Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ciltacabtagene autoleucel. Do not administer ciltacabtagene autoleucel to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Immune effector cell-associated neurotoxicity syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with ciltacabtagene autoleucel, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ciltacabtagene autoleucel. Provide supportive care and/or corticosteroids as needed.
Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with ciltacabtagene autoleucel.
Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with ciltacabtagene autoleucel. HLH/MAS can occur with CRS or neurologic toxicities.
Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with ciltacabtagene autoleucel.
Ciltacabtagene autoleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.
For autologous use only. Confirm patient identity matches cassette and infusion bag prior to infusion.
Note: A treatment course consists of lymphodepleting chemotherapy (with fludarabine and cyclophosphamide) for 3 days, followed by ciltacabtagene autoleucel infusion 2 to 4 days after completion of lymphodepleting chemotherapy. Confirm availability of autologous ciltacabtagene autoleucel prior to initiating lymphodepleting chemotherapy. Confirm that tocilizumab and emergency equipment are available prior to ciltacabtagene autoleucel infusion and during recovery period.
Premedication: Premedicate with acetaminophen 650 to 1,000 mg orally and diphenhydramine 25 to 50 mg IV or orally (or other H1 antihistamine) ~30 to 60 minutes prior to ciltacabtagene autoleucel infusion. Avoid prophylactic dexamethasone or other systemic corticosteroids, as they may interfere with ciltacabtagene autoleucel activity.
Prophylaxis: Administer prophylactic antimicrobials as clinically indicated for up to 6 months (or longer) according to standard institutional guidelines or consistent with post-American Society for Transplantation and Cellular Therapy consensus (Cohen 2022). Consider antiviral therapy to prevent viral reactivation as appropriate.
Multiple myeloma, relapsed or refractory: Target dose: IV: 0.5 to 1 × 106 chimeric antigen receptor (CAR)-positive viable T cells per kg of body weight (Berdeja 2021); maximum dose: 1 × 108 CAR-positive viable T cells per single infusion.
Delay lymphodepleting regimen for unresolved serious adverse events (eg, clinically significant active infection, cardiotoxicity, or pulmonary toxicity) from preceding bridging therapies or active graft-versus-host disease from prior allogeneic stem cell transplant. Delay ciltacabtagene autoleucel for clinically significant active infection or inflammatory disorders or for ≥ grade 3 nonhematologic toxicity due to lymphodepleting chemotherapy (excluding nausea, vomiting, diarrhea, or constipation) until recovered to ≤ grade 1. Consider repeating lymphodepleting regimen if ciltacabtagene autoleucel infusion is delayed by more than 14 days and patient has fully recovered from initial lymphodepleting regimen.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥60 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, mild renal impairment did not impact ciltacabtagene autoleucel pharmacokinetics.
CrCl <60 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Mild impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin ≤1.5 × ULN, or AST > ULN): There are no dosage adjustments provided in the manufacturer's labeling; however, mild impairment did not impact ciltacabtagene autoleucel pharmacokinetics.
Moderate or severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Refer to adult dosing.
Cytokine release syndrome: Monitor for cytokine release syndrome (CRS); if fever, hypoxia, and hypotension occur, evaluate for other causes, and manage as appropriate. If CRS is suspected, manage according to the CRS table at the first sign of CRS. If CRS occurs, monitor closely for cardiac and other organ function abnormalities until resolution of symptoms; consider antiseizure prophylaxis with levetiracetam. Monitor patients with ≥ grade 2 CRS (eg, hypotension unresponsive to fluids or hypoxia requiring supplemental oxygen) with continuous cardiac telemetry and pulse oximetry. Consider intensive care monitoring and supportive therapy for severe or life-threatening CRS.
Consider alternate treatment options (eg, higher corticosteroid dose, alternative anticytokine agents, anti–T-cell therapies) for CRS refractory to first-line interventions (tocilizumab or tocilizumab and corticosteroids). Refractory CRS is characterized by fevers, end-organ toxicity (eg, hypoxia, hypotension) not improving within 12 hours of first-line interventions, or development of hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
If concurrent neurologic toxicity is suspected during CRS, administer more aggressive corticosteroid intervention (based on the CRS and neurotoxicity tables), tocilizumab (according to the CRS table), and antiseizure mediations (according to the neurotoxicity table).
|
CRS grade |
Tocilizumaba |
Corticosteroidsb |
|---|---|---|
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a Also see tocilizumab monograph. | ||
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b If corticosteroids are initiated, continue corticosteroids until ≤ grade 1; taper corticosteroids if exposure is >3 days. | ||
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c Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia (may be masked by antipyretics and/or anticytokine therapy, such as tocilizumab or steroids). The absence of fever does not impact CRS management; CRS management is driven by hypotension and/or hypoxia and by the more severe symptom not attributable to any other cause. | ||
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dLow-flow nasal cannula is ≤6 L/min; high-flow nasal cannula is >6 L/min. | ||
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eFor unresponsive CRS, monoclonal antibodies that target cytokines may be considered (based on institutional practice). | ||
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Grade 1: Temperature ≥38°C (100.4°F)c |
If onset is <72 hours after cell infusion, consider tocilizumab 8 mg/kg (maximum dose: 800 mg) IV over 1 hour. |
– |
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Grade 2: Symptoms require and respond to moderate intervention. Temperature ≥38°C (100.4°F)c with: Hypotension not requiring vasopressors, and/or Hypoxia requiring oxygen via canulad or blow by, or Grade 2 organ toxicity |
Administer tocilizumab 8 mg/kg (maximum dose: 800 mg) IV over 1 hour. Repeat tocilizumab every 8 hours, as needed, if not responsive to IV fluids up to 1 L or increasing supplemental oxygen. |
Consider dexamethasone 10 mg IV every 12 to 24 hours. |
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If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dexamethasone to 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 tocilizumab doses, consider alternative anticytokine agentse. Do not exceed 3 tocilizumab doses per 24 hours, and maximum total of 4 tocilizumab doses. | ||
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Grade 3: Symptoms require and respond to aggressive intervention. Temperature ≥38°C (100.4°F)c with: Hypotension requiring one vasopressor ± vasopressin, and/or Hypoxia requiring oxygen via high-flow nasal canulad, face mask, non-rebreather mask, or Venturi mask, or Grade 3 organ toxicity or grade 4 transaminitis. |
Manage per grade 2. |
Administer dexamethasone 10 mg IV every 12 hours. |
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If no improvement within 24 hours or rapid CRS progression, repeat tocilizumab and escalate dexamethasone to 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 tocilizumab doses, consider alternative anticytokine agentse. Do not exceed 3 tocilizumab doses per 24 hours, and maximum total of 4 tocilizumab doses. | ||
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Grade 4: Life-threatening symptoms. Requires ventilator support, CVVHD. Temperature ≥38°C (100.4°F)c with: Hypotension requiring multiple vasopressor (excluding vasopressin), and/or Hypoxia requiring oxygen positive pressure (eg, CPAP, BiPAP, intubation, and mechanical ventilation), or Grade 4 organ toxicity (excluding transaminitis) |
Manage per grade 2. |
Administer dexamethasone 20 mg IV every 6 hours. |
|
After 2 tocilizumab doses, consider alternative anticytokine agentse. Do not exceed 3 tocilizumab doses per 24 hours, and maximum total of 4 tocilizumab doses. If no improvement within 24 hours, consider methylprednisolone (1 to 2 g IV, repeat every 24 hours, if needed; taper as clinically indicated) or other immunosuppressants (eg, other anti–T-cell therapies). | ||
Neurotoxicity: Monitor for signs/symptoms of neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS) and other neurotoxicities. Rule out other causes of neurologic signs/symptoms. Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities. If ICANS is suspected, manage according to the neurotoxicity table. If concurrent CRS is suspected during neurotoxicity, administer more aggressive corticosteroid intervention (based on the CRS and neurotoxicity tables), tocilizumab (according to the CRS table), and antiseizure mediations (according to the neurotoxicity table). ICANS grading/management is determined by the most severe event (ICE [immune effector cell-associated encephalopathy] score, level of consciousness, seizure, motor findings, raised intracranial pressure ([ICP]/cerebral edema) that is not attributable to any other cause.
|
Neurotoxicity (ICANS) grade |
Corticosteroids and antiseizure medication |
|---|---|
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a Dexamethasone or dexamethasone equivalent. | |
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b If patient is arousable and able to perform ICE assessment, assess:
If patient is unarousable and unable to perform ICE assessment (Grade 4 ICANS) = 0 points. | |
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c Intracranial hemorrhage ± associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. | |
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d Tremors and myoclonus associated with immune effector cell therapies may be graded; however, they do not influence ICANS grading. | |
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Grade 1 ICE score 7 to 9b or Depressed level of consciousness; awakens spontaneously |
Consider dexamethasonea 10 mg IV every 12 to 24 hours for 2 to 3 days. Consider nonsedating antiseizure medications (eg, levetiracetam) for seizure prophylaxis. |
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Grade 2 ICE score 3 to 6b or Depressed level of consciousness; awakens to voice |
Initiate dexamethasonea 10 mg IV every 12 hours for 2 to 3 days (or longer for persistent symptoms). Consider corticosteroid taper if total corticosteroid exposure is >3 days. If no improvement after 24 hours or worsening of neurologic toxicity, increase dexamethasonea dose and/or frequency up to a maximum of 20 mg IV every 6 hours. Consider nonsedating antiseizure medications (eg, levetiracetam) for seizure prophylaxis. |
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Grade 3 ICE score 0 to 2b (if ICE score is 0, but the patient is arousable [eg, awake with global aphasia] and able to perform assessment) or Depressed level of consciousness; awakens only to tactile stimulus or Seizures (any clinical seizure, focal or generalized, that resolves rapidly, or nonconvulsive seizures on EEG that resolve with intervention) or Raised ICP: Focal/local edema on neuroimagingc |
Initiate dexamethasonea 10 to 20 mg IV every 6 hours. If no improvement after 24 hours, or worsening neurologic toxicity, escalate dexamethasonea dose to at least 20 mg IV every 6 hours or escalate to high-dose methylprednisolone (1 to 2 g/day, repeat every 24 hours if needed; taper as clinically indicated). Consider non-sedating antiseizure medications (eg, levetiracetam) for seizure prophylaxis. If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Administer methylprednisolone 1 to 2 g IV, repeat every 24 hours, if needed; taper as clinically indicated. |
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Grade 4 ICE score 0b or Depressed level of consciousness; either patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or stupor or coma or Seizures (life-threatening prolonged seizure [>5 minutes], or repetitive clinical or electrical seizures without return to baseline in between) or Motor findingsd (deep focal motor weakness, such as hemiparesis or paraparesis) or Raised ICP/cerebral edema, with signs/symptoms, such as: diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, or Cushing’s triad |
Initiate dexamethasonea 20 mg IV every 6 hours. If no improvement after 24 hours, or worsening neurologic toxicity, escalate to high-dose methylprednisolone (1 to 2 g IV, repeat every 24 hours, if needed; taper as clinically indicated). Consider nonsedating antiseizure medications (eg, levetiracetam) for seizure prophylaxis. If raised ICP/cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Administer high-dose methylprednisolone (1 to 2 g IV, repeat every 24 hours, if needed; taper as clinically indicated). Consider neurology and/or neurosurgery consultation. |
Other toxicities:
Cranial nerve palsies: Consider management with systemic corticosteroids (depending on the severity and progression of signs/symptoms).
Cytopenias: Manage cytopenia with growth factor and blood product transfusion support (according to local institutional guidelines).
Guillain-Barré syndrome: Consider treatment with supportive care measures and in conjunction with IV immunoglobulin and plasma exchange (depending on the severity).
Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: Manage per institutional standards.
Hypersensitivity: Manage promptly and appropriately based on the severity of the hypersensitivity reaction.
Hypogammaglobulinemia (IgG <400 mg/dL): Administer IV immune globulin and manage as indicated per local institutional guidelines, including infection precautions and antibiotic and/or antiviral prophylaxis.
Infection: Administer prophylactic, preemptive, and/or therapeutic antimicrobials according to standard institutional guidelines. If infection occurs, manage appropriately.
Neutropenic fever: Evaluate for infection, and manage with broad-spectrum antibiotics, fluids, and other supportive care, as clinically indicated.
Parkinsonism: Manage with supportive care measures.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intravenous [preservative free]:
Carvykti: 100000000 CELLS (1 ea)
No
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Carvykti: https://www.janssenlabels.com/package-insert/product-patient-information/CARVYKTI-medication-guide.pdf
IV: For IV use only. Administer in a health care facility. Coordinate the timing of administration with thawing. Prime tubing set with NS prior to infusion. Once thawed, administer the entire contents of the bag by IV infusion within 2.5 hours using infusion sets fitted with an in-line filter (do not use a leukodepleting filter). Gently mix the contents of the bag during ciltacabtagene autoleucel infusion to disperse cell clumps. After the entire contents of infusion bag has infused, flush the administration line (including the in-line filter) with a volume of NS ≥ the total volume capacity of the administration set (including drip tube) to ensure all product is delivered. A central line may be used for administration (and is encouraged in patients with poor peripheral access). Monitor closely for 2 hours after infusion for signs and symptoms of severe hypersensitivity reaction.
Prior to administration: Ensure tocilizumab (at least 2 doses) and emergency equipment are available prior to infusion and during recovery period. Confirm patient identity and match to patient identifiers on the infusion bag (do not infuse if identifiers do not match). Apply universal precautions for product handling. Premedicate with acetaminophen 650 to 1,000 mg orally and diphenhydramine 25 to 50 mg IV or orally (or other H1 antihistamine) ~30 to 60 minutes prior to ciltacabtagene autoleucel infusion. Avoid prophylactic dexamethasone or other systemic corticosteroids, as they may interfere with the ciltacabtagene autoleucel activity.
Monitor patient daily (for signs/symptoms of cytokine release syndrome and neurotoxicity) at the health care facility for at least 10 days after cell infusion; monitor periodically for 4 weeks for signs/symptoms of delayed neurotoxicity. Patient should remain within proximity of the facility for at least 4 weeks after infusion.
Multiple myeloma, relapsed or refractory: Treatment of relapsed or refractory multiple myeloma in adults after ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
Ciltacabtagene autoleucel may be confused with axicabtagene ciloleucel, betibeglogene autotemcel, brexucabtagene autoleucel, elivaldogene autotemcel, idecabtagene vicleucel, lisocabtagene maraleucel, sipuleucel-T, tisagenlecleucel.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Cardiovascular: Edema (23%), hypertension (19%), hypotension (51%), tachycardia (27%)
Gastrointestinal: Constipation (22%), decreased appetite (29%), diarrhea (33%; grades ≥3: 1%), nausea (31%; grades ≥3: 1%), vomiting (20%)
Hematologic & oncologic: Anemia (grades 3/4: 72%), disorder of hemostatic components of blood (22%; grades ≥3: 2%; including disseminated intravascular coagulation, hypofibrinogenemia, increased INR, prolonged partial thromboplastin time, prolonged prothrombin time), hemorrhage (15%; grades ≥3: 4%), hypogammaglobulinemia (94%; grades ≥3: 2%), lymphocytopenia (grades 3/4: 99%), neutropenia (grades 3/4: 98%), thrombocytopenia (grades 3/4: 63%)
Hepatic: Increased serum aspartate aminotransferase (grades 3/4: 21%)
Hypersensitivity: Cytokine release syndrome (95%; serious: 21%)
Immunologic: Antibody development (20%)
Infection: Infection (41% to 59%; including bacterial infection [10%], fungal infection [grades 3/4: 1%], viral infection [23%])
Nervous system: Chills (33%), dizziness (23%), encephalopathy (30%), fatigue (47%), headache (27%), insomnia (13%), motor dysfunction (16%), neurotoxicity (26%; including cranial nerve palsy [3%], Guillain-Barre syndrome, Immune Effector Cell-associated Neurotoxicity Syndrome [ICANS: 23%], parkinsonism [4%], peripheral neuropathy [6%; grade 3: 2%])
Neuromuscular & skeletal: Musculoskeletal pain (48%)
Respiratory: Cough (39%), dyspnea (23%), hypoxia (12%), nasal congestion (15%), pneumonia (12%), upper respiratory tract infection (28%)
Miscellaneous: Fever (96%)
1% to 10%:
Cardiovascular: Cardiac arrhythmia (8%), cerebrovascular accident (1%), chest pain (7%), thrombosis (5%)
Dermatologic: Skin rash (8%)
Gastrointestinal: Dysphagia (1%)
Genitourinary: Urinary tract infection (4%)
Hematologic & oncologic: Febrile neutropenia (10%; grades ≥3: 10%), hemophagocytic lymphohistiocytosis (including macrophage activation syndrome: 1%), tumor lysis syndrome (1%)
Hypersensitivity: Hypersensitivity reaction (5%)
Infection: Sepsis (10%)
Nervous system: Aphasia (8%), ataxia (8%), cogwheel rigidity (1%), delirium (5%), depression (4%), falling (3%), mask-like face (3%), paresis (4%), psychomotor impairment (1%), seizure (1%), speech disturbance (low speech: 1%), writing difficulty (3%; micrographia: 4%)
Neuromuscular & skeletal: Abnormal posture (1%), bradykinesia (2%), tremor (6%)
Ophthalmic: Diplopia (1%), nystagmus disorder (1%)
Renal: Renal failure syndrome (7%)
Frequency not defined:
Endocrine & metabolic: Hypoalbuminemia, hypocalcemia, hypokalemia, hyponatremia, increased gamma-glutamyl transferase
Hepatic: Increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum bilirubin
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Cytokine release syndrome: Cytokine release syndrome (CRS), including fatal or life-threatening reactions, commonly occurred with ciltacabtagene autoleucel; grade 3 or higher CRS has occurred. The median time to onset of CRS was 7 days (range: 1 to 12 days) and the median duration was 4 days (range:1 to 40 days), although there was a case report of a CRS duration of 97 days (with a subsequent fatal outcome). In patients who experienced CRS, the most common manifestations included fever, chills, hypotension, increased AST or ALT, and/or sinus tachycardia. Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, fever, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, and increased C-reactive protein, ferritin, blood alkaline phosphatase, and gamma-glutamyl transferase. CRS has been reported to be associated with findings of HLH/MAS (the physiology of the syndromes may overlap). Patients should seek immediate medical attention if signs/symptoms of CRS occur at any time.
• Cytopenias: Prolonged and/or recurrent cytopenias with bleeding, infection, and/or requirement for stem cell transplantation for hematopoietic recovery have occurred following lymphodepleting chemotherapy and ciltacabtagene autoleucel. Prolonged (unresolved by day 30 after ciltacabtagene autoleucel infusion) grade 3 or 4 neutropenia and thrombocytopenia have been reported. Of patients recovering from grade 3 or 4 neutropenia after 1 month, the median time to recovery from ciltacabtagene autoleucel infusion was 1.8 months (range: 1 to ~4 months); of those recovering from grade 3 or 4 thrombocytopenia after 1 month, the median time to recovery from ciltacabtagene autoleucel infusion was 1.9 months (range: ~1 to 8.5 months). One patient required autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia. Recurrent grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia, and anemia were observed after recovery from initial grade 3 or 4 cytopenias. After day 60 following ciltacabtagene autoleucel, some patients experienced recurrent grade 3 or higher lymphopenia, neutropenia, and thrombocytopenia after initial recovery.
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: HLH/MAS, including a fatal case, has been observed with ciltacabtagene autoleucel. HLH is a life-threatening condition with a high mortality rate if not recognized and managed early. Manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction. HLH/MAS can occur with CRS or neurologic toxicities.
• Hypersensitivity: Hypersensitivity reactions have occurred following ciltacabtagene autoleucel infusion. Reactions were mild and symptoms included flushing, chest discomfort, tachycardia, wheezing, tremor, and burning sensation. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in ciltacabtagene autoleucel.
• Hypogammaglobulinemia: Hypogammaglobulinemia can occur with ciltacabtagene autoleucel. IgG levels fell below 500 mg/dL in a majority of patients. Some patients required IV immunoglobulin following ciltacabtagene autoleucel, for either management of an adverse reaction or for prophylaxis.
• Infections: Severe, life-threatening, or fatal infections have occurred with ciltacabtagene autoleucel, including viral, bacterial, and fungal infections, as well as unspecified pathogens. Neutropenic fever has been reported; may be concurrent with CRS. Hepatitis B virus reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients with hypogammaglobulinemia.
• Neurologic toxicities: Neurologic toxicities, which may be severe, life-threatening, or fatal, have occurred with ciltacabtagene autoleucel. Neurologic toxicities included immune effector cell-associated neurotoxicity syndrome (ICANS), neurotoxicity with signs/symptoms of parkinsonism, Guillain-Barré syndrome (GBS), peripheral neuropathies, and cranial nerve palsies. Patients should seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time (including delayed-onset neurotoxicity). Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients receiving ciltacabtagene autoleucel are at risk for altered/decreased consciousness or coordination in the 8 weeks following ciltacabtagene autoleucel infusion and should refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.
ICANS: ICANS, which may be fatal or life-threatening, occurred with ciltacabtagene autoleucel, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS; grade 3 or higher ICANS occurred. Common manifestations of ICANS included encephalopathy, aphasia, and headache. The median time to onset of ICANS was 8 days (range: 1 to 28 days). ICANS resolved in over three-fourths of patients; the median time to resolution was 6 days (range: 2 to 143 days), although ICANS symptoms may persist in some patients.
Parkinsonism: Parkinsonism and associated complications have occurred following treatment with ciltacabtagene autoleucel, including a fatal case. Parkinsonian and nonparkinsonian symptoms included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness/wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe–release signs. The median time to onset of parkinsonism was 43 days (range: 15 to 108 days); symptoms did not respond to multiple treatment lines.
GBS: GBS and associated complications have occurred, including a case report with a fatal outcome despite treatment with IV immunoglobulin; symptoms included those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances, and polyradiculoneuritis.
Peripheral neuropathy: Some patients developed peripheral neuropathy, which presented as sensory, motor, or sensorimotor neuropathies, including grade 3 events. The median time of symptom onset was 62 days (range: 4 to 136 days) and the median duration was 256 days (range: 2 to 465 days), including those with ongoing neuropathy. In some studies, patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS.
Cranial nerve palsies: A small number of patients experienced cranial nerve palsies; the median time to onset was 26 days (range: 21 to 101 days); all cases resolved following systemic corticosteroids (± valacyclovir) with a median time to resolution of 70 days (range: 1 to 79 days).
• Secondary malignancies: Patients treated with ciltacabtagene autoleucel may develop secondary malignancies. If a secondary malignancy develops, contact the manufacturer (800-526-7736) for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy of T-cell origin.
Concurrent drug therapy issues:
• Immunizations: Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ciltacabtagene autoleucel treatment, and until immune recovery following ciltacabtagene autoleucel treatment. Immunization with live viral vaccines during or following ciltacabtagene autoleucel has not been studied.
Special populations:
• Older age: The incidence of neurotoxicities (all grade and grade 3) was higher in patients ≥65 years of age, compared to patients <65 years of age.
Dosage form specific issues:
• Dimethyl sulfoxide: Ciltacabtagene autoleucel contains DMSO, which is associated with serious hypersensitivity reactions, including anaphylaxis.
Other warnings/precautions:
• REMS program: Ciltacabtagene autoleucel is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the CARVYKTI REMS Program. Further information is available at www.carvyktirems.com or 844-672-0067.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Corticosteroids (Systemic): May enhance the adverse/toxic effect of CAR-T Cell Immunotherapy. Specifically, the severity and duration of neurologic toxicities may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of CAR-T Cell Immunotherapy. Management: Avoid use of corticosteroids as premedication before treatment with CAR-T cell immunotherapy agents. Corticosteroids are indicated and may be required for treatment of toxicities such as cytokine release syndrome or neurologic toxicity. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): CAR-T Cell Immunotherapy may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: The CDC recommends that CAR-T-cell recipients who received COVID-19 vaccine prior to or during treatment with CAR-T-cell therapy should be revaccinated with a primary mRNA vaccine series at least 3 months (12 weeks) after CAR-T-cell therapy. Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): CAR-T Cell Immunotherapy may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: The CDC recommends that CAR-T-cell recipients who received COVID-19 vaccine prior to or during treatment with CAR-T-cell therapy should be revaccinated with a primary vaccine series at least 3 months (12 weeks) after CAR-T-cell therapy. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Rubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Verify pregnancy status prior to treatment initiation.
Patients were required to use contraception during therapy and for 1 year after the ciltacabtagene autoleucelinfusion in clinical studies. Patients who could become pregnant were required to use a highly effective method of contraception. Patients with partners who could become pregnant were required to use a barrier method of contraception.
Animal reproduction and toxicity studies have not been conducted. Based on the mechanism of action, in utero exposure to ciltacabtagene autoleucelmay cause fetal toxicity, including B-cell lymphocytopenia and hypogammaglobulinemia.
It is not known if ciltacabtagene autoleucelis present in breast milk.
According to the manufacturer, the decision to breastfeed should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Screen for cytomegalovirus, hepatitis B virus (HBV), hepatitis C virus, and HIV or any other infectious agents if clinically indicated in prior to collection of cells (for manufacturing) in accordance with clinical guidelines. Monitor blood counts prior to and after ciltacabtagene autoleucel infusion. Monitor immunoglobulin levels (IgG) after treatment. Consider laboratory testing to monitor for disseminated intravascular coagulation, as well as pulmonary, cardiac, renal, and hepatic function. Verify pregnancy status prior to treatment initiation (in patients who could become pregnant).
Monitor for cytokine release syndrome (CRS) and signs/symptoms of neurotoxicity during therapy and for at least 4 weeks after infusion. For ≥ grade 2 CRS, perform continuous cardiac telemetry and pulse oximetry. Monitor patient daily (for signs/symptoms of cytokine release syndrome and neurotoxicity [including immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms]) at the health care facility for at least 10 days after cell infusion; monitor periodically for 4 weeks for signs/symptoms of delayed neurotoxicity. Monitor for neurotoxicity after ciltacabtagene autoleucel treatment; monitor for signs/symptoms of parkinsonism (onset may be delayed), Guillain-Barré syndrome (GBS; patients presenting with peripheral neuropathy should be evaluated for GBS), and cranial nerve palsies. Evaluate for evidence of hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) in patients with progressive CRS symptoms or refractory CRS despite treatment. Monitor for signs/symptoms of infection (before and after treatment), and hepatitis B reactivation. Monitor life-long for secondary malignancies. Monitor closely for 2 hours after infusion for signs/symptoms of severe hypersensitivity reaction.
Additional neurotoxicity monitoring recommendations (Cohen 2022): In patients with preexisting neurologic disease, consider baseline MRI and EEG and neurologic consultation. Evaluate at the first sign of neurotoxicity, including ICANS and raised intracranial pressure/cerebral edema; assess with new onset of headache, seizure, speech or visual disorders, disturbances in consciousness, confusion, disorientation, coordination/balance/movement disorders, mental status changes, cognitive impairment, and/or personality changes. Evaluate at first sign of neurotoxicity for infectious (eg, human herpes virus), autoimmune, or paraneoplastic/tumoral or metabolic etiologies in blood, cerebrospinal fluid, and/or radiologic imaging. Perform immune effector cell–associated encephalopathy assessment tool at baseline and at least daily after first symptoms of neurotoxicity (eg, ICANS or other neurotoxicities) are suspected; continue until resolution. Consider handwriting assessments for early detection of neurotoxicity symptoms. Consider extending neurotoxicity monitoring up to 1 year following ciltacabtagene autoleucel infusion.
The American Society of Clinical Oncology HBV screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Ciltacabtagene autoleucel is a B cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy in which a patient's T cells are reprogrammed via transduction with a lentiviral vector to express an anti-BCMA chimeric antigen receptor (CAR). The CAR T-cell construct includes an anti-BCMA targeting domain consisting of a CD3-zeta signaling domain and a 4-1BB costimulatory domain. Ciltacabtagene autoleucel is prepared from the patient’s peripheral blood mononuclear cells (obtained via leukapheresis), which are enriched for T cells. When infused back into the patient, the anti-BCMA CAR T cells recognize and eliminate BCMA-expressing target cells. In addition to T cells, ciltacabtagene autoleucel may contain natural killer (NK) cells.
Note: Ciltacabtagene autoleucel exhibits an initial rapid expansion followed by a rapid decline, and then a slower decline. Patients who received tocilizumab, corticosteroids, or anakinra to manage cytokine release syndrome (CRS) experienced higher ciltacabtagene autoleucel AUC0 to 28d and Cmax compared to patients who did not receive tocilizumab, corticosteroids, or anakinra.
Duration: The median time for chimeric antigen receptor transgene levels in peripheral blood to return to predose baseline level was ~100 days postinfusion (range: 28 to 365 days).
Distribution: Distributes into bone marrow (from systemic circulation).
Half-life elimination: Median half-life: ~15 days (range: 3 to ~95 days).
Time to peak: Median time to maximal expansion (in peripheral blood): ~13 days after infusion.
Suspension (Carvykti Intravenous)
100000000CELLS (per each): $0.00
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