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WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY including
IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TECVAYLI™. Initiate treatment with TECVAYLI™ step-up dosing schedule to reduce risk of CRS. Withhold TECVAYLI™ until CRS resolves or permanently discontinue based on severity
Neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and serious and life-threatening reactions, can occur in patients receiving TECVAYLI™. Monitor patients for signs or symptoms of neurologic toxicity, including ICANS, during treatment and treat promptly. Withhold TECVAYLI™ until neurologic toxicity resolves or permanently discontinue based on severity.
TECVAYLI™ is available only through a restricted program called the TECVAYLI™ Risk Evaluation and Mitigation Strategy (REMS).
WARNINGS AND PRECAUTIONS
Cytokine Release Syndrome - TECVAYLI™ can cause cytokine release syndrome (CRS), including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 72% of patients who received TECVAYLI™ at the recommended dose, with Grade 1 CRS occurring in 50% of patients, Grade 2 in 21%, and Grade 3 in 0.6%. Recurrent CRS occurred in 33% of patients. Most patients experienced CRS following step-up dose 1 (42%), step-up dose 2 (35%), or the initial treatment dose (24%). Less than 3% ofpatients developed first occurrence of CRS following subsequent doses of TECVAYLI™.The median time to onset of CRS was 2 (range: 1 to 6) days after the most recent dose with a median duration of 2 (range: 1to 9) days. Clinical signs and symptoms of CRS included, but were not limited to, fever, hypoxia, chills, hypotension, sinus tachycardia, headache, and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation).
Initiate therapy according to TECVAYLI™ step-up dosing schedule to reduce risk of CRS. Administer pretreatment medications to reduce risk of CRS and monitor patients following administration of TECVAYLI™ accordingly. At the first sign of CRS, immediately evaluate patient for hospitalization. Administer supportive care based on severity and consider further management per current practice guidelines. Withhold or permanently discontinue TECVAYLI™ based on severity
TECVAYLI™ is available only through a restricted program under a REMS.
Neurologic Toxicity including ICANS - TECVAYLI™ can cause serious or life-threatening neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).
In the clinical trial, neurologic toxicity occurred in 57% of patients who received TECVAYLI™ at the recommended dose, with Grade 3 or 4 neurologic toxicity occurring in 2.4% of patients. The most frequent neurologic toxicities were headache (25%), motor dysfunction (16%), sensory neuropathy (15%), and encephalopathy (13%). With longer follow-up, Grade 4 seizure and fatal Guillain-Barré syndrome (one patient each) occurred in patients who received TECVAYLI™.
In the clinical trial, ICANS was reported in 6% of patients who received TECVAYLI™ at the recommended dose. Recurrent ICANS occurred in 1.8% of patients. Most patients experienced ICANS following step-up dose 1 (1.2%), step-up dose 2 (0.6%), or the initial treatment dose (1.8%). Less than 3% of patients developed first occurrence of ICANS following subsequent doses of TECVAYLI™. The median time to onset of ICANS was 4 (range: 2 to 8) days after the most recent dose with a median duration of 3 (range: 1 to 20) days. The most frequent clinical manifestations of ICANS reported were confusional state and dysgraphia. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.
Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or permanently discontinue TECVAYLI™ based on severity per recommendations and consider further management per current practice guidelines.
Due to the potential for neurologic toxicity, patients are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI™ step-up dosing schedule and in the event of new onset of any neurologic toxicity symptoms until neurologic toxicity resolves.
TECVAYLI™ is available only through a restricted program under a REMS.
TECVAYLI™ REMS - TECVAYLI™ is available only through a restricted program under a REMS called the TECVAYLI™ REMS because of the risks of CRS and neurologic toxicity, including ICANS.
Hepatotoxicity - TECVAYLI™ can cause hepatotoxicity, including fatalities. In patients who received TECVAYLI™ at the recommended dose in the clinical trial, there was one fatal case of hepatic failure. Elevated aspartate aminotransferase (AST) occurred in 34% of patients, with Grade 3 or 4 elevations in 1.2%. Elevated alanine aminotransferase (ALT) occurred in 28% of patients, with Grade 3 or 4 elevations in 1.8%. Elevated total bilirubin occurred in 6% of patients with Grade 3 or 4 elevations in 0.6%. Liver enzyme elevation can occur with or without concurrent CRS.
Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TECVAYLI™ or consider permanent discontinuation of TECVAYLI™ based on severity.
Infections - TECVAYLI™ can cause severe, life-threatening, or fatal infections. In patients who received TECVAYLI™ at the recommended dose in the clinical trial, serious infections, including opportunistic infections, occurred in 30% of patients, with Grade 3 or 4 infections in 35%, and fatal infections in 4.2%. Monitor patients for signs and symptoms of infection prior to and during treatment with TECVAYLI™ and treat appropriately. Administer prophylactic antimicrobials according to guidelines. Withhold TECVAYLI™ or consider permanent discontinuation of TECVAYLI™ based on severity.
Monitor immunoglobulin levels during treatment with TECVAYLI™ and treat according to guidelines, including infection precautions and antibiotic or antiviral prophylaxis.
Neutropenia - TECVAYLI™ can cause neutropenia and febrile neutropenia. In patients who received TECVAYLI™ at the recommended dose in the clinical trial, decreased neutrophils occurred in 84% of patients, with Grade 3 or 4 decreased neutrophils in 56%. Febrile neutropenia occurred in 3% of patients.
Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local institutional guidelines. Monitor patients with neutropenia for signs of infection. Withhold TECVAYLI™ based on severity.
Hypersensitivity and Other Administration Reactions - TECVAYLI™ can cause both systemic administration-related and local injection-site reactions. Systemic Reactions - In patients who received TECVAYLI™ at the recommended dose in the clinical trial, 1.2% of patients experienced systemic-administration reactions, which included Grade 1 recurrent pyrexia and Grade 1 swollen tongue. Local Reactions - In patients who received TECVAYLI™ at the recommended dose in the clinical trial, injection-site reactions occurred in 35% of patients, with Grade 1 injection-site reactions in 30% and Grade 2 in 4.8%. Withhold TECVAYLI™ or consider permanent discontinuation of TECVAYLI™ based on severity.
Embryo-Fetal Toxicity - Based on its mechanism of action, TECVAYLI™ 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 TECVAYLI™ and for 5 months after the last dose.
Adverse Reactions - The most common adverse reactions (≥20%) were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.
Please read full Prescribing Information, including Boxed WARNING, for TECVAYLI™.
cp-322928v1
Serious adverse reactions occurred in 54% of patients who received TECVAYLI™. Serious adverse reactions in >2% of patients included pneumonia (15%), cytokine release syndrome (8%), sepsis (6%), general physical health deterioration (6%), COVID-19 (6%), acute kidney injury (4.8%), pyrexia (4.8%), musculoskeletal pain (2.4%), and encephalopathy (2.4%).
Fatal adverse reactions occurred in 5% of patients who received TECVAYLI™, including COVID-19 (1.8%), pneumonia (1.8%), septic shock (0.6%), acute renal failure (0.6%), and hemoperitoneum (0.6%).
Adverse reactions (≥10%) in patients with RRMM treated with TECVAYLI™ in the MajesTEC-1 trial
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ASTCT, American Society for Transplantation and Cellular Therapy; COVID-19, coronavirus disease 2019; CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for Adverse Events; RRMM, relapsed or refractory multiple myeloma.
Adverse reactions were graded based on CTCAE Version 4.03, with the exception of CRS, which was graded per ASTCT 2019 criteria.
*Injection site reaction includes application site erythema, injection site bruising, injection site cellulitis, injection site discomfort, injection site erythema, injection site hematoma, injection site induration, injection site inflammation, injection site edema, injection site pruritus, injection site rash, injection site reaction and injection site swelling.
†Fatigue includes asthenia and fatigue
‡Pain includes ear pain, flank pain, groin pain, oropharyngeal pain, pain, pain in jaw, toothache and tumor pain.
§Edema includes face edema, fluid overload, fluid retention, edema peripheral and peripheral swelling.
¶Hypogammaglobulinemia includes hypogammaglobulinemia and hypoglobulinemia.
#Musculoskeletal pain includes arthralgia, back pain, muscle discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain and pain in extremity.
**Upper respiratory tract infection includes bronchitis, influenza like illness, nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection bacterial, rhinitis, rhinovirus infection, sinusitis, tracheitis, upper respiratory tract infection and viral upper respiratory tract infection.
††Pneumonia includes COVID-19 pneumonia, enterobacter pneumonia, lower respiratory tract infection, metapneumovirus pneumonia, pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia klebsiella, pneumonia moraxella, pneumonia pneumococcal, pneumonia pseudomonal, pneumonia respiratory syncytial viral, pneumonia staphylococcal and pneumonia viral.
‡‡Urinary tract infection includes cystitis, cystitis escherichia, cystitis klebsiella, escherichia urinary tract infection, urinary tract infection and urinary tract infection bacterial.
§§Motor dysfunction includes cogwheel rigidity, dysgraphia, dysphonia, gait disturbance, hypokinesia, muscle rigidity, muscle spasms, muscular weakness, peroneal nerve palsy, psychomotor hyperactivity, tremor and VIth nerve paralysis.
¶¶Sensory neuropathy includes dysesthesia, hypoesthesia, hypoesthesia oral, neuralgia, paresthesia, paresthesia oral, peripheral sensory neuropathy, sciatica and vestibular neuronitis.
##Encephalopathy includes agitation, apathy, aphasia, confusional state, delirium, depressed level of consciousness, disorientation, dyscalculia, hallucination, lethargy, memory impairment, mental status changes and somnolence.
***Hemorrhage includes conjunctival hemorrhage, epistaxis, hematoma, hematuria, hemoperitoneum, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage and subdural hematoma.
†††Hypertension includes essential hypertension and hypertension.
‡‡‡Cough includes allergic cough, cough, productive cough and upper-airway cough syndrome.
§§§Cardiac arrhythmia includes atrial flutter, cardiac arrest, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, tachycardia and ventricular tachycardia.
¶¶¶Acute kidney injury includes acute kidney injury and renal impairment.
###Only Grade 3 adverse reactions occurred.
***Includes the following fatal adverse reactions: hemorrhage (n=1), pneumonia (n=3).
CRS, including life-threatening or fatal reactions, may occur in patients receiving TECVAYLI™1
- CRS of any grade was reported in 72% of patients receiving TECVAYLI™
Median time to onset: 2 days (range: 1-6 days) after most recent dose
Median duration: 2 days (range: 1-9 days)
CRS experienced after specific dose of TECVAYLI™
- Recurrent CRS occurred in 33% of patients
Signs and symptoms of CRS may include:
- Fever
- Hypoxia
- Chills
- Hypotension
- Sinus tachycardia
- Headache
- Elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation)
At the first sign of CRS, immediately evaluate patient for hospitalization. Administer supportive care based on severity and consider further management per current practice guidelines. Withhold or permanently discontinue TECVAYLI™ based on severity.
TECVAYLI™ is available only through a restricted program under a REMS.
Patient counseling
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Discuss the signs and symptoms associated with CRS, including fever, hypoxia, chills, hypotension, sinus tachycardia, headache, and elevated liver enzymes. Advise patients to immediately contact their healthcare provider if they experience signs or symptoms of CRS.
- Fever (100.4°F or higher)
- Feeling anxious
- Difficulty breathing
- Confusion or restlessness
- Chills
- Headache
- Dizziness or lightheadedness
- Increased liver enzymes in their blood
- Fast heartbeat
Advise patients that they will be hospitalized for 48 hours after administration of all doses within the TECVAYLI™ step-up dosing schedule.
Serious or life-threatening neurologic toxicities, including ICANS, may occur following treatment with TECVAYLI™
In the clinical trial, neurologic toxicities were reported in 57% of patients receiving TECVAYLI™ at the recommended dose.
- The most frequent neurologic toxicities were headache (25%), motor dysfunction (16%), sensory neuropathy (15%), and encephalopathy (13%)
- With longer follow-up, 1 patient experienced Grade 4 seizure and 1 patient experienced fatal Guillain-Barré syndrome
- Grade 3 and Grade 4 neurologic toxicity events (2.4%) have been observed in patients treated with TECVAYLI™
Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate patient and provide supportive therapy based on severity.
Immune effector cell-associated neurotoxicity syndrome (ICANS)
In the clinical trial, ICANS was reported in 6% of patients receiving TECVAYLI™ at the recommended dose.
- Recurrent ICANS occurred in 1.8% of patients
- The most frequent clinical manifestations of ICANS reported were confusional state and dysgraphia
- Due to the potential for neurologic toxicity, patients receiving TECVAYLI™ are at risk of depressed level of consciousness
- Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI™ step-up dosing schedule and in the event of new onset of any neurologic toxicity symptoms until neurologic toxicity resolves
ICANS experienced after specific dose of TECVAYLI™
Median time to onset: 4 days (range: 2-8)
Median duration: 3 days (range: 1-20)
The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.
TECVAYLI™ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called TECVAYLI™ REMS. Visit TECVAYLIREMS.com
Patient counseling
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Discuss the signs and symptoms associated with neurologic toxicity, including ICANS, including headache, confusion, dysgraphia, motor dysfunction, neuropathy, or encephalopathy. Advise patients to immediately contact their healthcare provider if they experience any signs or symptoms of neurologic toxicity. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI™ step-up dosing schedule and in the event of new onset of any neurologic toxicity symptoms until neurologic toxicity resolves.
Symptoms of neurologic problems with TECVAYLI™ include:
- Headache
- Jerking movements
- Rigid muscles
- Feeling restless
- Numbness and tingling (feeling like “pins and needles”)
- Confusion
- Trouble speaking
- Muscle spasms
- Tremor
- Double vision
- Changes in your handwriting
- Problems walking
- Muscle weakness in your body or face
- Hearing loss
- Burning, throbbing, or stabbing pain
Advise patients that they will be hospitalized for 48 hours after administration of all doses within the TECVAYLI™ step-up dosing schedule.
Use in specific populations in the MajesTEC-1 trial1
Pregnancy Based on the mechanism of action, TECVAYLI™ may cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECVAYLI™ in pregnant women. No animal reproductive or developmental toxicity studies have been conducted with TECVAYLI™. Teclistamab-cqyv causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, teclistamab-cqyv has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. TECVAYLI™ is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with TECVAYLI™ should be considered. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Lactation There are no data on the presence of teclistamab-cqyv in human milk, the effect on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to TECVAYLI™ are unknown. Because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with TECVAYLI™ and for 5 months after the last dose.
Females and Males of Reproductive Potential TECVAYLI™ may cause fetal harm when administered to a pregnant woman.
- Pregnancy Testing: Verify pregnancy status of females of reproductive potential prior to initiating TECVAYLI™
- Contraception (females): Advise females of reproductive potential to use effective contraception during treatment and for 5 months after the last dose of TECVAYLI™
Pediatric Use The safety and efficacy of TECVAYLI™ have not been established in pediatric patients.
Geriatric Use Of the 165 patients with relapsed or refractory multiple myeloma treated with TECVAYLI™ in MajesTEC-1 at the recommended dosage, 48% were 65 years of age or older, and 15% were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients 65 to 74 years of age compared to younger patients. There is an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or effectiveness.
COVID-19, coronavirus disease 2019; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.
Reference:
- TECVAYLI™ (teclistamab-cqyv) Prescribing Information. Janssen Biotech, Inc., Horsham, PA 19044.
