crizanlizumab (Rx)

>10%

Nausea (18%)

Arthralgia (18%)

Back pain (15%)

Pyrexia (11%)

<10%

Oropharyngeal pain

Abdominal pain (abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort, and abdominal tenderness)

Diarrhea

Vomiting

Pruritus (pruritus and vulvovaginal pruritus)

Musculoskeletal chest pain

Myalgia

Infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling)

Infusion-related reaction

Postmarketing Reports

Pain (in various locations) occurring during/within 24 hr of infusion (eg, potential infusion-related reactions)

Contraindications

None

Cautions

Infusion-related reactions

• Infusion-related reactions (defined as occurring within 24 hr of infusion) were observed
• In the postmarketing setting, cases of infusion-related reactions, including severe pain events, reported, which required hospitalizations; the majority of these infusion-related reactions reported during first and second infusions
• The management of pain events has included acetaminophen, NSAIDs, opioids, antihistamines, intravenous fluids, and/or oxygen therapy
• Some patients have also experienced subsequent complications, such as acute chest syndrome and fat embolism, particularly those treated with steroids
• Monitor for and advise patients of signs and symptoms of infusion-related reactions, which may include pain in various locations, headache, fever, chills, nausea, vomiting, diarrhea, fatigue, dizziness, pruritus, urticaria, sweating, shortness of breath, or wheezing
• Discontinue infusion for severe infusion-related reactions and institute appropriate medical care
• Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (eg, treatment of anaphylaxis)

Drug interaction overview

• Interference with automated platelet counts (platelet clumping) has been observed following administration, in particular when blood samples were collected in tubes containing ethylenediaminetetraacetic acid (EDTA); mitigation strategies are recommended

Pregnancy

Based on data from animal studies, fetal harm may occur when administered to a pregnant woman

There are insufficient human data on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Advise pregnant women of the potential risk to a fetus

Only use during pregnancy if expected benefit justifies the potential risk to the fetus

Animal data

• In an animal reproduction study, IV administration of crizanlizumab-tmca to pregnant cynomolgus monkeys from onset of organogenesis through delivery resulted in a non-dose-related increased fetal loss (abortions/stillbirths) at doses ~2.8 times the exposure at the recommended clinical dose at 5 mg/kg/dose once q4Weeks

Disease-associated maternal and/or embryofetal risk

• Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for the mother and the fetus
• Pregnant women are at greater risk for vasoocclusive crises, preeclampsia, eclampsia, and maternal mortality
• For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality

Lactation

There are no data on the presence of crizanlizumab-tmca in human or animal milk, the effects on the breastfed child, or the effects on milk production

Maternal IgG is known to be present in human milk

Effects of local gastrointestinal exposure and

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

A humanized IgG2 kappa monoclonal antibody binds to P-selectin and blocks interactions with its ligands, including P-selectin glycoprotein ligand 1

Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes

Absorption

Peak plasma concentration: 0.16 mg/mL

AUC(inf): 34.6 mg⋅hr/mL

Distribution

Vd: 4.26 L (single 5-mg/kg dose)

Metabolism

Metabolized into small peptides by catabolic pathways

Elimination

Half-life: 10.6 days

Clearance: 11.7 mL/hr

IV Incompatibilities

Do not mix or coadminister with other drugs through the same IV line

IV Compatibilities

0.9% NaCl

Dextrose 5% (D5W)

IV Preparation

Bring vials to room temperature

Visually inspect the vials and parenteral drug products for particulate matter and discoloration before administration; solution appears clear to opalescent, colorless, or may have a slightly brownish-yellow tint; discard if particles are present

Obtain a 100-mL 0.9% NaCl or dextrose 5% infusion bag/container

Infusion bags/containers must be made of either polyvinyl chloride (PVC), polyethylene (PE), or polypropylene (PP)

Remove a volume from infusion bag/container that is equal to the required drug

Withdraw required drug solution and dilute by adding to the infusion bag/container

Drug volume added to the infusion bag/container should not exceed 96 mL

Gently invert the infusion bag to mix the diluted solution; do not shake

Discard any unused portion

Dilute drug in 0.9% NaCl or dextrose 5% to a total volume of 100 mL

IV Administration

Infuse IV over 30 minutes through a line that must contain a sterile, nonpyrogenic 0.2-micron inline filter

No incompatibilities have been observed with infusion sets composed of PVC, polyethylene (PE-lined PVC), polyurethane (PU), and inline filter membranes composed of polyethersulfone (PES, neutral and positively charged), positively charged polyamide (PA), and polysulphone (PSU)

After administration, flush line with at least 25 mL of 0.9% NaCl or dextrose 5%

Dispose of any unused product or waste material in accordance with local requirements

May be given with or without hydroxyurea

Missed dose

• If missed dose, administer as soon as possible
• If dose is administered within 2 weeks after missed dose, continue dosing according to the patient's original schedule
• If dose is administered >2 weeks after missed dose, continue dosing q4Weeks thereafter

Storage

Unused vials: Refrigerate at 2-8ºC (36-46ºF) in the original carton to protect from light; do not shake; do not freeze

Diluted solutions

• Administer diluted solution as soon as possible

• If not administered immediately

  • Store at room temperature up to 25ºC (77ºF) for no more than 4.5 hr from start of preparation (piercing the first vial) to completion of infusion OR
  • Refrigerate at 2-8ºC (36-46ºF) for no more than 24 hr, from the start of the time of the preparation (piercing the first vial) to the completion of infusion; this includes storage of diluted solution and the time to warm up to room temperature
  • Protect from light during storage under refrigeration