Dosage modifications & management
guidance for EPKINLY1

Dosage modifications and management for CRS, ICANS, and Other Adverse Reactions

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypotension, and hypoxia. If CRS is suspected, withhold EPKINLY until CRS resolves. Manage according to the recommendations in the CRS table below and consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS.

 

Monitor patients for signs and symptoms of ICANS. At the first sign of ICANS withhold EPKINLY and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for ICANS. Manage ICANS according to the recommendations in the ICANS table below and consider further management per current practice guidelines.

 

See below for recommended actions for other adverse reactions following administration of EPKINLY.

CRS CRS
ICANS ICANS
CRS grade* Presenting symptoms Actions

Grade 1

Temperature ≥100.4°F (38°C)†
  • Withhold EPKINLY and manage per current practice guidelines
  • Ensure CRS symptoms are resolved prior to next dose of
    EPKINLY‡

Grade 2

Temperature ≥100.4°F (38°C)† with:

  • Hypotension not requiring vasopressors

and/or

  • Hypoxia requiring low-flow oxygen§ by nasal cannula or blow-by
  • Withhold EPKINLY and manage per current practice guidelines
  • Ensure CRS symptoms are resolved prior to next dose of
    EPKINLY‡
  • Administer premedication prior to next dose of EPKINLY
  • For the next dose of EPKINLY, monitor more frequently and consider hospitalization

Grade 3

Temperature ≥100.4°F (38°C)† with:

  • Hypotension requiring a vasopressor (with or without vasopressin)

and/or

  • Hypoxia requiring high-flow oxygen§ by nasal cannula, face mask, non-rebreather mask, or Venturi mask
  • Withhold EPKINLY and manage per current practice guidelines, which may include intensive care
  • Ensure CRS symptoms are resolved prior to the next dose of EPKINLY††
  • Administer premedication
    prior to next dose of
    EPKINLY
  • Hospitalize for the next
    dose of EPKINLY

Recurrent grade 3 CRS

  • Permanently discontinue EPKINLY
  • Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care

Grade 4

Temperature ≥100.4°F (38°C)† with:

  • Hypotension requiring multiple vasopressors (excluding vasopressin)

and/or

  • Hypoxia requiring oxygen by positive pressure (eg, CPAP, BiPAP, intubation, and mechanical ventilation)
  • Permanently discontinue EPKINLY
  • Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care

Presenting symptoms:

Temperature ≥100.4°F (38°C)†

Actions

  • Withhold EPKINLY and manage per current practice guidelines
  • Ensure CRS symptoms are resolved prior to next dose of EPKINLY‡
ICANS grade* Presenting symptoms|| Actions

Grade 1

ICE score 7-9# or Depressed level of consciousness**:

  • Awakens spontaneously
  • Withhold EPKINLY until ICANS resolves††
  • Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis

Grade 2

ICE score 3-6# or Depressed level of consciousness**:

  • Awakens to voice
  • Withhold EPKINLY until ICANS resolves††
  • Administer dexamethasone‡‡ 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to grade 1 or less, then taper
  • Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis

Grade 3

ICE score 0-2# or Depressed level of consciousness**:

  • Awakens only to tactile stimulus

or Seizures,** either:

  • Any clinical seizure, focal or generalized, that resolves rapidly, or
  • Non-convulsive seizures on EEG that resolve with intervention

or Raised intercranial pressure:

  • Focal/local edema on neuroimaging**

First occurrence of grade 3
ICANS

  • Withhold EPKINLY until
    ICANS resolves††
  • Administer dexamethasone‡‡
    10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to grade 1 or less, then taper
  • Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis
  • Provide supportive therapy,
    which may include intensive
    care

Recurrent grade 3 ICANS

  • Permanently discontinue
    EPKINLY
  • Administer dexamethasone‡‡
    10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to grade 1 or less, then taper
  • Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis
  • Provide supportive therapy,
    which may include intensive
    care

Grade 4

ICE score 0# or Depressed level of consciousness**:

  • Patient is unarousable or requires vigorous or
    repetitive tactile stimuli to arouse, or
  • Stupor or coma

or Seizures,** either:

  • Life-threatening prolonged seizure (>5 minutes), or
  • Repetitive clinical or electrical seizures without return to baseline in between

or Motor findings**:

  • Deep focal motor weakness, such as
    hemiparesis or paraparesis

or Raised intracranial pressure/cerebral edema,** with signs/symptoms such as:

  • Diffuse cerebral edema on neuroimaging, or
  • Decerebrate or decorticate posturing, or
  • Cranial nerve VI palsy, or
  • Papilledema, or
  • Cushing’s triad
  • Permanently discontinue EPKINLY
  • Administer dexamethasone†† 10 mg intravenously every 6
    hours. Continue dexamethasone use until resolution to grade 1
    or less, then taper
  • Alternatively, consider administration of methylprednisolone
    1000 mg per day intravenously and continue
    methylprednisolone 1000 mg per day intravenously for 2 or
    more days
  • Monitor neurologic symptoms and consider consultation with
    neurologist and other specialists for further evaluation and
    management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis
  • Provide supportive therapy, which may include intensive care

Presenting symptoms||

ICE score 7-9# or Depressed level of consciousness**:

  • Awakens spontaneously

Actions

  • Withhold EPKINLY until ICANS resolves††
  • Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis

Manage CRS and ICANS according to the recommendations in the EPKINLY Dosage Modifications and Management of Adverse Reactions Section 2.6 of the Prescribing Information. Consider further management per current practice guidelines and provide supportive therapy, which may include intensive care.

Dosage modifications and management for Other Adverse Reactions1§§

For infections, grades 1-4

  • Withhold EPKINLY in patients with active infection, until the infection resolves‡
  • For grade 4, consider permanent discontinuation of EPKINLY

For Neutropenia, absolute neutrophil count (ANC) <0.5 x 109/L

  • Withhold EPKINLY until ANC ≥0.5 x 109/L‡

For Thrombocytopenia, platelet count <50 x 109/L

  • Withhold EPKINLY until platelet count ≥50 x 109/L‡

For other adverse reactions, grade 3 or higher

  • Withhold EPKINLY until the toxicity resolves to grade 1 or baseline‡

SELECT IMPORTANT SAFETY INFORMATION

Infections

  • EPKINLY can cause serious and fatal infections.
  • Monitor patients for signs and symptoms of infection prior to and during treatment and treat appropriately. Avoid administration in patients with active infections. Withhold or consider permanent discontinuation of EPKINLY based on severity. Prior to starting EPKINLY, provide Pneumocystis jirovecii pneumonia (PJP) prophylaxis and consider prophylaxis against herpes virus.

Cytopenias

  • EPKINLY can cause serious or severe cytopenias.
  • Monitor complete blood counts throughout treatment. Based on severity of cytopenias, temporarily withhold or permanently discontinue EPKINLY. Consider prophylactic granulocyte colony-stimulating factor administration as applicable.

Adverse Reactions

  • Most common (≥20%) adverse reactions were CRS, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. Most common grade 3 to 4 laboratory abnormalities (≥10%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.

*Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS and ICANS.

†Premedication may mask fever; therefore, if clinical presentation is consistent with CRS, follow these management guidelines.

‡Refer to Table 2 in Section 2.2 of the full Prescribing Information for information on restarting EPKINLY after dose delays.

§Low-flow oxygen defined as oxygen delivered at <6 L/minute; high-flow oxygen defined as oxygen delivered at ≥6 L/minute.

If grade 2 or 3 CRS occurs with the second full dose (48 mg) or beyond, administer CRS premedications with each subsequent dose until an EPKINLY dose is given without subsequent CRS of grade 2 or higher. Refer to Table 3 in Section 2.3 of the full Prescribing Information for additional information on premedication.

||Management is determined by the most severe event, not attributable to any other cause.

#If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital=4 points); Naming (names 3 objects, eg, point to clock, pen, button=3 points); Following Commands (eg, “show me 2 fingers” or “close your eyes and stick out your tongue”=1 point); Writing (ability to write a standard sentence=1 point); and Attention (count backwards from 100 by 10=1 point). If patient is unarousable and unable to perform ICE Assessment (grade 4 ICANS)=0 points.

**Not attributable to any other cause.

††See Table 2 in Section 2.2 of the full Prescribing Information for recommendations on restarting EPKINLY after dose delays.

‡‡All references to dexamethasone administration are dexamethasone or equivalent.

§§Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.

 

BiPAP=bilevel positive airway pressure; CPAP=continuous positive airway pressure; CRS=cytokine release syndrome; ICANS=immune effector cell‑associated neurotoxicity syndrome; ICE=impact, confidence, and ease; IV=intravenous; SC=subcutaneous.

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