of subjects was headache (12/224, 5%).In the RE-VERSE AD(TM) (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial, total of 503 dabigatran-treated patients were administered idarucizumab either because they required an emergency surgery or urgent procedure, or because they presented with life-threatening or uncontrolled bleeding [see Clinical Studies (14)]. The adverse reactions reported in >=5% of patients were constipation (33/503, 7%) and nausea (23/503, 5%). Of the 503 dabigatran-treated patients in the entire study period, 101 patients died, 19 within the first day after idarucizumab dosing; each of these deaths could be attributed either as complication of the index event or associated with co-morbidities.Thromboembolic EventsIn the RE-VERSE AD trial, 33 of 503 patients reported thrombotic events, 11 patients within days after treatment with idarucizumab and 22 patients days or more after treatment with idarucizumab. Most of these patients were not on antithrombotic therapy at the time of the event, and in each of these cases, the thrombotic event could be attributed to the underlying medical condition of the patient [see Warnings and Precautions (5.1)].HypersensitivityPyrexia, bronchospasm, hyperventilation, rash, and pruritus have been reported in clinical trials with idarucizumab [see Warnings and Precautions (5.3)].. 6.2 Immunogenicity. As with all proteins there isa potential for immunogenicity with idarucizumab. Detection of antibodyformation is highly dependent on the sensitivity and specificity ofthe assay. Additionally, the observed incidence of antibody (includingneutralizing antibody) positivity in an assay may be influenced byseveral factors including assay methodology, sample handling, timingof sample collection, concomitant medications and underlying disease.For these reasons, comparison of the incidence of antibodies to idarucizumabin the studies described below with the incidence of antibodies inother studies or to other products may be misleading.Using an electro-chemiluminescence(ECL) based assay, plasma samples from 283 subjects (224 treated withidarucizumab) in phase trials and 501 patients were tested for antibodiescross-reacting with idarucizumab. Pre-existing antibodies with cross-reactivityto idarucizumab were detected in approximately 12% (33/283) of thesubjects and 4% (19/501) of patients. The majority of pre-existingantibodies were shown to have low titers. No impact on the pharmacokineticsor the reversal effect of idarucizumab or hypersensitivity reactionswere observed. Treatment-emergent possibly persisting anti-idarucizumabantibodies with low titers were observed in 4% (10/224) of the subjectsand 2% (8/501) of patients treated with idarucizumab. Nine patientswere re-dosed with idarucizumab. All nine patients were re-dosed within6 days after the first idarucizumab dose. None of these patients re-dosedwith idarucizumab tested positive for anti-idarucizumab antibodies.The epitope specificity of antibodiesto idarucizumab was characterized using probe molecules. For pre-existingantibodies in patients, 95% (18/19) had specificity for the C-terminus,a region of idarucizumab to which dabigatran does not bind. For treatmentemergent antibodies in patients, 67% (6/9) had specificity for theC-terminus, 22% (2/9) had specificity for the variable region, and11% (1/9) had mixed specificity.

DESCRIPTION SECTION.

11 DESCRIPTION. Idarucizumab is humanized monoclonal antibodyfragment (Fab) derived from an IgG1 isotype molecule, whose targetis the direct thrombin inhibitor dabigatran. Using recombinant expressiontechnology, idarucizumab is produced in well characterized recombinant(mammalian) CHO cell line and is purified using standard technology.Idarucizumab is composed of light chain of 219 amino acids and aheavy chain fragment of 225 amino acids, covalently linked togetherby one disulfide bond between cysteine 225 of the heavy chain fragmentand cysteine 219 of the light chain, and has an estimated molecularmass of approximately 47,766 Daltons.PRAXBIND (idarucizumab) is sterile, preservative-free,colorless to slightly yellow, clear to slightly opalescent solutionfor intravenous administration. PRAXBIND (idarucizumab) is suppliedin single-dose vials, each containing 2.5 of idarucizumab in 50mL formulated as buffered, isotonic, solution containing aceticacid glacial (10.05 mg), polysorbate 20 (10 mg), sodium acetate trihydrate(147.35 mg), sorbitol (2004.20 mg), and water for injection with anosmolality of 270-330 mOsm/kg and pH of 5.3-5.7.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intravenous use only.The recommended dose of PRAXBIND is g, provided as twoseparate vials each containing 2.5 g/50 mL idarucizumab. (2.1)There is limited data to support administration of an additional5 of PRAXBIND. (2.1). The recommended dose of PRAXBIND is g, provided as twoseparate vials each containing 2.5 g/50 mL idarucizumab. (2.1). There is limited data to support administration of an additional5 of PRAXBIND. (2.1). 2.1 Recommended Dose. The recommended dose of PRAXBIND is g, provided as two separate vials each containing 2.5 g/50 mL idarucizumab (see Figure 1). Both vials are packaged together in one carton. For intravenous use only.There is limited data to support administration of an additional g of PRAXBIND [see Warnings and Precautions (5.2)]. 2.2 Preparation. Remove both vials (each containing 2.5 g/50 mL idarucizumab) from carton.Ensure aseptic handling when preparing the infusion.Parenteral drug products should be inspected visually forparticulate matter and discoloration prior to administration, wheneversolution and container permit. Once solution has been removed from thevial, administration should begin promptly. The solution in vialsmay be stored at room temperature, 25C (77F), but must be used within6 hours [see How Supplied/Storage and Handling (16.2)]. Remove both vials (each containing 2.5 g/50 mL idarucizumab) from carton.. Ensure aseptic handling when preparing the infusion.. Parenteral drug products should be inspected visually forparticulate matter and discoloration prior to administration, wheneversolution and container permit.. Once solution has been removed from thevial, administration should begin promptly. The solution in vialsmay be stored at room temperature, 25C (77F), but must be used within6 hours [see How Supplied/Storage and Handling (16.2)]. 2.3 Administration. Do not mix with other medicinal products. Use aseptic techniquewhen administering PRAXBIND.Intravenously administer the dose of g (2 vials, eachcontains 2.5 g) asTwo consecutive infusions (see Figure 2) or Bolus injection by injecting both vials consecutively oneafter another via syringe (see Figure 3). pre-existing intravenous line may be used for administrationof PRAXBIND. The line must be flushed with sterile 0.9% Sodium ChlorideInjection, USP solution prior to infusion. No other infusion shouldbe administered in parallel via the same intravenous access.PRAXBIND treatment can be used in conjunction with standardsupportive measures, which should be considered as medically appropriate [see Clinical Pharmacology (12.2)]. Do not mix with other medicinal products. Use aseptic techniquewhen administering PRAXBIND.. Intravenously administer the dose of g (2 vials, eachcontains 2.5 g) asTwo consecutive infusions (see Figure 2) or Bolus injection by injecting both vials consecutively oneafter another via syringe (see Figure 3). Two consecutive infusions (see Figure 2) or Bolus injection by injecting both vials consecutively oneafter another via syringe (see Figure 3).. pre-existing intravenous line may be used for administrationof PRAXBIND. The line must be flushed with sterile 0.9% Sodium ChlorideInjection, USP solution prior to infusion. No other infusion shouldbe administered in parallel via the same intravenous access.. PRAXBIND treatment can be used in conjunction with standardsupportive measures, which should be considered as medically appropriate [see Clinical Pharmacology (12.2)]. figure-1. figure-2. figure-3. 2.4 RestartingAntithrombotic Therapy. Patients being treated with dabigatran therapyhave underlying disease states that predispose them to thromboembolicevents. Reversing dabigatran therapy exposes patients to the thromboticrisk of their underlying disease. To reduce this risk, resumptionof anticoagulant therapy should be considered as soon as medicallyappropriate.Idarucizumabis specific reversal agent for dabigatran, with no impact on theeffect of other anticoagulant or antithrombotic therapies.Pradaxa treatment can be initiated24 hours after administration of PRAXBIND [see Clinical Pharmacology(12.2)].

HOW SUPPLIED SECTION.

16 HOWSUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. PRAXBIND is sterile, preservative-free, colorless to slightlyyellow, clear to slightly opalescent solution supplied as single-dosevials each containing 2.5 g/50 mL of idarucizumab.NDC number 0597-0197-05: Carton containing two 2.5 g/50mL vials.. PRAXBIND is sterile, preservative-free, colorless to slightlyyellow, clear to slightly opalescent solution supplied as single-dosevials each containing 2.5 g/50 mL of idarucizumab.. NDC number 0597-0197-05: Carton containing two 2.5 g/50mL vials.. 16.2 Storage and Handling. Store PRAXBIND vials in the refrigerator at 2oC to 8oC (36oFto 46oF) in the original carton to protect from light. Do not freeze.Do not shake.PRAXBIND vials may be stored at room temperature, 25C (77F),for up to 48 hours in the original carton to protect from light.PRAXBIND vials may be stored at room temperature, 25C (77F),out of the carton and exposed to light but must be used within hours [see Dosage and Administration (2.2)].. Store PRAXBIND vials in the refrigerator at 2oC to 8oC (36oFto 46oF) in the original carton to protect from light. Do not freeze.Do not shake.. PRAXBIND vials may be stored at room temperature, 25C (77F),for up to 48 hours in the original carton to protect from light.. PRAXBIND vials may be stored at room temperature, 25C (77F),out of the carton and exposed to light but must be used within hours [see Dosage and Administration (2.2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Thromboembolic RiskInform patients that reversing dabigatran therapy exposes them to the thromboembolic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as the patient is sufficiently stable [see Warnings and Precautions (5.1)].Recurrence of BleedingInform patients to get immediate medical attention for any signs or symptoms of bleeding [see Warnings and Precautions (5.2)].Hypersensitivity ReactionsInform patients of signs and symptoms of allergic hypersensitivity reactions such as anaphylactoid reactions that may be experienced during or after injection of PRAXBIND [see Warnings and Precautions (5.3)].Risk of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol ExcipientInform patients with hereditary fructose intolerance (HFI) that PRAXBIND contains sorbitol. Parenteral administration of sorbitol in patients who have HFI has been associated with reports of hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function, and death and may occur during or after injection of PRAXBIND [see Warnings and Precautions (5.4)].Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USAUS License No. 2006Product of GermanyLicensed from:Boehringer Ingelheim International GmbHCopyright (C) 2021 Boehringer Ingelheim International GmbHALL RIGHTS RESERVEDCOL10514AJ182021.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In healthy subjects aged 45 to 64 years,the plasma concentrations of unbound dabigatran were reduced to belowthe lower limit of quantification immediately after the administrationof g idarucizumab. Subjects diluted thrombin time (dTT), ECT, aPTT,thrombin time (TT), and activated clotting time (ACT) parameters returnedto baseline levels (see Figure and Figure 5). This reduction ofdabigatran plasma concentration was observed over the entire observationperiod of at least 24 hours. Similar findings were also observed inelderly subjects (aged 65 to 80 years) as well as subjects with mildand moderate renal impairment [see Clinical Pharmacology (12.3)].In limited number of patients, re-distributionof dabigatran from the periphery to plasma led to re-elevation ofdTT, ECT, aPTT, and TT [see Warnings and Precautions (5.2)]. Re-dosing with 2.5 idarucizumab in healthysubjects aged 45-64 years at months after first infusion revealedno differences in safety and no indication of allergic reactions [see Clinical Pharmacology (12.3)].No changesin the pharmacokinetics or pharmacodynamics of dabigatran were notedupon re-initiation 24 hours after the administration of idarucizumab [see Dosage and Administration (2.4)].Thrombin Generation ParametersIdarucizumab alone has shown no procoagulant effect measuredas endogenous thrombin potential (ETP).Cardiac ElectrophysiologyClinical trials with idarucizumab in healthy subjectsmeasured heart rate and electrocardiogram (ECG) parameters (waveformmorphology, wave duration, and PR, QRS, QT, and QTc intervals).There were no clinically relevant abnormal findings related to ECG.Drug InteractionsIn vitro Assessment of Drug InteractionsInvitro data suggest that the inhibition of dabigatran by idarucizumabis not affected by coagulation factor concentrates [3- or 4-factorprothrombin complex concentrates (PCCs), activated PCC, or recombinantFactor VIIa].Assessment of Drug Interactions in Animal StudiesThe potential effect of the binding of idarucizumab to dabigatranin the presence of volume replacement agents (e.g., crystalloids,colloids, and retransfusion of washed red blood cells) was investigatedin swine. The results of this study suggest that neutralization ofdabigatran anticoagulant activity is not influenced by 50% hemodilutionwith routinely used volume replacement strategies.. figure-4. figure-5.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. There were no obvious differences in the idarucizumab plasma concentration time profiles when idarucizumab was administered alone or after pretreatment with dabigatran. dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine was observed.DistributionIdarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of 5 dose, the geometric mean volume of distribution at steady state (Vss) was 8.9 (geometric coefficient of variation (gCV 24.8%)).EliminationIdarucizumab was rapidly eliminated with total clearance of 47.0 mL/min (gCV 18.4%), an initial half-life of 47 minutes (gCV 11.4%), and terminal half-life of 10.3 (gCV 18.9%). After intravenous administration of g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within collection period of hours and less than 1% in the following 18 hours. The remaining part of the dose is assumed to be eliminated via protein catabolism, mainly in the kidney.MetabolismSeveral pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve biodegradation of the antibody to smaller molecules, i.e., small peptides or amino acids which are then reabsorbed and incorporated in the general protein synthesis.Specific PopulationsAge, Sex, Race and Body WeightAge, sex, race (Caucasian vs Asian) and body weight had no clinically important effect on systemic exposure of idarucizumab based on population pharmacokinetic analyses which included data from 220 volunteers and 486 patients.Patients with Renal ImpairmentIdarucizumab has been studied in 12 subjects with mild renal impairment (creatinine clearance [CrCl] 60 to <90 mL/min, by Cockcroft-Gault equation) and subjects with moderate impairment (CrCl30 to <60 mL/min). Compared to healthy subjects, the total clearance was reduced, leading to an increase in idarucizumabs area under the curve (AUC) by 43.5% and 83.5% in mild and moderate renal impairment, respectively. No dose adjustment is required in renally impaired patients.Based on pharmacokinetic data from 347 patients with varying degrees of renal function (median CrCl 21 to 99 mL/min) it is estimated that mean idarucizumab exposure (AUC0-24h) increased by 38%, 90%, and 146% in patients with mild renal impairment (CrCl 50 to <80 mL/min), moderate renal impairment (CrCl 30 to <50 mL/min) and severe renal impairment (CrCl to <30 mL/min), respectively. Since dabigatran is also excreted primarily via the kidneys, increases in the exposure to dabigatran are also seen with worsening renal function.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. RiskSummaryThere are no available data on PRAXBINDuse in pregnant women to inform drug-associated risk of major birthdefects and miscarriage. Animal reproductive and development studieshave not been conducted with idarucizumab. It is also not known whetherPRAXBIND can cause fetal harm when administered to pregnant womanor can affect reproduction capacity. PRAXBIND should be given to apregnant woman only if clearly needed.The background risk of major birth defectsand miscarriage for the indicated population is unknown. Adverse outcomesin pregnancy occur regardless of the health of the mother orthe use of medications. In the U.S. general population, the estimatedbackground risk of major birth defects and miscarriage in clinicallyrecognized pregnancies is 2-4% and 15-20%, respectively.. 8.2 Lactation. Risk SummaryThere are no data on theeffects of PRAXBIND on the breastfed child or on milk production.It is not known whether idarucizumabis excreted in human milk. Because many drugs are excreted in humanmilk, caution should be exercised when PRAXBIND is administered toa nursing woman.Thedevelopmental and health benefits of breastfeeding should be consideredalong with the mothers clinical need for PRAXBIND and any potentialadverse effects on the breastfed child from PRAXBIND or from the underlyingmaternal condition.. 8.4 Pediatric Use. Safety and effectiveness have not been established in pediatricpatients.. 8.5 Geriatric Use. totalof 454 (90%) patients treated with idarucizumab in the case seriestrial were 65 years of age and older, and 318 (63%) were 75 yearsof age and older. No overall differences in safety or effectivenesswere observed between these subjects and younger subjects, and otherreported clinical experience has not identified differences in responsesbetween the elderly and younger patients, but greater sensitivityof some older individuals cannot be ruled out.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Thromboembolic Risk: Reversing dabigatran therapy exposespatients to the thrombotic risk of their underlying disease. Resumeanticoagulant therapy as soon as medically appropriate. (2.4, 5.1)Re-elevation of Coagulation Parameters: In patients withelevated coagulation parameters and reappearance of clinically relevantbleeding or requiring second emergency surgery/urgent procedure,an additional g dose of PRAXBIND may be considered. (5.2)Hypersensitivity reactions: Discontinue administration andevaluate. (5.3)Risks of Serious Adverse Reactions in Patients with HereditaryFructose Intolerance due to Sorbitol Excipient: Patients with hereditaryfructose intolerance may be at risk of adverse reactions. (5.4). Thromboembolic Risk: Reversing dabigatran therapy exposespatients to the thrombotic risk of their underlying disease. Resumeanticoagulant therapy as soon as medically appropriate. (2.4, 5.1). Re-elevation of Coagulation Parameters: In patients withelevated coagulation parameters and reappearance of clinically relevantbleeding or requiring second emergency surgery/urgent procedure,an additional g dose of PRAXBIND may be considered. (5.2). Hypersensitivity reactions: Discontinue administration andevaluate. (5.3). Risks of Serious Adverse Reactions in Patients with HereditaryFructose Intolerance due to Sorbitol Excipient: Patients with hereditaryfructose intolerance may be at risk of adverse reactions. (5.4). 5.1 ThromboembolicRisk. Patientsbeing treated with dabigatran therapy have underlying disease statesthat predispose them to thromboembolic events. Reversing dabigatrantherapy exposes patients to the thrombotic risk of their underlyingdisease. To reduce this risk, resumption of anticoagulant therapyshould be considered as soon as medically appropriate [seeDosage and Administration (2.4)]. 5.2 Re-elevationof Coagulation Parameters. In limited number of patients in the clinicalprogram, between 12 and 24 hours after administration of g idarucizumab,elevated coagulation parameters (e.g., activated partial thromboplastintime (aPTT) or ecarin clotting time (ECT)) have been observed [see Dosage and Administration (2.1)]. If reappearanceof clinically relevant bleeding together with elevated coagulationparameters is observed after administration of g PRAXBIND, administrationof an additional g dose of PRAXBIND may be considered. Similarly,patients who require second emergency surgery/urgent procedure andhave elevated coagulation parameters may receive an additional gdose of PRAXBIND.Thesafety and effectiveness of repeat treatment with PRAXBIND have notbeen established [see Clinical Pharmacology (12.2)].. 5.3 HypersensitivityReactions. Thereis insufficient clinical experience with PRAXBIND in patients to evaluaterisk of hypersensitivity to idarucizumab. In clinical studies adverseevents possibly indicative of hypersensitivity reactions where possiblerelationship could not be excluded were reported [see AdverseReactions (6.1)]. The riskof using PRAXBIND in patients with known hypersensitivity (e.g., anaphylactoidreaction) to idarucizumab or to any of the excipients needs to beweighed cautiously against the potential benefit of such an emergencytreatment. If an anaphylactic reaction or other serious allergic reactionoccurs, immediately discontinue administration of PRAXBIND and instituteappropriate treatment.. 5.4 Risksof Serious Adverse Reactions in Patients with Hereditary FructoseIntolerance due to Sorbitol Excipient. In patients with the condition of hereditary fructose intolerance who have received parenteral administration of sorbitol, serious adverse reactions, including fatal reactions, have been reported. Reactions have included hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function.The recommended dose of PRAXBIND contains g sorbitol as an excipient. When prescribing PRAXBIND to patients with hereditary fructose intolerance, consider the combined daily metabolic load of sorbitol/fructose from all sources, including PRAXBIND and other drugs containing sorbitol. The minimum amount of sorbitol at which serious adverse reactions may occur in these patients is not known.