Overview
Concizumab is a humanized IgG4 monoclonal antibody made in Chinese hamster ovary (CHO) cells using recombinant DNA Deoxyribonucleic acid technology. Seven reverse mutations were incorporated in the tissue factor pathway inhibitor (TFPI) to maintain the strong affinity for the Kunitz 2 (K2) domain. Lastly, a proline was substituted for the serine at position 241 (Kabat annotation) in the heavy chain to stop the production of half-antibodies.
TFPI regulates a different blood clotting route that does not involve factor VIII or IX. This medication works by inhibiting TFPI, which should improve blood clotting and assist in managing bleeding disorders without requiring replacement factor VIII or IX. In contrast to replacement factor VIII or IX, which must be injected directly into the vein, Concizumab is a once-daily injection administered beneath the skin. It can be used at home and is more straightforward to administer.
For Patients
What Are the Indications of Concizumab Injection?
Adolescents and adults with hemophilia B (congenital factor IX [FIX] deficiency) who are 12 years of age or older may be treated with Concizumab injection. FIX inhibitors and necessitate regular preventative measures to stop or lessen bleeding episodes. There is little clinical evidence supporting the use of Concizumab in patients with mild to moderate hemophilia B (activity greater than two percent on the FIX test).
Hemophilia B patients bleed for a more extended period rather than faster than those without the condition. This is due to their inability to effectively halt blood flow from a wound, injury, or bleeding site due to a lack of or reduced protein level involved in blood clotting. This is also known as an episode of bleeding or protracted bleeding.
The severity of hemophilia B is determined by the factor IX activity level, which can be low, moderate, or severe. In less severe situations, bleeding symptoms might not appear until after an injury, surgery, or dental procedure. In certain moderate to severe cases, bleeding symptoms might happen spontaneously—without a known reason—or in response to a minor injury.
Changes (variants or mutations) in the factor IX gene (F9) on the X chromosome result in hemophilia B. Males are more frequently found to have hemophilia B; however, female carriers of the gene may experience milder or, in rare cases, more severe bleeding symptoms and should have their factor IX level evaluated.
Children's Health - Pediatrics (Ages 12 to under 18):
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Based on the data submitted and examined by Health Canada, Concizumab's effectiveness and safety in teenage patients between the ages of 12.
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It has been determined that the age is under 18; hence, Health Canada has approved the use for adolescents aged 12 to under 18.
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Patients younger than 12 years old have yet to experience the safety and effectiveness of Concizumab.
Elderly - Geriatrics (Over 65 Years):
More participants should have been included in clinical trials of patients 65 years of age and above to ascertain whether Concizumab's overall risk-benefit profile is advantageous for these patients.
What Are the Contraindications of Concizumab Injection?
There are two contraindications. Patients hypersensitive to this medication or its ingredients should not use Concizumab, the mixture, including any component of the container or non-medicinal substance.
Missed Dosage
It is unnecessary to provide an additional dose or raise the amount the following day to make up for a missed dose. Return to the once-daily schedule as directed.
Overdosage:
Experience with Concizumab injection overdose is scarce.
To report a suspected drug overdose, get in touch with your local poison control center.
In addition, patients who unintentionally overdose should call their doctor right away and be closely watched.
For Doctors:
Clinical Pharmacology
Mechanism Of Actions:
Concizumab is an antibody that binds to the Kunitz-2 domain of tissue factor pathway inhibitor (TFPI) and inhibits TFPI from binding to activated Factor X (FXa). Concizumab's decreased TFPI activity enables FXa, which is generated by the activated coagulation Factor VII (FVIIa)/tissue factor (TF) complex, to boost thrombin generation and subsequent clot formation. This helps hemophilia patients achieve hemostasis.
Pharmacodynamics:
For patients receiving Concizumab prophylaxis, the geometric mean (CV %) of free TFPI (plasma TFPI not bound to Concizumab) dropped from 20 percent at baseline to 10.7 (105 percent) ng/mL at week 24. In contrast, the mean thrombin peak increased to within the normal plasma range in study NN7415-4311.
Pharmacokinetics:
According to AUC and Cmax measurements, Concizumab showed non-linear pharmacokinetics when exposed systemically, rising more than in a dose-proportionate way. Target-mediated drug disposal (TMDD), which happens when Concizumab binds to endothelial cell-anchored TFPI and the drug-target complex is subsequently eliminated, is the source of this nonlinear pharmacokinetic behavior. Patients with hemophilia A and B had similar levels of Concizumab exposure.
Absorption:
In both healthy individuals and patients with hemophilia, a single-dose subcutaneous injection of Concizumab at a dose of 0.05 to 3 mg/kg (milligram per kilogram) resulted in a time to maximum plasma concentration (tmax) of between 8 to 99 hours (4.1 days). Using population pharmacokinetic modeling, the bioavailability of Concizumab following subcutaneous dosing was calculated to be 77.7 percent.
Distribution:
The model estimates the steady-state volume of distribution for a typical subject to be 5.92 L (liter).
Metabolism:
No research has been done on concizumab's metabolism. Lysosomal proteolysis mostly catabolizes IgG antibodies, which are subsequently removed or recycled by the body.
Elimination:
Concizumab is removed through both linear and non-linear routes. Because of the non-linear elimination, the half-life depends on the concentration of the drug. When hemophilia patients and healthy individuals were given a single subcutaneous dose of 0.25 to 3 mg/kg, the terminal half-life ranged from 39 hours (1.6 days) to 195 hours (8.1 days).
According to a population PK analysis, the linear clearance after several subcutaneous injections was roughly 0.192 L/day (0.008 L/h), and the estimated half-life at steady-state Ctrough (665 ng/mL) was about 38 hours.
Suggested Dose and Adjustment for Dosage
The suggested Concizumab injection dosage is as follows:
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On Day 1, a one mg/kg loading dose is administered once.
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Dosing once daily at 0.20 mg/kg until Day 2 and until the individual maintenance dose setting.
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Four weeks after the start of therapy, Concizumab pre-dose plasma concentration is measured using a validated enzyme-linked immunoassay (ELISA).
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The individual maintenance dose will be provided after the Concizumab plasma concentration result for week four is available.
If the treatment is momentarily stopped, the patient can resume Concizumab injection
treatment with the same maintenance dose without taking a fresh loading dose.
Geriatrics (Over 65 Years)
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No dose modifications are advised for patients 65 or older except the personalized maintenance dose setting.
Pediatrics (Children Under 12)
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It is still being determined if Concizumab injection is safe and effective for use in children under the age of twelve.
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Individuals who are hepatic and renal insufficient.
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Patients with hepatic and renal impairment do not require dosage changes (other than an individual maintenance dose setting.
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Individuals with significant hepatic impairment (AST or ALT greater than 3x ULN combined with total bilirubin greater than 1.5x ULN) and severe renal impairment (eGFR ≤ 30 mL/min/1.73 m2) were excluded from the clinical trial.
Advice for Using the Most Innovative Bleed Treatment:
In the event of breakthrough bleeding, the Concizumab injection dosage should not be changed. To reduce the risk of thromboembolic events for mild and moderate bleeding, health professionals should talk with all patients and caregivers about the dosage and timing of bypassing agents to use, if necessary, while receiving Concizumab injection Prophylaxis. The dosage schedule listed on the authorized label for the particular medication may need to be followed in cases of severe bleeding; however, this should only be done after careful consideration of clinical judgment and the risk of potentially fatal thromboembolic events.
In the Perioperative Context:
In the perioperative context, management, or minor procedures, there is no need to modify the dosage of Concizumab injection. Consult a medical expert with experience treating hemophilia and bleeding problems before undergoing major surgery. Given the patient's overall clinical picture, it is generally advised to cease Concizumab injection before significant surgery and restart 10 to 14 days after the procedure, as there is no clinical experience with its usage during large surgeries due to its prohibition in clinical trial protocols. Without needing a fresh loading dose, the patient can resume Concizumab injection therapy on the same maintenance dose.
Administration:
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Subcutaneously inject Concizumab into the thigh or belly, rotating the injection location each day. Subcutaneous injections shouldn't be administered where there are moles, scars, stretch marks, or irritated, bruised, red, or hard skin.
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With every injection, use a fresh needle.
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Concizumab injection is a colorless to slightly yellow solution that is transparent to faintly opalescent.
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Translucent protein particles are okay. Do not use a solution that is discolored or contains solid foreign particles.
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Concizumab injection can be taken by the patient or given by a caregiver if the patient has read the usage instructions and received the necessary training from a healthcare professional.
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A single patient may use each prefilled Concizumab injection pen. Even once the needle is changed, a Concizumab injection pen should never be shared between patients.
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It is advised to inject into a loosely-held skin fold in lean and younger patients, as intramuscular injections should be avoided and may happen unintentionally in these cases.
What Are the Drug Interactions When Concizumab Injection?
The research was done to determine if any synergistic or additive interactions between Concizumab injection and other hemostatic agents, such as recombinant FVII (rFVIIa), have been activated.
Interactions Between Drugs:
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Ex vivo and in vitro, pharmacodynamic interaction studies revealed the impacts of Concizumab combined with activated prothrombin complex and recombinant FVIIa (rFVIIa).
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rFVIII, rFIX, or concentrates (aPCC) were primarily additive, accounting for a synergistic impact that provided up to 40 percent of the observed effect.
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New safety precautions were implemented after the treatment pause, suggesting the lowest dose of bypassing drugs that can be used to treat mild to moderate breakthrough bleeding for individuals using Concizumab to lower their risk of thromboembolism.
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For significant bleeding, the suggested label dosage could be necessary.
Food and Drug Interactions:
Due to the subcutaneous administration of Concizumab, no documented interactions have been found with meals.
Incompatible Drugs and Herbs:
It is unknown whether herbal products interact with one another.
Drug Interactions With Laboratory Tests:
Studies conducted in vitro revealed no discernible influence from Concizumab on normal prothrombin and activated partial thromboplastin time tests or the use of clot and FVIII or FIX activity measurement.
What Are the Serious Cautions and Warnings With Concizumab Injection?
There have been reports of the following severe side effects linked to the usage of Concizumab:
Thromboembolic Events:
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There have been reports of thromboembolic events in patients receiving Concizumab. Patients should stop receiving preventive therapy with bypassing drugs before starting Concizumab injection.
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Clinical studies have typically excluded individuals who are at high risk of thromboembolic events, and it is important to carefully assess whether the potential benefit of Concizumab treatment justifies the potential risk of thromboembolic complications in these patients.
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The lowest effective dose of these hemostatic medicines should be given to patients who need further therapy with bypassing agents for mild or moderate breakthrough bleeding.
Dosage Recommendations
• A medical expert with experience treating hemophilia and bleeding disorders should oversee the start of treatment.
• Patients should stop receiving preventive treatment with bypassing drugs before starting Concizumab injection.
• The patient should not be bleeding when the treatment is started. It is recommended that rFVIIa treatment be stopped at least 12 hours before starting Concizumab injection and that a PCC medication be stopped at least 48 hours before beginning Concizumab injection.
• Concizumab injections are meant to be administered by the patient themselves or, with appropriate training from a medical practitioner, by a caregiver (such as a parent). A person who has received the necessary training should administer the medication.
• It is advised to inject into a loosely-held skin fold in lean and younger patients, as intramuscular injections should be avoided and may happen unintentionally in these cases.
