Idarucizumab is a humanized monoclonal antibody fragment indicated for dabigatran-treated patients when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery or urgent procedures or in life-threatening or uncontrolled bleeding. It was initially granted accelerated approval based on data which showed a reduction of unbound dabigatran and normalization of coagulation parameters in healthy volunteers. In the RE-VERSE AD study of patients who were receiving dabigatran and had uncontrolled bleeding or were to undergo an urgent procedure and had a prolonged diluted thrombin time or ecarin clotting time at baseline (n = 503), idarucizumab reversed anticoagulation rapidly and completely to a median maximum percentage of 100% within 4 hours in more than 98% of the patients. A single idarucizumab dose was sufficient in 98% of patients, and reversal was maintained for 24 hours in most patients. Idarucizumab is a reversal agent specific for dabigatran and has no impact on the effect of other anticoagulant or antithrombotic therapies. Reversing the effect of dabigatran exposes patients to the thrombotic risk of their underlying disease; therefore, anticoagulant therapy should resume as soon as medically appropriate.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Idarucizumab solution is colorless to slightly yellow and clear to slightly opalescent.
Intravenous Administration
-The recommended dose of idarucizumab is provided as 2 separate vials, each containing idarucizumab 2.5 g/50 mL. Both vials are packaged together in the same carton.
-Remove both vials from the carton.
-Use aseptic technique when preparing the infusion.
-Administer 5 g dose as either 2 consecutive infusions by hanging vials or inject both vials consecutively via syringe.
-Do not mix with other drugs or medicinal products.
-A pre-existing intravenous line may be used for administration. Flush the line with 0.9% Sodium Chloride Injection prior to infusion. Do not administer any other infusions in parallel via the same intravenous access.
-Storage: Once solution has been removed from the vial, administer promptly. Solution in vials may be stored at room temperature, 25 degrees C (77 degrees F), but must be used within 6 hours.
Antibody formation may occur with idarucizumab. During clinical trials, 13% of patients were found to have pre-existing antibodies and cross-reactivity to idarucizumab. The majority of the pre-existing antibodies were shown to have low titers. No difference was seen in the pharmacokinetics or the reversal effect of idarucizumab or hypersensitivity reactions in these patients. Treatment-emergent and possible persisting anti-idarucizumab antibodies with low titers were detected in 4% of patients treated with idarucizumab. The detection of antibodies is dependent on the sensitivity and specificity of the assay, and the incidence of positive antibodies may be influenced by assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. Therefore, the incidence of antibody formation to idarucizumab cannot be directly compared to other products.
Among patients treated with dabigatran and receiving idarucizumab for uncontrolled bleeding or undergoing an urgent procedure (n = 503), thrombosis was reported in 4.8% of patients at 30 days after treatment and in 6.8% at 90 days. The mean times to reinitiation of antithrombotic therapy (prophylactic or therapeutic doses of an anticoagulant or with an antiplatelet drug) were 13.2 days and 3.5 days for the majority of idarucizumab-treated patients for uncontrolled bleeding and an urgent procedure, respectively.
Adverse reactions reported in 5% or more of patients undergoing dabigatran treatment and administered idarucizumab (n = 123) include hypokalemia (7%), delirium (7%), constipation (7%), fever (6%), and infection (pneumonia, 6%). Of 123 patients, 26 died, 11 within the first day after idarucizumab dosing; each of these deaths could be attributed to a complication of the index event or associated with comorbidities.
Adverse reactions related to hypersensitivity including fever, bronchospasm, hyperventilation, pruritus, and rash (unspecified) have been reported in idarucizumab clinical trials.
Among 3 placebo-controlled clinical trials of healthy volunteers treated with idarucizumab (n = 224), the only adverse reaction reported in 5% or more of subjects was headache (5%).
There is insufficient clinical experience to evaluate the risk of hypersensitivity to idarucizumab. Adverse events possibly associated with hypersensitivity in which a relationship could not be excluded were reported in clinical trials. Carefully evaluate the risk of using idarucizumab in patients with a known hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or to any of its excipients against the potential benefit of treatment. If signs or symptoms of serious allergic reactions occur, discontinue idarucizumab, and provide appropriate care.
Elevated coagulation parameters (e.g., activated partial thromboplastin time [aPTT] or ecarin clotting time [ECT]) have been reported in a limited number of patients between 12 and 24 hours after administration of 5 g idarucizumab. There is limited data to support administration of an additional 5 g dose of idarucizumab, and safety and efficacy of repeat treatment with idarucizumab have not been established.
Anticoagulant therapy should be resumed as soon as medically appropriate in patients treated with idarucizumab. Patients receiving dabigatran therapy have underlying disease states that predispose them to thromboembolic disease. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Dabigatran can be initiated 24 hours after the administration of idarucizumab.
Administer idarucizumab cautiously in patients with hereditary fructose intolerance. The recommended dose of idarucizumab contains 4 g sorbitol as an excipient. Serious adverse reactions, some fatal, have been reported in patients with hereditary fructose intolerance who have received parenteral sorbitol. Reactions include hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, and acute liver failure with breakdown of excretory and synthetic function. When administering idarucizumab to patients with hereditary fructose intolerance, consider the combined daily metabolic load of sorbitol/fructose from all sources, including idarucizumab and other drugs containing sorbitol. The minimum amount of sorbitol at which serious adverse reactions may occur in patients with hereditary fructose intolerance is unknown.
It is unknown if idarucizumab can cause fetal harm when administered during pregnancy or if it can affect reproductive ability. There are no adequate or well-controlled studies in pregnant women, and animal reproductive and developmental studies have not been conducted with idarucizumab. Administer idarucizumab to a pregnant woman only if clearly needed.
According to the manufacturer, it is unknown if idarucizumab is excreted in human milk. There are no data on the effects of idarucizumab on milk production or the breastfed infant. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.
For dabigatran reversal during emergency surgery, urgent procedures, or for life-threatening or uncontrolled bleeding:
Intravenous dosage:
Adults: 5 g IV as a single dose. The safety and effectiveness of repeat treatment with idarucizumab have not been established, and data supporting the administration of an additional dose is limited. May consider a repeat dose if clinically relevant bleeding in combination with elevated coagulation parameters recurs or a patient requires a second emergency surgery or urgent procedure and has elevated coagulation parameters. Resume anticoagulant therapy as soon as medically appropriate. Dabigatran therapy may be initiated 24 hours after the administration of idarucizumab.
Maximum Dosage Limits:
-Adults
5 g IV.
-Geriatric
5 g IV.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Idarucizumab products.
Idarucizumab is a humanized monoclonal antibody fragment that binds to dabigatran and its acylglucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin, thus neutralizing their anticoagulant effect.
Idarucizumab is administered intravenously. It exhibits limited extravascular distribution and follows multiphasic disposition kinetics. Idarucizumab undergoes biodegradation of the antibody to smaller peptides or amino acids which are then reabsorbed and incorporated in the general protein synthesis. Idarucizumab is rapidly eliminated with an initial half-life of 47 minutes and a terminal half-life of 10.3 hours. Approximately 32% of the dose is recovered in the 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.
In healthy subjects aged 45 to 64 years, the plasma concentrations of unbound dabigatran were decreased to the lower limit of quantification immediately after administration of idarucizumab 5 g. The diluted thrombin time, ecarin clotting time, activated partial thromboplastin time, thrombin time, and activated clotting time returned to baseline. The reduction in dabigatran plasma concentration was seen over the entire observation period of at least 24 hours. Among patients receiving dabigatran and treated with idarucizumab for uncontrolled bleeding or undergoing an urgent procedure (total n = 503), the median maximum percentage reversal within 4 hours of idarucizumab administration was 100%, as assessed by either diluted thrombin time or the ecarin clotting time. Reversal was rapid and occurred independently of baseline dabigatran concentration. In patients with uncontrolled, extracranial bleeding, the median time to hemostasis was 2.5 hours after idarucizumab administration. For patients undergoing an urgent procedure, the median time to procedure initiation was 1.6 hours after idarucizumab administration.
Affected cytochrome P450 isoenzymes and transporters: none
-Special Populations
Renal Impairment
Renal impairment did not impact the reversal effect of idarucizumab. The pharmacokinetics of idarucizumab have been studied in 12 subjects with mild renal impairment (CrCl 60 to 89 mL/minute) and 6 subjects with moderate renal impairment (CrCl 30 to 59 mL/minute). Compared to healthy subjects, the total clearance was reduced, resulting in an increase in the AUC by 43.5% in the mild renal impairment group and 83.5% in the moderate renal impairment group.
Geriatric
Age had no clinically important effect on the systemic exposure of idarucizumab in a healthy volunteer cohort of 201 males and 19 females.
Gender Differences
Sex had no clinically important effect on the systemic exposure of idarucizumab in a healthy volunteer cohort of 201 males and 19 females.
Ethnic Differences
Race (Caucasian vs. Asian) had no clinically important effect on the systemic exposure of idarucizumab in a healthy volunteer cohort of 201 males and 19 females.
Obesity
Body weight had no clinically important effect on the systemic exposure of idarucizumab in a healthy volunteer cohort of 201 males and 19 females.