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Composition:


active ingredient: idarucizumab;


1 ml of solution for injection/infusion contains 50 mg of idarucizumab;


1 bottle (50 ml of solution) contains 2.5 g of idarucizumab;


excipients: sodium acetate, trihydrate; acetic acid; sorbitol; polysorbate 20; water for injection.


Dosage form. Solution for injection/infusion.


Basic physical and chemical properties: colorless or slightly yellowish, transparent or slightly opalescent solution.


Pharmacotherapeutic group. Antidotes.


ATX code V03A B37.


Pharmacological properties.


Pharmacodynamics.


Mechanism of action


Idarucizumab is a specific antidote to dabigatran. It is a fragment of human monoclonal antibodies (Fab) that binds to dabigatran with a very high affinity, about 300 times higher than the binding affinity of dabigatran to thrombin. The idarucizumab–dabigatran complex is characterized by a rapid reaction and very slow decomposition, which results in the formation of a very stable complex. Idarucizumab binds strongly and specifically to dabigatran and its metabolites and neutralizes their anticoagulant effect.


Clinical efficacy and safety


The study patient population included healthy volunteers and patients with specific characteristics such as age, body weight, race, gender, and the presence of impaired renal function. During these studies, the dose range of idarucizumab was from 20 mg to 8 g, and the infusion time was from 5 minutes to 1 hour.


Characteristic values of pharmacokinetic and pharmacodynamic parameters were established in healthy volunteers aged 45 to 64 years who took 5 g of idarucizumab.


In a study on the treatment of adult patients with the threat of uncontrolled or life-threatening episodes of bleeding (Group A) during the use of dabigatran or in case of emergency surgery or emergency manipulations (Group B), the primary endpoint was the maximum percentage of neutralization of the anticoagulant effect of dabigatran within 4 hours after the use of idarucizumab based on the values of diluted thrombin time (RTCH) or ecarin coagulation time (IFSC) established in the central laboratory. The key secondary endpoint was the restoration of hemostasis.


Results of a clinical study of 503 patients: 301 patients with severe bleeding (Group A) and 202 patients requiring emergency manipulation/Surgery (Group B). Approximately half of these patients in each group were male. The mean age was 78 years and the mean creatinine clearance was 52.6 mL/min. 61.5% of patients in Group A and 62.4% of patients in Group B received dabigatran at a dose of 110 mg twice daily.


Neutralization was evaluated only for those patients who had extended coagulation time prior to starting idarucizumab therapy. In the majority of patients in groups A and B, the anticoagulant effect of dabigatran was completely neutralized (rth:98.7%; APTT: 82.2%; APTT: 92.5% in the evaluated patients, respectively) in the first 4 hours after taking 5 g of idarucizumab. The neutralizing effect becomes apparent immediately after application.


Restoration of hemostasis was achieved in 80.3% of the examined patients who had significant bleeding, and normal hemostasis was observed in 93.4% of patients who required emergency manipulations.


Of all 503 patients, 101 died; each of these deaths could have been either a complication of the underlying condition or related to comorbidities. Thrombotic complications were observed in 34 patients; (23 out of 34 patients did not receive antithrombotic therapy to treat the complication), and in each of these cases, thrombotic events can be considered as a complication of the patient's underlying disease. Moderate symptoms of hypersensitivity (fever, bronchospasm, hyperventilation, rash, and pruritus) have been reported. A causal relationship between idarucizumab and adverse reactions cannot be established.


Effect on pharmacodynamics


The pharmacodynamics of idarucizumab after administration of dabigatran etexylate were studied in 141 patients during Phase I studies.the results were compared with a representative subgroup of 6 healthy volunteers aged 45 to 64 years who received a dose of 5 G by intravenous infusion. The average peak exposure to dabigatran in healthy volunteers was observed in the range of 150 mg of dabigatran etexylate twice daily.


Effect of idarucizumab on the exposure and anticoagulant effect of dabigatran


Immediately after administration of idarucizumab, plasma concentrations of Unbound dabigatran decreased by more than 99%, to levels that did not show signs of anticoagulant action.


In most patients, there was a prolonged change in the concentration of dabigatran in blood plasma for 12 hours ((≥ 90%). In a subgroup of patients, there was a recovery in plasma levels of Unbound dabigatran and a simultaneous increase in blood clotting assessment tests, probably as a result of redistribution of dabigatran from the periphery. This occurred 1-24 hours after idarucizumab administration, mainly at a time of ≥12 hours.


Dabigatran prolongs the clotting time of markers of coagulation activity, namely: dilute thrombin time (RTCH), thrombin time (PM), activated partial thromboplastin time (APTT) and ecarin blood clotting time (IFSC) – which give a rough idea of the intensity of anticoagulant effects. A value within the normal range after idarucizumab Administration indicates that the patient is no longer receiving anticoagulant therapy. A value higher than normal may indicate residual active dabigatran or other clinical conditions, such as the presence of other agents or transfusion coagulopathy. These tests are used to evaluate the anticoagulant effect of dabigatran. Complete or prolonged changes in dabigatran-induced prolongation of blood clotting time were observed immediately after idarucizumab infusion, which lasted for the entire follow-up period (at least 24 hours).


Indicators of the thrombin generation test


Dabigatran has a pronounced effect on the indicators of endogenous thrombin potential (ETP). Treatment with idarucizumab normalized both the ratio of the period of initiation of thrombin formation and the ratio of time to peak initial levels 0.5–12 hours after the end of the idarucizumab infusion. Idarucizumab as monotherapy did not show the procoagulant effect measured as ETP. This suggests that idarucizumab does not have a prothrombotic effect.


Repeated use of dabigatran etexylate


24 hours after the infusion of idarucizumab, repeated use of dabigatran etexylate caused the expected anticoagulant effect.


Immunogenicity


Serum samples taken from 283 patients in the first phase of the study (224 volunteers received idarucizumab) were tested, and 501 patients were tested to detect antibodies to idarucizumab before and after treatment. Cross-reactivity antibodies to idarucizumab were detected in approximately 12% (33 out of 283) of Phase I subjects and 3.8% (19 out of 501) of patients. There was no effect on the pharmacokinetics or neutralizing effect of idarucizumab or hypersensitivity reactions.


Therapy-related significantly resistant antibodies to idarucizumab in low titers were observed in 4% (10 out of 224) of Phase I subjects and 1.6% (8 out of 501) of patients, indicating a low immunogenic potential of idarucizumab. In a subgroup of 6 patients, Phase I idarucizumab was administered again two months after the first injection. Prior to repeated use, no antibodies to idarucizumab were detected in these patients. In one patient, therapy-related antibodies to idarucizumab were detected after the second administration. Nine patients received a second dose of idarucizumab within 6 days of the first dose of idarucizumab. None of them tested positive for detecting antibodies to idarucizumab.


Pharmacokinetics.


The pharmacokinetics of idarucizumab were studied in 224 patients during Phase I trials.the results were compared with a representative subgroup of 6 healthy volunteers aged 45 to 64 years who received a dose of 5 G by intravenous infusion.


Distribution


Idarucizumab exhibits multiphase distribution Kinetics, as well as limited extravascular distribution. After intravenous infusion at a dose of 5 g, the geometric mean volume of distribution at steady state (Vss) was 8.9 L (geometric coefficient of variation (gCV) 24.8%).


Biotransformation


Several pathways that can contribute to antibody metabolism have been described. All of these pathways involve the biodegradation of antibodies to smaller molecules, i.e. low-molecular-weight peptides and amino acids, which are subsequently reabsorbed and involved in overall protein synthesis.


Output


Idarucizumab was rapidly eliminated from the body at 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 hours (gCV 18.9 %). After intravenous administration of 5 g of idarucizumab, 32.1 % (GCV 60.0 %) of the dose was detected in the urine during the 6-hour collection period, and less than 1% during the next 18 hours. The rest of the dose is excreted by protein catabolism, mainly by the kidneys.


Cases of proteinuria have been reported after treatment with idarucizumab. Transient proteinuria is a physiological response to increased kidney load due to protein intake after bolus/short-term administration of 5 g of idarucizumab intravenously. The peak of transient proteinuria usually occurred approximately 4 hours after administration of idarucizumab. The patient's condition returned to normal within 12-24 hours. In isolated cases, transient proteinuria lasted more than 24 hours.


Depending on the degree of renal impairment, total clearance decreased compared to that in healthy volunteers, which led to increased exposure to idarucizumab.


Gender, age, and race do not have a clinically significant effect on the pharmacokinetics of idarucizumab.


Clinical characteristics.

Indications.


PRAXBIND is a specific antidote to dabigatran and is intended for adult patients receiving treatment with Pradaxa (dabigatran etexylate) when sudden withdrawal of the anticoagulant effect is necessary:


• for emergency surgery/ emergency manipulations;


* if there is a threat to life or uncontrolled bleeding.


Contraindications.


Missing.


Interactions with other drugs and other types of interactions.


Studies of the interaction of PRAXBIND with other drugs have not been conducted. Given the pharmacokinetic properties and high specificity of binding to dabigatran, clinically significant interactions with other drugs are unlikely.


The results of preclinical studies indicated that there was no interaction with:


* vasopressor agents;


* blood clotting factor concentrates, namely: prothrombin complex concentrates (KPC, for example, factor 3 and 4), activated prothrombin complex concentrates (CAPC) and recombinant blood clotting Factor VIIa;


* other anticoagulants (for example, thrombin inhibitors other than dabigatran, Factor Xa inhibitors, including low-molecular-weight heparin, vitamin K antagonists, heparin).


Thus, idarucizumab does not inhibit the action of other anticoagulants.


Application features.


Idarucizumab specifically binds to dabigatran and completely neutralizes its anticoagulant effect. It does not eliminate the effect of other anticoagulants (see the section "pharmacological properties.  Pharmacodynamics").


The drug PRAXBIND can be used simultaneously with the usual maintenance measures that are considered medically necessary.


Traceability


In order to improve the traceability of biological drugs, it is necessary to clearly write down the name and serial number of the administered drug.


Hypersensitivity


The risk of using PRAXBIND in patients with known hypersensitivity (for example, anaphylactoid reactions) to idarucizumab or to any other components of the drug should be carefully weighed against the potential benefits of such emergency medical care. In case of anaphylactic reaction or other serious allergic reaction, the use of PRAXBIND should be stopped immediately and appropriate therapy should be initiated.


Hereditary fructose intolerance


The recommended dose of PRAXBIND contains 4 g of sorbitol as an excipient. In patients with hereditary fructose intolerance, parenteral administration of sorbitol was associated with hypoglycemia, hypophosphatemia, metabolic acidosis, increased uric acid levels, acute hepatic insufficiency with impaired excretory and synthetic function, and death. Therefore, for patients with hereditary fructose intolerance, the risk of treatment with PRAXBIND should be carefully weighed against the potential benefits of such emergency medical care. If these patients are using PRAXBIND, intensive medical care should be provided during the use of PRAXBIND and within 24 hours after administration.


Thromboembolic complications


Patients who use dabigatran have an underlying disease that provokes the development of thromboembolic complications. Changes in dabigatran therapy increase the risk of concomitant prothrombotic effects in these patients. To reduce the risk, anticoagulant therapy should be resumed as soon as it is medically necessary (see the section "dosage and administration").


Determination of protein in urine


PRAXBIND causes transient proteinuria as a physiological response to increased kidney load due to protein intake after bolus/short-term administration of 5 g of idarucizumab intravenously (see the section "pharmacological properties.  Pharmacokinetics").


Transient proteinuria does not indicate renal failure, which should be taken into account when performing a urine test.


Sodium content


PRAXBIND contains 50 mg of sodium per dose, which is equivalent to 2.5% of the WHO recommended maximum daily dose of 2 g of sodium for adults.


Use during pregnancy or lactation.


Pregnancy


There are no data on the use of PRAXBIND in pregnant women. Studies of reproductive toxicity and embryotoxicity have not been conducted, taking into account the nature and targeted clinical use of the drug. PRAXBIND can be used during pregnancy if the expected clinical benefit outweighs the potential risks.


Breast-feeding


It is not known whether idarucizumab passes into breast milk.


Fertility


There are no data on the effect of PRAXBIND on fertility.


Ability to influence the reaction rate when driving vehicles or other mechanisms.


The drug is used only in a hospital setting.

Dosage and administration.


The drug is used only in a hospital setting.


Doses


The recommended dose of PRAXBIND is 5 g (2×2.5 g/50 ml).


In a subgroup of patients, repeated plasma concentrations of Unbound dabigatran and simultaneous prolongation of blood clotting time were observed within 24 hours after idarucizumab administration (see Section "pharmacological properties.  Pharmacodynamics").


Consideration should be given to taking a second dose 5 g of PRAXBIND in the following cases:


* relapse of clinically significant bleeding along with prolonged clotting time;


• if a possible relapse of bleeding is life-threatening and there is a prolonged clotting time;


* the patient needs a second emergency operation/ emergency manipulation and has a prolonged clotting time.


Suitable coagulation parameters are activated partial thromboplastin time (APTT), diluted thrombin time (RTT), or ecarin blood clotting time (APCC) (see the section "pharmacological properties.  Pharmacodynamics").


The maximum daily dose has not been studied.


Restoration of antithrombotic therapy


Treatment with Pradaxa (dabigatran etexylate) can be resumed 24 hours after the use of PRAXBIND in clinically stable patients and after achieving proper hemostasis.


After using PRAXBIND, other antithrombotic therapy (for example, taking low-molecular-weight heparin) can be initiated at any time in stable patients and after achieving proper hemostasis.


The absence of antithrombotic therapy increases the risk of developing concomitant prothrombotic effects.


Patients with impaired renal function


Patients with impaired renal function do not need to adjust the dose of the drug. Impaired renal function does not affect the reverse effect of idarucizumab (see the section "pharmacological properties.  Pharmacokinetics").


Patients with impaired liver function


Patients with impaired liver function do not need to adjust the dose of the drug (see the section "pharmacological properties.  Pharmacokinetics").


Elderly patients


Elderly patients (over 65 years of age) do not need to adjust the dose of the drug (see the section "pharmacological properties.  Pharmacokinetics").


Method of application


For intravenous use.


PRAXBIND (2×2.5 g/50 ml) is administered intravenously as two consecutive infusions for 5-10 minutes each or as a bolus injection.


Before applying the solution, it is necessary to check visually for mechanical inclusions and color changes.


It is necessary to use a separate infusion system for infusing the drug PRAXBIND. The system should be washed with a sodium chloride solution of 9 mg/mL (0.9 %) for injection before and after infusion. Other infusions should not be administered in parallel through a single intravenous catheter.


PRAXBIND does not contain preservatives and is intended for single use only (see the section "expiration date").


Children.


The safety and efficacy of PRAXBIND in children (under 18 years of age) have not been established.


No data available.


Overdose.


There is no clinical experience of overdose of PRAXBIND.


The highest single dose of PRAXBIND, which was studied in healthy volunteers, was 8 g. no warning symptoms of overdose were found in this group.


Adverse reactions.


The safety of PRAXBIND was evaluated during a Phase III study involving 503 patients treated with Pradaxa (dabigatran etexylate), with the threat of uncontrolled bleeding or in case of emergency surgery or emergency manipulations, and safety was also evaluated with the participation of 224 volunteers during the Phase I study.


No adverse reactions were detected.


Reports of suspected adverse reactions


Reporting suspected adverse reactions after drug registration is important. This allows you to continue monitoring the benefit/risk ratio of the drug. Health professionals are asked to report any suspected adverse reactions.

Tags: Praxbind® [Idarucimab]