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  • CLASSES

    Sickle Cell Disease Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous selectin blocker
    Used to reduce the frequency of vasoocclusive crises in patients with sickle cell disease
    Monitor for infusion-related reactions and interference with automated platelet counts

    COMMON BRAND NAMES

    ADAKVEO

    HOW SUPPLIED

    ADAKVEO Intravenous Inj Sol: 10mL, 100mg

    DOSAGE & INDICATIONS

    For the treatment of sickle cell disease, to reduce the frequency of vasoocclusive crises.
    NOTE: Crizanlizumab may be given with or without hydroxyurea.
    Intravenous dosage
    Adults

    5 mg/kg/dose IV infused over 30 minutes at Week 0, Week 2, and every 4 weeks thereafter.

    Adolescents 16 to 17 years

    5 mg/kg/dose IV infused over 30 minutes at Week 0, Week 2, and every 4 weeks thereafter.

    MAXIMUM DOSAGE

    Adults

    5 mg/kg/dose IV.

    Geriatric

    5 mg/kg/dose IV.

    Adolescents

    16 to 17 years: 5 mg/kg/dose IV.
    13 to 15 years: 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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Crizanlizumab is clear to opalescent, colorless, or may have a slightly brownish-yellow tint. Do not use if particles are present in the solution.
    Crizanlizumab should be prepared and administered by a healthcare professional.
    If a dose is missed, administer as soon as possible. If the drug is administered within 2 weeks after the missed dose, continue dosing according to the patient's original schedule. If the drug is administered more than 2 weeks after the missed dose, continue dosing every 4 weeks thereafter.

    Intravenous Administration

    Dilution
    Bring vials to room temperature for a maximum of 4 hours prior to the start of preparation (piercing the first vial).
    Dilute in 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a total volume of 100 mL. The volume of crizanlizumab added to the infusion bag/container should not exceed 96 mL.
    Infusion bags/containers must be made of polyvinyl chloride (PVC), polyethylene (PE), or polypropylene (PP).
    Gently invert the infusion bag/container to mix the dilute solution. Do not shake.
    Administer diluted solution as soon as possible
    Storage: Prepared solution may be stored at room temperature up to 25 degrees C (77 degrees F) for no more than 4.5 hours or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F) for no more than 24 hours from the start of preparation to the completion of the infusion. This includes the storage of diluted solution and the time to warm to room temperature. Protect from light during refrigerated storage. Vials are single-dose; discard unused drug.
     
    Administration
    Infuse over 30 minutes through an IV line containing a sterile, nonpyrogenic 0.2-micron inline filter.
    After administration, flush the line with at least 25 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
    No incompatibilities have been observed with infusion sets composed of PVC, PE-lined PVC, polyurethane (PU), and in-line filter membranes composed of polyethersulfone (PES, neutral and positively charged), positively charged polyamide (PA), and polysulphone (PSU).
    Do not mix or coadminister with other drugs through the same IV line.

    STORAGE

    ADAKVEO:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Laboratory test interference

    Laboratory test interference with automated platelet counts (platelet clumping) has been observed after administration of crizanlizumab, particularly when blood samples were collected in tubes containing ethylenediaminetetraacetic acid (EDTA). This may lead to unevaluable or falsely decreased platelet counts. Run blood samples within 4 hours of blood collection or collect blood samples in tubes containing citrate. Estimate platelet count via peripheral blood smear when needed.

    Pregnancy

    Crizanlizumab crosses the placental barrier and has the potential to cause fetal harm when administered during human pregnancy. Advise pregnant women of the potential risk to the fetus. Use crizanlizumab during pregnancy only if the expected benefit to the patient justifies the potential risk to the fetus. There are insufficient human data on crizanlizumab use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, administration to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increase in fetal loss (abortions/stillbirths) at doses approximately 2.8 times the human clinical exposure. No maternal toxicity was observed and there were no effects on infant growth and development through 6-months postpartum that were attributable to crizanlizumab. Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for both the mother and fetus. Pregnant women are at greater risk for vasoocclusive crisis, preeclampsia, eclampsia, and maternal mortality. Fetal complications include an increased risk of intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality.

    Breast-feeding

    There is no data on the presence of crizanlizumab in human or animal milk, the effects on the breast-fed child, or the effects on milk production. Maternal IgG is present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure to crizanlizumab in the breast-fed child are unknown. Consider the benefits of breast-feeding, the risk of potential 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, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Moderate

    chest pain (unspecified) / Early / 0-10.0
    infusion-related reactions / Rapid / 3.0-3.0
    antibody formation / Delayed / Incidence not known

    Mild

    arthralgia / Delayed / 18.0-18.0
    nausea / Early / 18.0-18.0
    back pain / Delayed / 15.0-15.0
    fever / Early / 11.0-11.0
    abdominal pain / Early / 0-10.0
    vomiting / Early / 0-10.0
    myalgia / Early / 0-10.0
    pruritus / Rapid / 0-10.0
    diarrhea / Early / 0-10.0

    DRUG INTERACTIONS

    There are no drug interactions associated with Crizanlizumab products.

    PREGNANCY AND LACTATION

    Pregnancy

    Crizanlizumab crosses the placental barrier and has the potential to cause fetal harm when administered during human pregnancy. Advise pregnant women of the potential risk to the fetus. Use crizanlizumab during pregnancy only if the expected benefit to the patient justifies the potential risk to the fetus. There are insufficient human data on crizanlizumab use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, administration to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increase in fetal loss (abortions/stillbirths) at doses approximately 2.8 times the human clinical exposure. No maternal toxicity was observed and there were no effects on infant growth and development through 6-months postpartum that were attributable to crizanlizumab. Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for both the mother and fetus. Pregnant women are at greater risk for vasoocclusive crisis, preeclampsia, eclampsia, and maternal mortality. Fetal complications include an increased risk of intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality.

    There is no data on the presence of crizanlizumab in human or animal milk, the effects on the breast-fed child, or the effects on milk production. Maternal IgG is present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure to crizanlizumab in the breast-fed child are unknown. Consider the benefits of breast-feeding, the risk of potential 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, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Crizanlizumab, a humanized IgG2 kappa monoclonal antibody, inhibits adhesion of sickled red blood cells by binding to P-selectin and preventing interaction with P-selectin glycoprotein ligand 1. Binding P-selectin on the surface of activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes.

    PHARMACOKINETICS

    Crizanlizumab is administered intravenously. Mean Vd is 4.26 L after a single dose. Crizanlizumab is expected to be metabolized into small peptides by catabolic pathways. Mean clearance and elimination half-life is 11.7 mL/hour and 10.6 days, respectively, in healthy subjects. Mean elimination half-life in patients with sickle cell disease is 7.6 days.
     
    Crizanlizumab inhibits P-selectin in a dose-dependent fashion.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Intravenous Route

    Mean Cmax, AUClast, and AUCinfinity were 0.16 mg/mL, 33.6 mg/mL x hour, and 34.6 mg/mL x hour, respectively, in healthy volunteers during pharmacokinetic trials. These parameters increased disproportionally over the dosage range of 0.2 to 8 mg/kg (0.04 to 1.6 times the recommended dosage) in healthy volunteers.