Praxbind (Page 2 of 4)

6.2 Immunogenicity

As with all proteins there is a potential for immunogenicity with idarucizumab. Detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay 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 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Using an electro-chemiluminescence (ECL) based assay, plasma samples from 283 subjects (224 treated with idarucizumab) in phase I trials and 501 patients were tested for antibodies cross-reacting with idarucizumab. Pre-existing antibodies with cross-reactivity to idarucizumab were detected in approximately 12% (33/283) of the subjects and 4% (19/501) of patients. 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. Treatment-emergent possibly persisting anti-idarucizumab antibodies with low titers were observed in 4% (10/224) of the subjects and 2% (8/501) of patients treated with idarucizumab. Nine patients were re-dosed with idarucizumab. All nine patients were re-dosed within 6 days after the first idarucizumab dose. None of these patients re-dosed with idarucizumab tested positive for anti-idarucizumab antibodies.

The epitope specificity of antibodies to idarucizumab was characterized using probe molecules. For pre-existing antibodies in patients, 95% (18/19) had specificity for the C-terminus, a region of idarucizumab to which dabigatran does not bind. For treatment emergent antibodies in patients, 67% (6/9) had specificity for the C-terminus, 22% (2/9) had specificity for the variable region, and 11% (1/9) had mixed specificity.

8  USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
There are no available data on PRAXBIND use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. 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. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. 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.

8.2 Lactation

Risk Summary There are no data on the effects of PRAXBIND on the breastfed child or on milk production.

It is not known whether idarucizumab is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRAXBIND is administered to a nursing woman.

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.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

A total of 454 (90%) patients treated with idarucizumab in the case series trial were 65 years of age and older, and 318 (63%) 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.

11  DESCRIPTION

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-dose 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

12.1 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.

12.2 Pharmacodynamics

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)].

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figure-5
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Thrombin Generation Parameters
Idarucizumab alone has shown no procoagulant effect measured as endogenous thrombin potential (ETP).

Cardiac Electrophysiology
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.

Drug Interactions
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.

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