WARNINGS AND PRECAUTIONS
Cytokine Release Syndrome (CRS): TALVEY™ can cause cytokine release syndrome, including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 76% of patients who received TALVEY™ at the recommended dosages, with Grade 1 CRS occurring in 57% of patients, Grade 2 in 17%, and Grade 3 in 1.5%. Recurrent CRS occurred in 30% of patients. CRS occurred in 33% of patients with step-up dose 3 in the biweekly dosing schedule (N=153). CRS occurred in 30% of patients with the first 0.4 mg/kg treatment dose and in 12% of patients treated with the first 0.8 mg/kg treatment dose. The CRS rate for both dosing schedules combined was less than 3% for each of the remaining doses in Cycle 1 and less than 3% cumulatively from Cycle 2 onward. The median time to onset of CRS was 27 (range: 0.1 to 167) hours from the last dose, and the median duration was 17 (range: 0 to 622) hours. Clinical signs and symptoms of CRS include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).
Initiate therapy with step-up dosing and administer pre-treatment medications (corticosteroids, antihistamine, and antipyretics) prior to each dose of TALVEY™ in the step-up dosing schedule to reduce the risk of CRS. Monitor patients following administration accordingly. In patients who experience CRS, pre-treatment medications should be administered prior to the next TALVEY™ dose.
Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care based on severity, and consider further management per current practice guidelines. Withhold TALVEY™ until CRS resolves or permanently discontinue based on severity.
Neurologic Toxicity including ICANS: TALVEY™ can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), including fatal reactions. In the clinical trial, neurologic toxicity occurred in 55% of patients who received the recommended dosages, with Grade 3 or 4 neurologic toxicity occurring in 6% of patients. The most frequent neurologic toxicities were headache (20%), encephalopathy (15%), sensory neuropathy (14%), and motor dysfunction (10%).
ICANS was reported in 9% of 265 patients where ICANS was collected and who received the recommended dosages. Recurrent ICANS occurred in 3% of patients. Most patients experienced ICANS following step-up dose 1 (3%), step-up dose 2 (3%), step-up dose 3 of the biweekly dosing schedule (1.8%), or the initial treatment dose of the weekly dosing schedule (2.6%) (N=156) or the biweekly dosing schedule (3.7%) (N=109). The median time to onset of ICANS was 2.5 (range: 1 to 16) days after the most recent dose with a median duration of 2 (range: 1 to 22) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.
Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient and provide supportive care based on severity; withhold or permanently discontinue TALVEY™ based on severity and consider further management per current practice guidelines. [see Dosage and Administration (2.5)].
Due to the potential for neurologic toxicity, patients receiving TALVEY™ are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during the step-up dosing schedule and for 48 hours after completion of the step-up dosing schedule, and in the event of new onset of any neurological symptoms, until symptoms resolve.
TECVAYLI® and TALVEY™ REMS: TALVEY™ is available only through a restricted program under a REMS, called the TECVAYLI® and TALVEY™ REMS because of the risks of CRS and neurologic toxicity, including ICANS.
Further information about the TECVAYLI® and TALVEY™ REMS program is available at www.TEC-TALREMS.com or by telephone at 1-855-810-8064.
Oral Toxicity and Weight Loss: TALVEY™ can cause oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis. In the clinical trial, 80% of patients had oral toxicity, with Grade 3 occurring in 2.1% of patients who received the recommended dosages. The most frequent oral toxicities were dysgeusia (49%), dry mouth (34%), dysphagia (23%), and ageusia (18%). The median time to onset of oral toxicity was 15 (range: 1 to 634) days, and the median time to resolution to baseline was 43 (1 to 530) days. Oral toxicity did not resolve to baseline in 65% of patients.
TALVEY™ can cause weight loss. In the clinical trial, 62% of patients experienced weight loss of 5% or greater, regardless of having an oral toxicity, including 28% of patients with Grade 2 (10% or greater) weight loss and 2.7% of patients with Grade 3 (20% or greater) weight loss. The median time to onset of Grade 2 or higher weight loss was 67 (range: 6 to 407) days, and the median time to resolution was 50 (range: 1 to 403) days. Weight loss did not resolve in 57% of patients who reported weight loss.
Monitor patients for signs and symptoms of oral toxicity. Counsel patients to seek medical attention should signs or symptoms of oral toxicity occur and provide supportive care as per current clinical practice, including consultation with a nutritionist. Monitor weight regularly during therapy. Evaluate clinically significant weight loss further. Withhold TALVEY™ or permanently discontinue based on severity.
Infections: TALVEY™ can cause infections, including life-threatening or fatal infections. Serious infections occurred in 16% of patients, with fatal infections in 1.5% of patients. Grade 3 or 4 infections occurred in 17% of patients. The most common serious infections reported were bacterial infection (8%), which included sepsis and COVID-19 (2.7%).
Monitor patients for signs and symptoms of infection prior to and during treatment with TALVEY™ and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Withhold or permanently discontinue TALVEY™ as recommended, based on severity.
Cytopenias: TALVEY™ can cause cytopenias, including neutropenia and thrombocytopenia. In the clinical trial, Grade 3 or 4 decreased neutrophils occurred in 35% of patients, and Grade 3 or 4 decreased platelets occurred in 22% of patients who received TALVEY™. The median time to onset for Grade 3 or 4 neutropenia was 22 (range: 1 to 312) days, and the median time to resolution to Grade 2 or lower was 8 (range: 1 to 79) days. The median time to onset for Grade 3 or 4 thrombocytopenia was 12 (range: 2 to 183) days, and the median time to resolution to Grade 2 or lower was 10 (range: 1 to 64) days. Monitor complete blood counts during treatment and withhold TALVEY™ as recommended, based on severity.
Skin Toxicity: TALVEY™ can cause serious skin reactions, including rash, maculo-papular rash, erythema, and erythematous rash. In the clinical trial, skin reactions occurred in 62% of patients, with grade 3 skin reactions in 0.3%. The median time to onset was 25 (range: 1 to 630) days. The median time to improvement to grade 1 or less was 33 days.
Monitor for skin toxicity, including rash progression. Consider early intervention and treatment to manage skin toxicity. In the clinical trial, supportive care included topical steroids (15%). Oral steroid tapers (4.4%) were typically administered for Grade 3 skin reactions. Withhold or permanently discontinue TALVEY™, based on severity.
Hepatotoxicity: TALVEY™ can cause hepatotoxicity. Elevated ALT occurred in 33% of patients, with grade 3 or 4 ALT elevation occurring in 2.7%; elevated AST occurred in 31% of patients, with grade 3 or 4 AST elevation occurring in 3.3%. Grade 3 or 4 elevations of total bilirubin occurred in 0.3% of patients. Liver enzyme elevation can occur with or without concurrent CRS.
Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TALVEY™ or consider permanent discontinuation of TALVEY™, based on severity [see Dosage and Administration (2.5)].
Embryo-Fetal Toxicity: Based on its mechanism of action, TALVEY™ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TALVEY™ and for 3 months after the last dose.
Adverse Reactions: The most common adverse reactions (≥20%) are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, weight decreased, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, and headache.
The most common Grade 3 or 4 laboratory abnormalities (≥30%) are lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, and hemoglobin decreased.
Please read full Prescribing Information, including Boxed WARNING, for TALVEY™.