epcoritamab (Rx)

>10%

All grades

• Lymphocyte count decreased (87%)
• Hemoglobin decreased (62%)
• Sodium decreased (56%)
• Phosphate decreased (56%)
• White blood cell count decreased (53%)
• Cytokine release syndrome (51%)
• Neutrophil count decreased (50%)
• Platelet count decreased (48%)
• AST increased (48%)
• ALT increased (45%)
• Potassium decreased (34%)
• Magnesium decreased (31%)
• Fatigue (29%)
• Musculoskeletal pain (28%)
• Injection site reactions (27%)
• Pyrexia (24%)
• Creatinine increased (24%)
• Abdominal pain (23%)
• Potassium increased (21%)
• Diarrhea (20%)
• Nausea (20%)
• Rash (15%)
• Edema (14%)
• Headache (13%)
• Decreased appetite (12%)
• Vomiting (12%)

Grade 3 or 4

• Lymphocyte count decreased (77%)
• Neutrophil count decreased (32%)
• White blood cell count decreased (22%)
• Platelet count decreased (12%)
• Hemoglobin decreased (12%)

1-10%

All grades

• Cardiac arrhythmias (10%)
• Grade 3 or 4 H4
• ALT increased (5.3%)
• Potassium decreased (5.3%)
• AST increased (4.6%)
• Creatinine increased (3.3%)
• Sodium decreased (2.6%)
• Cytokine release syndrome (2.5%)
• Fatigue (2.5%)
• Edema (1.9%)
• Abdominal pain (1.9%)
• Nausea (1.3%)
• Musculoskeletal pain (1.3%)
• Potassium increased (1.3%)

<1%

Grade 3 or 4

• Vomiting (0.6%)
• Rash (0.6%)
• Headache (0.6%)
• Decreased appetite (0.6%)
• Cardiac arrhythmias (0.6%)

Contraindications

None

Cautions

Serious or severe cytopenias, including neutropenia, anemia, and thrombocytopenia reported; based on the severity of cytopenias, temporarily withhold or permanently discontinue therapy; consider prophylactic granulocyte colony-stimulating factor administration as applicable

Based on its mechanism of action, fetal harm may occur when administered to pregnant females

Cytokine release syndrome

• Can cause CRS, including serious or life-threatening reactions
• Signs and symptoms include pyrexia, hypotension, hypoxia, dyspnea, chills, and tachycardia
• Concurrent neurologic adverse reactions associated with CRS include headache, confusional state, tremors, dizziness, and ataxia
• Initiate therapy according to step-up dosing schedule
• Administer premedications to reduce the risk of CRS and monitor for potential CRS following dose
• Following administration of first 48 mg dose, hospitalize patient for 24 hr
• At first signs or symptoms of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care as appropriate
• Withhold or discontinue therapy based on the severity of CRS

ICANS

• May cause life-threatening and fatal ICANS
• Clinical manifestations include confusional state, lethargy, tremor, dysgraphia, aphasia, and nonconvulsive status epilepticus
• Onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS
• Monitor for potential ICANS following administration
• At first signs or symptoms of ICANS, immediately evaluate patient and provide supportive therapy based on severity
• Withhold or discontinue therapy per recommendations and consider further management per current practice guidelines
• Advise patients of increased risk, and to refrain from driving and from operating heavy or potentially dangerous machinery until resolution

Infections

• Serious and fatal infections reported; monitor for signs and symptoms of infection before and during treatment and treat appropriately; avoid administration in patients with active infections
• Provide Pneumocystis jirovecii pneumonia (PJP) and herpes virus prophylaxis before initiating

Drug interaction overview

• For certain cytochrome P450 (CYP) substrates, minimal changes in concentration may lead to serious adverse reactions
• Monitor for toxicity or drug concentrations of such CYP substrates when co-administered
• Epcoritamab causes release of cytokines that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates
• Increased exposure of CYP substrates is more likely to occur after first dose (Cycle 1 Day 1) and up to 14 days after first 48-mg dose on Cycle 1 Day 15, and during and after CRS

Pregnancy

Based on mechanism of action, epcoritamab fetal harm when administered to pregnant females

There are no available data on use in pregnant females to evaluate for a drug-associated risk

No animal reproductive or developmental toxicity studies have been conducted with epcoritamab

Epcoritamab causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance; based on expression of CD20 on B-cells and finding of B-cell depletion in nonpregnant animals, epcoritamab can cause B-cell lymphocytopenia in infants exposed to epcoritamab in utero

Human immunoglobulin G (IgG) is known to cross the placenta; therefore, epcoritamab has may be transmitted from mother to developing fetus. Advise women of the potential

Verify pregnancy status in females of reproductive potential before initiating

Contraception

• Advise females of reproductive potential to use effective contraception during treatment and for 4 months after last dose

Lactation

There is no information regarding presence of epcoritamab in human milk, effect on breastfed children, or milk production

Advise females not to breastfeed during treatment and for 4 months after last dose

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

IgG1-bispecific antibody designed to simultaneously bind to CD3 on T-cells and CD20 on B-cells, and induce T-cell mediated lysis of CD20+ cells

CD20 is expressed on B-cells and is a clinically validated therapeutic target in many B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia

Absorption

Trough plasma concentration

• First full 48-mg dose: 1.7 mcg/mL
• End of weekly dosing (end of Cycle 3): 8.4 mcg/mL
• End of every 2-week dosing (end of Cycle 9): 4.1 mcg/mL
• Steady state with every 4-week dosing: 1.2 mcg/mL

Peak plasma concentration

• First full 48-mg dose: 2.2 mcg/mL
• End of weekly dosing (end of Cycle 3): 10.8 mcg/mL
• End of every 2-week dosing (end of Cycle 9): 7.5 mcg/mL
• Steady state with every 4-week dosing: 4.8 mcg/mL

Peak plasma time

• First full 48-mg dose: 4 days
• End of the weekly dosing regimen (end of Cycle 3): 2.3 days

Distribution

• Vd=25.6 L

Metabolism

• Expected to be metabolized into small peptides by catabolic pathways

Elimination

Clearance: 0.53 L/day (after end of Cycle 3)

Half-life: 22 days (first full 48-mg dose)

SC Preparation

0.16 mg-Dose

• Retrieve one 4 mg/0.8 mL vial from refrigerator
• Allow vial to come to room temperature for ≤1 hour
• Gently swirl vial; DO NOT invert, vortex, or vigorously shake vial

• First dilution

  • Label an appropriately sized empty vial as “Dilution A”
  • Transfer 0.8 mL of epcoritamab into Dilution A vial
  • Transfer 4.2 mL of 0.9% NaCl into Dilution A vial; initial diluted solution contains 0.8 mg/mL of epcoritamab
  • Gently swirl Dilution A vial for 30-45 seconds

• Second dilution

  • Label an appropriately sized empty vial as “Dilution B”
  • Transfer 2 mL of solution from Dilution A vial into Dilution B vial; Dilution A vial is no longer needed
  • Transfer 8 mL of 0.9% NaCl into the Dilution B vial; final concentration of 0.16 mg/mL
  • Gently swirl the Dilution B vial for 30-45 seconds
  • Withdraw 1 mL of the diluted from Dilution B vial into a syringe
  • Label syringe 0.16 mg and the time of day
  • Discard vial containing unused drug

0.8 mg-Dose

• Retrieve one 4 mg/0.8 mL vial from refrigerator
• Allow vial to come to room temperature for ≤1 hour
• Gently swirl vial; DO NOT invert, vortex, or vigorously shake vial

• First dilution

  • Label an appropriately sized empty vial as “Dilution A”
  • Transfer 0.8 mL of epcoritamab into Dilution A vial
  • Transfer 4.2 mL of 0.9% NaCl into Dilution A vial; initial diluted solution contains 0.8 mg/mL of epcoritamab
  • Gently swirl Dilution A vial for 30-45 seconds
  • Withdraw 1 mL of the diluted from Dilution B vial into a syringe
  • Label syringe 0.8 mg and time of day
  • Discard vial containing unused drug

48-mg dose

• No dilution required
• Retrieve one 48 mg/0.8 mL vial from refrigerator
• Allow vial to come to room temperature for ≤1 hour
• Gently swirl vial; DO NOT invert, vortex, or vigorously shake vial
• Withdraw 0.8 mL into syringe
• Label syringe with 48 mg and time of day
• Discard vial containing unused drug

Premedications

Premedicate to reduce CRS risk

Cycle 1 (all patients)

• Administer 30-120 minutes before each weekly administration
• Acetaminophen 650-1,000 mg PO, AND
• Diphenhydramine 50 mg PO/IV or equivalent, AND
• Prednisolone 100 mg PO/IV or dexamethasone 15 mg PO/IV or equivalent; continue for 3 consecutive days following each weekly administration in Cycle 1

Cycle 2 and thereafter (Grade 2 or 3 CRS experienced with previous dose)

• Prednisolone 100 mg PO/IV or dexamethasone 15 mg PO/IV or equivalent
• Administer 30-120 minutes before next administration after a Grade 2 or 3 CRS event, and for 3 consecutive days following next administration until dose is given without subsequent CRS of Grade ≥2
• Note: Permanently discontinue for Grade 4 CRS

Prophylaxis

• Provide Pneumocystis jirovecii pneumonia (PJP) prophylaxis before starting treatment
• Consider initiating prophylaxis against herpes virus before initiating to prevent herpes zoster reactivation

SC Administration

Inject required drug volume in SC tissue of lower part of the abdomen (preferred injection site) or thigh

Change injection site from left or right side or vice versa recommended, especially during weekly administrations (Cycles 1-3)

Do not inject into tattoos, scars, or areas where skin is red, bruised, tender, hard, or not intact

Dose delay (based on last dose administered)

• Premedicate before each dose and monitor patients accordingly

• 0.16 mg on Cycle 1 Day 1 and >8 days elapsed

  • Repeat 0.16 mg, THEN
  • Administer 0.8 mg the following week, followed by 48 mg weekly x 2, THEN
  • Resume planned dosage schedule beginning with Day 1 of subsequent cycle

• 0.8 mg on Cycle 1 Day 8 and ≤14 days elapsed

  • Administer 48 mg, THEN
  • Resume recommended dosage schedule

• 0.8 mg on Cycle 1 Day 8 and >14 days elapsed

  • Repeat 0.16 mg, THEN
  • Administer 0.8 mg the following week, followed by 48 mg weekly x 2, THEN
  • Resume planned dosage schedule beginning with Day 1 of subsequent cycle

• 48 mg on Cycle 1 Day 15 onwards and ≤6 weeks elapsed

  • Administer 48 mg, THEN
  • Resume recommended dosage schedule

• 48 mg on Cycle 1 Day 15 onwards and >6 weeks

  • Repeat 0.16 mg, THEN
  • Administer 0.8 mg the following week, followed by 48 mg weekly x 2, THEN
  • Resume planned dosage schedule beginning with Day 1 of subsequent cycle

Storage

Unopened vials

• Refrigerate at 2-8ºC (36-46ºF)
• Keep in original carton to protect from light
• Do not freeze
• Do not shake

Diluted solution

• Use immediately
• If not used immediately, refrigerate at 2-8ºC (36-46ºF) for up to 24 hours or at room temperature at 20-25°C (68-77°F) for up to 12 hours
• Total storage time from the start of dose preparation to administration should not exceed 24 hours
• Protect from direct sunlight
• Allow solution to equilibrate to room temperature for no more than 1 hour before administration
• Discard unused solution beyond the allowable storage time