Drug Detail:Carvykti (Ciltacabtagene autoleucel)
Generic Name: CILTACABTAGENE AUTOLEUCEL 1000000001
Dosage Form: injection, suspension
Drug Class: Miscellaneous antineoplastics
For autologous use only. For intravenous use only.
Dose
CARVYKTI is provided as a single dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells in one infusion bag.
The recommended dose range is 0.5–1.0×10 6 CAR-positive viable T cells per kg of body weight, with a maximum dose of 1×10 8 CAR-positive viable T cells per single infusion.
Administration
CARVYKTI is for autologous use only. The patient's identity must match the patient identifiers on the CARVYKTI cassette and infusion bag. Do not infuse CARVYKTI if the information on the patient-specific labels does not match the intended patient.
Preparing the Patient for CARVYKTI Infusion
Confirm availability of CARVYKTI prior to starting the lymphodepleting chemotherapy regimen.
Pretreatment
Administer the lymphodepleting chemotherapy regimen: cyclophosphamide 300 mg/m 2 intravenously (IV) and fludarabine 30 mg/m 2 IV daily for 3 days.
See the prescribing information of cyclophosphamide and fludarabine for information on dose adjustment in renal impairment.
Lymphodepleting regimen must be delayed if a patient has serious adverse reactions from preceding bridging therapies (including clinically significant active infection, cardiac toxicity, and pulmonary toxicity) or active graft versus host disease in patient with prior allogeneic stem cell transplant. Consider repeating lymphodepleting regimen if CARVYKTI dosing is delayed by more than 14 days and patient has recovered from toxicity of the first lymphodepleting regimen.
Administer CARVYKTI infusion 2 to 4 days after the completion of the lymphodepleting chemotherapy regimen.
CARVYKTI infusion should be delayed if a patient has any of the following conditions:
- Clinically significant active infection or inflammatory disorders.
- Grade ≥3 non-hematologic toxicities of cyclophosphamide and fludarabine conditioning, except for Grade 3 nausea, vomiting, diarrhea, or constipation. CARVYKTI infusion should be delayed until resolution of these events to Grade ≤1.
Premedication
Administer the following pre-infusion medications to all patients 30 – 60 minutes prior to CARVYKTI infusion:
- Antipyretics (oral or intravenous acetaminophen 650 to 1000 mg).
- Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).
Avoid prophylactic use of systemic corticosteroids, because their use may interfere with the activity of CARVYKTI.
Receipt of CARVYKTI
- All sites approved for infusion will support required storage conditions for vapor phase of liquid nitrogen.
- CARVYKTI is shipped directly to the cell laboratory or clinical pharmacy associated with the infusion center in the vapor phase of a liquid nitrogen shipper.
- Confirm the patient's identity with the patient identifiers on the shipper.
- If the patient is not expected to be ready for same-day administration, before the shipper expires, transfer CARVYKTI to onsite vapor phase of liquid nitrogen storage.
Preparation of CARVYKTI for Infusion
Do not thaw the product until it is ready to be used. Coordinate the timing of CARVYKTI thaw and infusion. Confirm the infusion time in advance and adjust the start time for thaw so that CARVYKTI is available for infusion when the patient is ready. Once thawed, the CARVYKTI infusion must be completed within 2.5 hours at room/ambient temperature (20°C to 25°C).
Prior to thawing the product, confirm that tocilizumab and emergency equipment are available prior to the infusion and during the recovery period.
- Confirm patient identity: Prior to CARVYKTI preparation, match the patient's identity with the patient identifiers on the CARVYKTI cassette. Do not remove the CARVYKTI infusion bag from the cassette if the information on the patient-specific label does not match the intended patient. Contact Janssen Biotech, Inc. at 1-800-526-7736 if there are any discrepancies between the labels and the patient identifiers.
- Once patient identification is confirmed, remove the CARVYKTI product bag from the cassette and check that the patient information on the cassette label matches the patient information on the bag label.
- Inspect the product bag for any breaches of container integrity, such as breaks or cracks before thawing. Do not administer if the bag is compromised, and contact Janssen Biotech, Inc. at 1-800-526-7736.
- Place the infusion bag inside a sealable plastic bag (preferably sterile) prior to thawing.
- Thaw CARVYKTI at 37°C±2°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Total time from start of thaw until completion of thawing should be no more than 15 minutes.
- Remove the infusion bag from the sealable plastic bag and wipe dry. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain, continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not pre-filter into a different container, wash, spin down, or resuspend CARVYKTI in new media prior to infusion.
- Do not re-freeze or refrigerate thawed product.
Administration
- For autologous infusion only.
- Do NOT use a leukocyte-depleting filter.
- Ensure that a minimum of two doses of tocilizumab and emergency equipment are available prior to infusion and during the recovery period.
- Central venous access may be utilized for the infusion of CARVYKTI and is encouraged in patients with poor peripheral access.
- Confirm the patient's identity with the patient identifiers on the infusion bag. Do not infuse CARVYKTI if the information on the patient-specific label does not match the intended patient.
- Prime the tubing of the infusion set with normal saline prior to infusion.
- Once thawed, administer the entire contents of the CARVYKTI bag by intravenous infusion within 2.5 hours using infusion sets fitted with an in-line filter.
- Gently mix the contents of the bag during CARVYKTI infusion to disperse cell clumps.
- After the entire content of the product bag is infused, flush the administration line, inclusive of the in-line filter, with normal saline with a volume equal or greater to the total hold up volume of the primary administration set used inclusive of the drip tube, to ensure that all product is delivered.
CARVYKTI contains human blood cells that are genetically modified with replication-incompetent, self-inactivating, lentiviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal of CARVYKTI to avoid potential transmission of infectious diseases.
Monitoring After Infusion
Administer CARVYKTI at a REMS-certified healthcare facility.
Monitor patients at least daily for 10 days following CARVYKTI infusion at a certified healthcare facility for signs and symptoms of cytokine release syndrome (CRS) and neurologic toxicities. Monitor periodically for 4 weeks for signs and symptoms of delayed neurologic toxicity.
Instruct patients to remain within proximity of a certified healthcare facility for at least 4 weeks following infusion.
Instruct patients to refrain from driving or hazardous activities for at least 8 weeks following infusion.
Management of Severe Adverse Reactions
Cytokine Release Syndrome
Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)] . Evaluate for and treat other causes of fever, hypoxia and hypotension. Consider laboratory testing to monitor for disseminated intravascular coagulation, hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. If CRS is suspected, manage according to the recommendations in Table 1.
Patients who experience CRS should be closely monitored for cardiac and other organ function until resolution of symptoms. Consider anti-seizure prophylaxis with levetiracetam in patients who experience CRS.
Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous telemetry and pulse oximetry.
For severe or life-threatening CRS, consider intensive care unit level monitoring and supportive therapy.
For CRS refractory to first line interventions such as tocilizumab or tocilizumab and corticosteroids, consider alternate treatment options (i.e., higher corticosteroid dose, alternative anti-cytokine agents, e.g., anti-IL1 and/or anti-TNFα, anti-T cell therapies). Refractory CRS is characterized by fevers, end-organ toxicity (e.g., hypoxia, hypotension) not improving within 12 hours of first line interventions or development of HLH/MAS.
If concurrent neurologic toxicity is suspected during CRS, administer:
- Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
- Tocilizumab according to the CRS grade in Table 1
- Anti-seizure medication according to the neurologic toxicity in Table 2
| CRS Grade * | Tocilizumab † | Corticosteroids ‡ |
|---|---|---|
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| Grade 1 | ||
| Temperature ≥38°C § | In patients with:
|
N/A |
| Grade 2 | ||
| Symptoms require and respond to moderate intervention. Temperature ≥38°C § with: Hypotension not requiring vasopressors, and/or, Hypoxia requiring oxygen via canula Þ or blow-by, or, Grade 2 organ toxicity. ¶ |
Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids up to 1 liter or increasing supplemental oxygen. |
Consider dexamethasone 10 mg IV every 12–24 hours. |
| If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg IV every 12 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents. # Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. |
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| Grade 3 | ||
| Symptoms require and respond to aggressive intervention. Temperature ≥38°C § with: Hypotension requiring one vasopressor with or without vasopressin, and/or, Hypoxia requiring oxygen via high-flow nasal canula Þ, facemask, non-rebreather mask, or Venturi mask, or, Grade 3 organ toxicity or Grade 4 transaminitis. |
Per Grade 2 | Administer dexamethasone 10 mg IV every 12 hours. |
| If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg IV every 12 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents. # Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. |
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| Grade 4 | ||
| Life-threatening symptoms. Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD). Temperature ≥38°C § with: Hypotension requiring multiple vasopressors (excluding vasopressin), and/or, Hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation), or, Grade 4 organ toxicity (excluding transaminitis). |
Per Grade 2 | Administer dexamethasone 20 mg IV every 6 hours. |
| After 2 doses of tocilizumab, consider alternative anti-cytokine agents #. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. If no improvement within 24 hours, consider methylprednisolone (1–2 g IV, repeat every 24 hours if needed; taper as clinically indicated) or other immunosuppressants (e.g. other anti-T cell therapies). |
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Neurologic Toxicities
Monitor patients for signs and symptoms of neurologic toxicities (ICANS and other neurologic toxicities) (Table 2). Rule out other causes of neurologic signs or symptoms. Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities. Please see section 5.2 for non ICANS neurologic toxicities. If ICANS is suspected, manage according to the recommendations in Table 2.
If concurrent CRS is suspected during the neurologic toxicity event, administer:
- Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
- Tocilizumab according to CRS grade in Table 1
- Anti-seizure medication according to neurologic toxicity in Table 2
| ICANS Grade * | Corticosteroids | ||
|---|---|---|---|
| Note: ICANS grade and management is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema), not attributable to any other cause. | |||
|
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| Grade 1 ICE score 7–9 † or depressed level of consciousness: awakens spontaneously. |
Consider dexamethasone ‡ 10 mg IV every 12 to 24 hours for 2 to 3 days. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. |
||
| Grade 2 ICE score-3–6 † or depressed level of consciousness: awakens to voice |
Administer dexamethasone ‡ 10 mg IV every 12 hours for 2–3 days, or longer for persistent symptoms. Consider steroid taper if total corticosteroid exposure is greater than 3 days. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. |
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| Grade 3 ICE score-0–2 † (If ICE score is 0, but the patient is arousable (e.g., awake with global aphasia) and able to perform assessment) or depressed level of consciousness: awakens only to tactile stimulus, or seizures, either:
|
Administer dexamethasone ‡ 10 mg-20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate dexamethasone ‡ dose to at least 20 mg IV every 6 hours, OR escalate to high-dose methylprednisolone (1–2 g/day, repeat every 24 hours if needed; taper as clinically indicated) Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1–2 g, repeat every 24 hours if needed; taper as clinically indicated). |
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| Grade 4 ICE score-0 † (Patient is unarousable and unable to perform ICE assessment) or depressed level of consciousness either:
|
Administer dexamethasone ‡ 20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (1–2 g/day, repeated every 24 hours if needed; taper as clinically indicated). Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. If raised ICP/cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1–2 g/day, repeat every 24 hours if needed; taper as clinically indicated), and consider neurology and/or neurosurgery consultation. |
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