- For emergency surgery/urgent procedures
- In life-threatening or uncontrolled bleeding
This indication is approved under accelerated approval based on a reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study.
2 DOSAGE AND ADMINISTRATION
There is limited data to support administration of an additional 5 g of Praxbind [see Warnings and Precautions (5.2)].
- Ensure aseptic handling when preparing the infusion.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Once solution has been removed from the vial, administration should begin promptly or within 1 hour.
- Do not mix with other medicinal products. Use aseptic technique when administering Praxbind.
- Intravenously administer the dose of 5 g (2 vials, each contains 2.5 g) as
- Two consecutive infusions (see Figure 2) or
- Bolus injection by injecting both vials consecutively one after another via syringe (see Figure 3).
- A pre-existing intravenous line may be used for administration of Praxbind. The line must be flushed with sterile 0.9% Sodium Chloride Injection, USP solution prior to infusion. No other infusion should be administered in parallel via the same intravenous access.
- Praxbind treatment can be used in conjunction with standard supportive measures, which should be considered as medically appropriate [see Clinical Pharmacology (12.2)].
Restarting Antithrombotic Therapy
Patients being treated with dabigatran therapy have underlying disease states that predispose them to thromboembolic events. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.
Pradaxa treatment can be initiated 24 hours after administration of Praxbind [see Clinical Pharmacology (12.2)].
3 DOSAGE FORMS AND STRENGTHS
5 WARNINGS AND PRECAUTIONS
Patients being treated with dabigatran therapy have underlying disease states that predispose them to thromboembolic events. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate [see Dosage and Administration (2.4)].
Re-elevation of Coagulation Parameters
In a limited number of patients in the clinical program, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT)) have been observed [see Dosage and Administration (2.1)].
If reappearance of clinically relevant bleeding together with elevated coagulation parameters is observed after administration of 5 g Praxbind, administration of an additional 5 g dose of Praxbind may be considered. Similarly, patients who require a second emergency surgery/urgent procedure and have elevated coagulation parameters may receive an additional 5 g dose of Praxbind.
The safety and effectiveness of repeat treatment with Praxbind have not been established [see Clinical Pharmacology (12.2)].
There is insufficient clinical experience with Praxbind in patients to evaluate risk of hypersensitivity to idarucizumab. In clinical studies adverse events possibly indicative of hypersensitivity reactions where a possible relationship could not be excluded were reported [see Adverse Reactions (6.1)]. The risk of using Praxbind in patients with known hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or to any of the excipients needs to be weighed cautiously against the potential benefit of such an emergency treatment. If an anaphylactic reaction or other serious allergic reaction occurs, immediately discontinue administration of Praxbind and institute appropriate treatment.
Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance 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 4 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.
6 ADVERSE REACTIONS
- Thromboembolic Risk [see Warnings and Precautions (5.1)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
- Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient [see Warnings and Precautions (5.4)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction 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 clinical practice.
Three clinical trials in healthy volunteers have been completed, in which 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 greater than or equal to 5% of subjects was headache (12/224, 5%).
In the interim analysis of the RE-VERSE AD™ (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial, a total of 123 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)]. Adverse reactions reported in greater than or equal to 5% of patients were: hypokalemia (9/123, 7%), delirium (9/123, 7%), constipation (8/123, 7%), pyrexia (7/123, 6%), pneumonia (7/123, 6%). Of the total, 26 patients died, 11 within the first day after idarucizumab dosing; each of these deaths could be attributed either as a complication of the index event or associated with co-morbidities.
In the interim analysis of the RE-VERSE AD trial, 5 of 123 patients reported thrombotic events, 1 patient 2 days after treatment with idarucizumab and 4 patients 7 days or more after treatment with idarucizumab. None of these patients were 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)].
Pyrexia, bronchospasm, hyperventilation, rash, and pruritus have been reported in clinical trials with idarucizumab [see Warnings and Precautions (5.3)].
As with all proteins there is a potential for immunogenicity with idarucizumab. Using an electro-chemiluminescence (ECL) based assay, plasma samples from 283 subjects (224 treated with idarucizumab) were tested for antibodies cross-reacting with idarucizumab. Pre-existing antibodies with cross-reactivity to idarucizumab were detected in approximately 13% (36/283) of the subjects. The majority of pre-existing antibodies were shown to have low titers. No impact on the pharmacokinetics or the reversal effect of idarucizumab or hypersensitivity reactions were observed in these subjects. Treatment-emergent possibly persisting anti-idarucizumab antibodies with low titers were observed in 4% (9/224) of the subjects treated with idarucizumab.
The epitope specificity of antibodies to idarucizumab was characterized using probe molecules. For pre-existing antibodies, 97% (35/36) had specificity for the C-terminus, a region of idarucizumab to which dabigatran does not bind. For treatment emergent possibly persisting antibodies, 56% (5/9) had specificity for the C-terminus, 22% (2/9) had specificity for the variable region, 11% (1/9) had mixed specificity and 11% (1/9) was indeterminate.
Detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to idarucizumab with the incidence of antibodies to other products may be misleading.
8 USE IN SPECIFIC POPULATIONS
There are no adequate and well-controlled studies of Praxbind in pregnant women to inform on associated risks. Animal reproductive and development studies have not been conducted with idarucizumab. It is also not known whether Praxbind can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Praxbind should be given to a pregnant woman only if clearly needed.
The background risk of major birth defects and miscarriage for the indicated population is unknown. 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.
Labor or Delivery
Praxbind has not been studied for use during labor and delivery. Safety and effectiveness of Praxbind during labor and delivery have not been studied in clinical trials.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Praxbind and any potential adverse effects on the breastfed child from Praxbind or from the underlying maternal condition.
A total of 111 (90%) patients treated with idarucizumab in the case series trial were 65 years of age and older, and 74 (60%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Renal impairment did not impact the reversal effect of idarucizumab [see Clinical Pharmacology (12.3)]. No dose adjustment is required in renally impaired patients.
Idarucizumab is a humanized monoclonal antibody fragment (Fab) derived from an IgG1 isotype molecule, whose target is the direct thrombin inhibitor dabigatran. Using recombinant expression technology, idarucizumab is produced in a well characterized recombinant (mammalian) CHO cell line and is purified using standard technology. Idarucizumab is composed of a light chain of 219 amino acids and a heavy chain fragment of 225 amino acids, covalently linked together by one disulfide bond between cysteine 225 of the heavy chain fragment and cysteine 219 of the light chain, and has an estimated molecular mass of approximately 47,766 Daltons.
Praxbind (idarucizumab) is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution for intravenous administration. Praxbind (idarucizumab) is supplied in 2 single-use vials, each containing 2.5 g of idarucizumab in 50 mL formulated as a buffered, isotonic, solution containing acetic acid glacial (10.05 mg), polysorbate 20 (10 mg), sodium acetate trihydrate (147.35 mg), sorbitol (2004.20 mg), and water for injection with an osmolality of 270-330 mOsm/kg and a pH of 5.3-5.7.
12 CLINICAL PHARMACOLOGY
Mechanism of Action
Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran and its acylglucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin, neutralizing their anticoagulant effect.
In healthy subjects aged 45 to 64 years, the plasma concentrations of unbound dabigatran were reduced to below the lower limit of quantification immediately after the administration of 5 g idarucizumab. Subjects’ diluted thrombin time (dTT), ECT, aPTT, thrombin time (TT), and activated clotting time (ACT) parameters returned to baseline levels (see Figure 4 and Figure 5). This reduction of dabigatran plasma concentration was observed over the entire observation period of at least 24 hours. Similar findings were also observed in elderly subjects (aged 65 to 80 years) as well as subjects with mild and moderate renal impairment [see Clinical Pharmacology (12.3)].
In a limited number of patients, re-distribution of dabigatran from the periphery to plasma led to re-elevation of dTT, ECT, aPTT, and TT [see Warnings and Precautions (5.2)].
Re-dosing with 2.5 g idarucizumab in 6 healthy subjects aged 45-64 years at 2 months after first infusion revealed no differences in safety and no indication of allergic reactions [see Clinical Pharmacology (12.3)].
No changes in the pharmacokinetics or pharmacodynamics of dabigatran were noted upon re-initiation 24 hours after the administration of idarucizumab [see Dosage and Administration (2.4)].
Clinical trials with idarucizumab in healthy subjects measured heart rate and electrocardiogram (ECG) parameters (waveform morphology, P wave duration, and PR, QRS, QT, and QTc intervals). There were no clinically relevant abnormal findings related to ECG.
In vitro Assessment of Drug Interactions
In vitro data suggest that the inhibition of dabigatran by idarucizumab is not affected by coagulation factor concentrates [3- or 4-factor prothrombin complex concentrates (PCCs), activated PCC, or recombinant Factor VIIa].
Assessment of Drug Interactions in Animal Studies
The potential effect of the binding of idarucizumab to dabigatran in the presence of volume replacement agents (e.g., crystalloids, colloids, and retransfusion of washed red blood cells) was investigated in swine. The results of this study suggest that neutralization of dabigatran anticoagulant activity is not influenced by 50% hemodilution with routinely used volume replacement strategies.
There were no obvious differences in the idarucizumab plasma concentration time profiles when idarucizumab was administered alone or after pretreatment with dabigatran. A dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine was observed.
Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of a 5 g dose, the geometric mean volume of distribution at steady state (Vss) was 8.9 L (geometric coefficient of variation (gCV 24.8%)).
Idarucizumab was rapidly eliminated with a total clearance of 47.0 mL/min (gCV 18.4%), an initial half-life of 47 minutes (gCV 11.4%), and a terminal half-life of 10.3 h (gCV 18.9%). After intravenous administration of 5 g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within a collection period of 6 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.
Several 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.
Age, Sex, Race and Body Weight
Age, sex, race (Caucasian vs Asian) and body weight had no clinically important effect on systemic exposure of idarucizumab based on population pharmacokinetic analyses in a healthy volunteer cohort of 201 males and 19 females.
Idarucizumab has been studied in 12 subjects with mild renal impairment (creatinine clearance ≥60 to <90 mL/min, by Cockcroft-Gault equation) and 6 subjects with moderate impairment (creatinine clearance ≥30 to <60 mL/min). Compared to healthy subjects, the total clearance was reduced, leading to an increase in idarucizumab’s area under the curve (AUC) by 43.5% and 83.5% in mild and moderate renal impairment, respectively [see Use in Specific Populations (8.6)].
13 NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or genotoxicity studies have been conducted with idarucizumab. No animal studies have been performed to evaluate the potential effects of idarucizumab on fertility in males or females or on reproduction and development.
14 CLINICAL STUDIES
The safety and effectiveness of Praxbind has been investigated in pharmacokinetic/pharmacodynamic trials with healthy volunteers and in an ongoing single cohort case series trial with dabigatran-treated patients who have life-threatening or uncontrolled bleeding, or who require emergency surgery or urgent procedure (RE-VERSE AD).
Three randomized, placebo-controlled trials in a total of 283 subjects assessed the safety, dose-response, and effect of idarucizumab on reducing unbound dabigatran and coagulation parameters. Of the 283 subjects, 224 received at least one dose of idarucizumab. These trials included 19 females and 30 subjects aged 65 years or older (median age 36 years).
The tables below summarize the idarucizumab effect on coagulation parameters dTT, aPTT, ECT, TT, and ACT over time for 14 subjects treated in one of the healthy volunteer trials. Fourteen subjects received dabigatran 220 mg orally twice daily for three days and an additional single 220 mg dose of dabigatran on day four, two hours before receiving idarucizumab. Idarucizumab was administered as one 5 g intravenous infusion over five minutes. Table 1 shows the results of the idarucizumab treatment group and Table 2 shows the results of the placebo treatment group.
(Mean and Standard Deviation)
|End of infusion of Idarucizumab
|24 hours after
|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)|
(Mean and Standard Deviation)
|End of infusion of Placebo
|24 hours after
|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)|
RE-VERSE AD Patient Experience
In an ongoing single cohort case series trial, 5 g idarucizumab was administered to patients treated with dabigatran who presented with dabigatran-related life-threatening or uncontrolled bleeding (Group A) or who required emergency surgery or urgent procedures (Group B). The primary endpoint was the maximum percentage reversal of the pharmacodynamic anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, based on central laboratory determination of dTT or ECT.
An interim analysis of the ongoing single cohort case series trial included data for 123 patients: 66 patients with serious bleeding (Group A) and 57 requiring an urgent procedure (Group B). Approximately half of the patients in each group were male. The median age was 77 years and the median creatinine clearance was 55 mL/min. Approximately 67% of patients in Group A and 63% of patients in Group B had been treated with dabigatran 110 mg BID. Results of central laboratory evaluations were available for a subset of 90 patients (51 in Group A, 39 in Group B).
Among the 90 patients with available data, the median maximum reversal of the pharmacodynamic anticoagulant effect of dabigatran as measured by ECT or dTT in the first 4 hours after administration of 5 g idarucizumab was 100%, with most patients (>89%) achieving complete reversal. Reversal of the pharmacodynamics effects was evident immediately after administration. Results for Groups A and B were similar. In a limited number of patients, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., aPTT or ECT) have been observed. ECT measures over the 24-hour observation time are shown in Figure 6.
16 HOW SUPPLIED/STORAGE AND HANDLING
- Praxbind is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution supplied as 2 single-use vials each containing 2.5 g/50 mL of idarucizumab.
- NDC number 0597-0197-05: Carton containing two 2.5 g/50 mL vials.
Storage and Handling
- Store Praxbind vials in the refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Do not shake.
- Prior to use, the unopened vial may be kept at room temperature 25°C (77°F) for up to 48 hours, if stored in the original package in order to protect from light, or up to 6 hours when exposed to light.
17 PATIENT COUNSELING INFORMATION
Inform 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 Bleeding
Inform patients to get immediate medical attention for any signs or symptoms of bleeding [see Warnings and Precautions (5.2)].
Inform 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 Excipient
Inform 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)].
|Labeler - Boehringer Ingelheim Pharmaceuticals, Inc. (603175944)|
|Registrant - Boehringer Ingelheim Pharmaceuticals, Inc. (603175944)|
|Boehringer Ingelheim Pharma GmbH and Co. KG||340700520||PACK(0597-0197), API MANUFACTURE(0597-0197), LABEL(0597-0197), ANALYSIS(0597-0197)|
|Boehringer Ingelheim Roxane, Inc.||058839929||PACK(0597-0197), LABEL(0597-0197)|
|SGC Institute Fresenius GmbH||317219699||ANALYSIS(0597-0197)|
|Labor L + S AG||313710642||ANALYSIS(0597-0197)|