Concizumab (Monograph)

Brand name: Alhemo
Drug class: Hemostatics

Introduction

Concizumab-mtci is a tissue factor pathway inhibitor (TFPI) antagonist.

Uses for Concizumab

Concizumab-mtci has the following uses:

Concizumab-mtci is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia A (congenital factor VIII deficiency) with FVIII inhibitors.

Concizumab-mtci is also indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia B (congenital factor IX deficiency) with FIX inhibitors.

Concizumab Dosage and Administration

General

Concizumab-mtci is available in the following dosage form(s) and strength(s):

60 mg/1.5 mL (40 mg/mL) in a single-patient-use prefilled injection pen for subcutaneous administration.
150 mg/1.5 mL (100 mg/mL) in a single-patient-use prefilled injection pen for subcutaneous administration.
300 mg/3 mL (100 mg/mL) in a single-patient-use prefilled injection pen for subcutaneous administration.

Dosage

Adults and Pediatric Patients 12 Years of Age and Older

Administer concizumab-mtci once daily by subcutaneous injection to the abdomen or thigh with daily rotation of injection sites.
Concizumab-mtci is Intended for use under the guidance of a healthcare provider but may be self-administered or administered by a caregiver after appropriate training is provided. Treatment should be initiated in a non-bleeding state.
Recommended dosing regimen is as follows:
Day 1: Loading dose of 1 mg/kg.
Day 2: Once-daily dose of 0.2 mg/kg until individualization of maintenance dose (see below).
4 weeks after initiation of treatment: For dose optimization, measure concizumab-mtci plasma concentration by Concizumab Enzyme-Linked Immunosorbent Assay (ELISA) prior to administration of next scheduled dose. An FDA-authorized test for the measurement of concizumab-mtci concentration in plasma is not currently available.
Once the concizumab-mtci concentration result is available, individualize the maintenance dose of concizumab-mtci no later than 8 weeks after initiation of treatment, based on the following concizumab plasma concentrations.
Less than 200 ng/mL: adjust to a once-daily dose of 0.25 mg/kg.
200 to 4000 ng/mL: continue once-daily dose of 0.2 mg/kg.
Greater than 4000 ng/mL: adjust to a once-daily dose of 0.15 mg/kg.
Maintenance of concizumab plasma concentration above 200 ng/mL is important to decrease the risk of bleeding episodes.
Adherence to daily dosing of concizumab-mtci is important to maintain protection against bleeding.
See Full Prescribing Information for additional information on preparation and administration.

Cautions for Concizumab

Contraindications

Concizumab-mtci is contraindicated in patients with a history of known serious hypersensitivity to concizumab-mtci or its components or the inactive ingredients.

Warnings/Precautions

Thromboembolic Events

Venous and arterial thromboembolic events were reported in 1.3% of patients (4/320) in concizumab-mtci clinical trials. These cases occurred in patients with multiple risk factors for thromboembolism, including the use of high doses or prolonged treatment with factor product or bypassing agent (2 of 4 events). Risk factors for thromboembolism may include the use of high and/or frequent doses of breakthrough bleed treatments (factor products or bypassing agents) or conditions in which tissue factor is overexpressed (e.g., atherosclerotic disease, crush injury, cancer, disseminated intravascular coagulation, thrombotic microangiopathy, or septicemia). Inform concizumab treated patients of signs and symptoms of thromboembolic events. Monitor patients for thromboembolic events. In case of suspicion of thromboembolic events, discontinue concizumab and initiate further investigations and management strategies.

Hypersensitivity Reactions

Concizumab-mtci is contraindicated in patients with a history of known serious hypersensitivity to concizumab-mtci or its components or the inactive ingredients. Hypersensitivity reactions including erythema, rash, pruritus, and abdominal pain have occurred in concizumab-mtci treated patients. One patient (less than 1% of patients treated in the clinical studies) experienced anaphylaxis which resolved after treatment with antihistamines and corticosteroids. Instruct patients of the signs of acute hypersensitivity reactions. Instruct patients to contact their healthcare provider for mild reactions and to seek urgent medical attention for moderate to severe reactions. Discontinue concizumab if severe hypersensitivity symptoms occur, and initiate medical management.

Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment 1+2

Increased levels of fibrin D-dimer and increased levels of prothrombin fragment 1.2 were seen in 29 (9.1%) and 18 (5.6%) of patients, respectively. The plasma concentration of concizumab is positively correlated with fibrin D-dimer and prothrombin fragments 1.2 indicating a hemostatic effect of the drug. For patients taking concizumab, these coagulation biomarkers may not be reliable predictive markers for clinical decision-making with suspicion of thrombosis such as deep vein thrombosis (DVT) and pulmonary embolism (PE).

Specific Populations

Pregnancy

Based on its mechanism of action, concizumab may cause fetal harm when administered to a pregnant woman. There are no available data on concizumab-mtci use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with concizumab-mtci. Although there are no data on concizumab-mtci, monoclonal antibodies can be actively transported across the placenta, and concizumab may cause fetal harm. It is unknown whether concizumab can affect reproductive capacity. Concizumab-mtci should only be used during pregnancy if the potential benefit for the mother outweighs the potential risk to the fetus. The estimated background risk of birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Lactation

There is no information regarding the presence of concizumab in either human or animal milk, the effect on the breastfed child, or the effects on milk production. Human IgGs are known to be excreted in breast milk during the first few days after birth, decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, concizumab could be used during breast-feeding if clinically needed.

Females and Males of Reproductive Potential

Pregnancy testing is recommended for females of reproductive potential. Women of childbearing potential should use a highly effective form of contraception during treatment with concizumab-mtci and for 7 weeks after ending treatment. The benefits and thromboembolic risks of the type of contraceptives used should be evaluated by the treating physician.

Pediatric Use

The safety and effectiveness of concizumab-mtci for hemophilia A and B with inhibitors have been established in pediatric patients 12 years of age and older. Use of concizumab-mtci for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients 12 years of age and older. The safety and effectiveness of concizumab-mtci for hemophilia A and B with inhibitors have not been established in pediatric patients younger than 12 years of age.

Geriatric Use

Clinical studies of concizumab-mtci did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Increased Body Weight

The apparent clearance and volume of distribution of concizumab decreased with increasing body weight. However, patients should receive the approved recommended concizumab-mtci dosage titration and plasma concentration monitoring regardless of body weight.

Common Adverse Effects

The most frequently reported adverse reactions (incidence ≥5%) were injection site reactions and urticaria.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

While treatment with all bypassing agents (e.g., rFVIIa or aPCC) can be used for breakthrough bleeds, high and/or frequent doses of bypassing agents with concizumab increases the risk of thromboembolism.

Actions

Mechanism of Action

Concizumab-mtci is a monoclonal antibody antagonist of endogenous Tissue Factor Pathway Inhibitor (TFPI). Through the inhibition of TFPI, concizumab-mtci acts to enhance FXa production during the initiation phase of coagulation which leads to improved thrombin generation and clot formation with the goal of achieving hemostasis in patients with Hemophilia A or B with inhibitors. The effect of concizumab-mtci is not influenced by the presence of inhibitory antibodies to FVIII or FIX. There is no structural relationship or sequence homology between concizumab-mtci and FVIII or FIX and, as such, treatment with concizumab-mtci does not induce or enhance the development of direct inhibitors to FVIII or FIX.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Inform patients of the signs and symptoms of thromboembolic events, including swelling, warmth, pain, or redness of the skin (and that these could be symptoms of a blood clot in the legs or arms); shortness of breath or severe chest pain (and that these could be symptoms of blood clots in the chest [heart and lungs]); headache, confusion, difficulty with speech or movement, numbness of the face, eye pain or swelling, or vision problems (and that these could be symptoms of a blood clot in the brain or eyes); or sudden pain in the stomach or lumbar area (and that these could be symptoms of blood clots in the gut or kidneys). Advise patients to contact their healthcare provider for mild reactions and to seek urgent medical attention for moderate to severe reactions. In conditions in which tissue factor is overexpressed (e.g., advanced atherosclerotic disease, crush injury, cancer, or septicemia), there may be a risk of thromboembolic events or disseminated intravascular coagulation (DIC) with concizumab-mtci treatment.
Inform patients of the early signs of hypersensitivity reactions, including rash, redness, hives, and itching, facial swelling, tightness of the chest, and wheezing as well the signs of an anaphylactic reaction such as itching on large areas of skin; redness and/or swelling of lips, tongue, face, or hands; difficulty swallowing; shortness of breath; wheezing; tightness of the chest; pale and cold skin; fast heartbeat; or dizziness/low blood pressure. Advise patients to discontinue use of concizumab-mtci immediately and contact their healthcare provider if any signs or symptoms occur.
Advise patients on the importance of adherence to daily dosing and to speak with their healthcare provider before discontinuing treatment with concizumab-mtci as patients who are not adhering to daily dosing or stop treatment with concizumab-mtci may no longer be protected against bleeding.
Advise patients to follow the recommendations regarding proper sharps disposal provided in the FDA-approved Instructions for Use.

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Concizumab-mtci
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for subcutaneous use	60 mg/1.5 mL (40 mg/mL)	Alhemo (available in a single-patient-use prefilled pen)	Novo Nordisk
	Injection	150 mg/1.5 mL (100 mg/mL)	Alhemo (available in a single-patient-use prefilled pen)	Novo Nordisk
	Injection	300 mg/3 mL (100 mg/mL)	Alhemo (available in a single-patient-use prefilled pen)	Novo Nordisk