Approved Drug Label (PDF)
5
Warnings and Precautions
5.1
Cytokine Release Syndrome
Additions
and/or revisions underlined:
TECVAYLI
can cause cytokine release syndrome (CRS), including life-threatening or fatal
reactions [see Adverse Reactions (6.1)].
In
the clinical trials (monotherapy and combination therapy trials; N=448),
CRS occurred in 64% of patients who received TECVAYLI at the recommended
dosage, with Grade 1 CRS occurring in 46% of patients, Grade 2 in 18%,
and Grade 3 in 0.2%. Recurrent CRS occurred in 27% of patients.
Most patients experienced CRS during the initial step-up dosing schedule
(step-up dose 1 (37%), step-up dose 2 (32%), or the initial
treatment dose (20%)). CRS first occurred following subsequent doses of
TECVAYLI in 2.5% of patients. The median time to onset of CRS was 2
(range: 1 to 9) days after the most recent dose and the median
duration of CRS was 2 (range: 1 to 22) 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 [see Dosage and Administration (2.1, 2.5)].
Administer pretreatment medications to reduce risk of CRS and monitor patients
following administration of TECVAYLI accordingly [see Dosage and Administration (2.3, 2.5)].
At
the first sign of CRS, immediately evaluate the patient for
hospitalization. Administer supportive care based on severity and consider
further management per current practice guidelines. Withhold until CRS
resolves or permanently discontinue TECVAYLI based on severity [see Dosage and Administration (2.5)].
5.2
Neurologic Toxicity including Immune Effector
Cell-Associated Neurotoxicity Syndrome
Additions
and/or revisions underlined:
TECVAYLI
can cause serious, life-threatening or fatal neurologic toxicity, including
immune effector cell-associated neurotoxicity syndrome (ICANS) [see Adverse Reactions (6.1)].
In
the clinical trials (monotherapy and combination therapy trials; N=448),
neurologic toxicity occurred in 60% of patients who received TECVAYLI at
the recommended dosage, with Grade 3 or 4 neurologic toxicity in 6%.
Neurologic toxicities reported in greater than or equal to 5% of patients
included headache (27%), sensory neuropathy (16%), motor
dysfunction (15%), insomnia (12%) encephalopathy (11%), and dizziness
(8%). Fatal neurologic toxicity occurred in 0.4% of patients, including
Guillain-Barré syndrome and status epilepticus (one patient each).
In
MajesTEC-1, ICANS was reported in 6% of patients who received TECVAYLI as
monotherapy at the recommended dosage [see
Adverse Reactions (6.1)]. 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 TECVAYLI doses.
The median time to onset of ICANS was 4 days (range: 2 to 8 days)
after the most recent TECVAYLI dose with a median duration of 3 days (range: 1
to 20 days). The most frequent clinical manifestations of ICANS reported were
confusional state and dysgraphia.
In
MajesTEC-3, ICANS was reported in 1.1% of patients who received the recommended
TECVAYLI dosage in combination with daratumumab hyaluronidase-fihj, including
Grade 4 ICANS in 1 patient. All events of ICANS occurred during the step-up
dosing schedule [see Adverse Reactions
(6.1)]. The median time
to onset of ICANS was 2 days (range: 1 to 3 days) after the most
recent dose and the median duration of ICANS was 2 days (range: 1
to 2 days). The clinical manifestations of ICANS reported were amnesia,
encephalopathy and delirium.
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, including ICANS
during TECVAYLI treatment. At the first sign of neurologic toxicity,
including ICANS, immediately evaluate patient and provide supportive therapy
based on severity. Withhold until neurologic toxicity resolves or
permanently discontinue TECVAYLI based on severity per recommendations and
consider further management per current practice guidelines [see Dosage and Administration (2.5)].
.
. .
5.4
Hepatotoxicity
Additions
and/or revisions underlined:
TECVAYLI
can cause hepatotoxicity, including fatalities. There was one fatal case of
hepatic failure in MajesTEC-1. In patients who received TECVAYLI at the
recommended dosage in the clinical trials (monotherapy and combination
therapy trials; N=448), elevated aspartate aminotransferase (AST) occurred
in 47% of patients, with Grade 3 or 4 elevations in 2.9%.
Elevated alanine aminotransferase (ALT) occurred in 48% of patients,
with Grade 3 or 4elevations in 3.8%. Elevated total bilirubin occurred
in 10% of patients with Grade 3 or 4 elevations in 0.7%. Liver
enzyme elevation can occur with or without concurrent CRS.
Monitor
liver enzymes and bilirubin at baseline and during TECVAYLI treatment as
clinically indicated. Withhold TECVAYLI or consider permanent discontinuation
of TECVAYLI based on severity [see Dosage
and Administration (2.5)].
5.5
Infections
Additions
and/or revisions underlined:
TECVAYLI
can cause severe, life-threatening, or fatal infections.
In
MajesTEC-1 (N=165), in patients who received the recommended TECVAYLI
dosage, serious infections, including opportunistic infections, occurred in 30%
of patients, Grade 3 or 4 infections occurred in 35% of patients,
and fatal infections occurred in 4.2% of patients [see Adverse Reactions (6.1)].
In
MajesTEC-3 (N=283), in patients who received TECVAYLI in combination with
daratumumab hyaluronidase-fihj at the recommended dosage, serious infections,
including opportunistic infections, occurred in 54% of patients, Grade 3 or
Grade 4 infections occurred in 54% of patients and fatal infections occurred in
4.6% of patients [see Adverse Reactions (6.1)].
Monitor
patients for signs and symptoms of infection prior to and during treatment with
TECVAYLI and treat appropriately. Administer prophylactic antimicrobials
according to current practice guidelines [see Dosage and Administration (2.3)].
Withhold
TECVAYLI or consider permanent discontinuation of TECVAYLI based on severity [see Dosage and
Administration (2.5)].
Monitor
immunoglobulin levels prior to and during treatment with TECVAYLI and administer
subcutaneous or intravenous immunoglobulin (IVIG) to maintain the serum
levels >400 mg/dL.
5.6
Neutropenia
Additions
and/or revisions underlined:
TECVAYLI
can cause neutropenia and febrile neutropenia. In patients who received
TECVAYLI at the recommended dosage in the clinical trials (monotherapy and
combination therapy trials; N=448), decreased neutrophils occurred in 88%
of patients, with Grade 3 or 4 decreased neutrophils in 70%. Febrile
neutropenia occurred in 6% of patients [see Adverse Reactions (6.1)].
.
. .
5.7
Hypersensitivity and Other Administration Reactions
Additions
and/or revisions underlined:
TECVAYLI
can cause both systemic administration-related reactions and local
injection-site reactions.
Systemic
Reactions
In
patients who received the recommended TECVAYLI dosage in the clinical trials (monotherapy
and combination therapy trials; N=448), 2.5% of patients experienced
systemic-administration reactions, which included recurrent pyrexia and rash.
Local
Reactions
In
patients who received TECVAYLI at the recommended dosage in the clinical trials
(monotherapy and combination therapy trials; N=448), injection-site
reactions occurred in 37% of patients with Grade 1 injection-site
reactions in 29% and Grade 2 in 9%.
Withhold
TECVAYLI or consider permanent discontinuation of TECVAYLI based on severity [see Dosage and
Administration (2.5)].
6
Adverse Reactions
6.1
Clinical Trials Experience
Additions
and/or revisions underlined:
.
. .
Relapsed/Refractory
Multiple Myeloma
In Combination
with Daratumumab Hyaluronidase-fihj
The
safety of TECVAYLI in combination with daratumumab hyaluronidase-fihj
(N=283) compared with either daratumumab hyaluronidase-fihj, pomalidomide and
dexamethasone (DPd) or daratumumab hyaluronidase-fihj, bortezomib and
dexamethasone (DVd) (N=290) was evaluated in patients with relapsed or
refractory multiple myeloma in MajesTEC-3 [see Clinical Studies (14.1)]. Patients received step-up doses of
0.06 mg/kg and 0.3 mg/kg of TECVAYLI followed by TECVAYLI 1.5 mg/kg once
weekly, followed by TECVAYLI 3 mg/kg every two weeks, followed by TECVAYLI 3
mg/kg every four weeks, subcutaneously.
Among
patients who received TECVAYLI in combination with daratumumab
hyaluronidase-fihj the median exposure was 32 (range 0.03 to 43) months. Among
patients who received DPd or DVd the median exposure was 16 (range 0.03 to 45)
months.
Serious
adverse reactions occurred in 71% of patients who received TECVAYLI in
combination with daratumumab hyaluronidase-fihj. Serious adverse reactions
reported in greater than or equal to 3% of patients included pneumonia (33%),
upper respiratory tract infection (15%), cytokine release syndrome (10%),
COVID-19 (7%), sepsis (6%), second primary malignancy (5%), pyrexia (4.9%),
febrile neutropenia (4.6%), and gastroenteritis (4.2%).
Fatal
adverse reactions occurred in 2.5% of patients who received TECVAYLI in
combination with daratumumab hyaluronidase-fihj, and included sepsis (0.7%),
pneumonia (0.4%), sudden death (0.4%), myocardial infarction (0.4%),
enterovirus myocarditis (0.4%) and hemophagocytic lymphohistiocytosis (0.4%).
Permanent
discontinuation of TECVAYLI due to adverse reactions occurred in 6% of
patients. Adverse reactions leading to discontinuation of TECVAYLI in more than
one patient were pneumonia (1.1%), diarrhea (0.7%), fatigue (0.7%), second
primary malignancy (0.7%), upper respiratory tract infection (0.7%) and cough
(0.7%).
Dosage
interruptions of TECVAYLI due to an adverse reaction occurred in 94% of
patients. Adverse reactions which required dosage interruption of TECVAYLI in greater
than or equal to 5% of patients included neutropenia (53%), upper respiratory
tract infection (48%), COVID-19 (34%), pneumonia (34%), thrombocytopenia (14%),
cytokine release syndrome (13%), gastroenteritis (10%), cough (10%), pyrexia
(8%), diarrhea (7%), sepsis (6%) and fatigue (5%).
The
most common adverse reactions (greater than or equal to 20%) were
hypogammaglobulinemia, upper respiratory tract infection, cytokine release
syndrome, cough, diarrhea, musculoskeletal pain, COVID-19, pneumonia, injection
site reaction, fatigue, pyrexia, headache, nausea, gastroenteritis, and weight
decreased.
The
most common Grade 3 to 4 laboratory abnormalities (greater than or equal to 20%)
were decreased lymphocytes, decreased neutrophils, decreased white blood cells
and decreased platelets.
Table
12 summarizes the adverse reactions in MajesTEC-3.
Table 12: Adverse
Reactions (greater than or equal to 10%) in Patients with Multiple Myeloma Who Received TECVAYLI in
Combination with Daratumumab Hyaluronidase-fihj in MajesTEC-3
Newly
added table; please refer to label for complete information.
Clinically
relevant adverse reactions in <10% of patients who received TECVAYLI in
combination with daratumumab hyaluronidase-fihj included sepsis,
encephalopathy, CMV infection, febrile neutropenia and ICANS.
Table
13 summarizes laboratory abnormalities in MajesTEC-3.
Table 13: Select
Laboratory Abnormalities (greater than or equal to 30%) that Worsened from
Baseline in Patients with Multiple Myeloma who Received TECVAYLI in Combination
with Daratumumab Hyaluronidase-fihj in MajesTEC-3
Newly
added table; please refer to label for complete information.
Monotherapy
The
safety of TECVAYLI monotherapy
(N=165) in patients with relapsed or refractory multiple myeloma was
evaluated in MajesTEC-1 [see Clinical
Studies (14.1)]. Patients received step-up doses of 0.06 mg/kg and 0.3
mg/kg of TECVAYLI followed by TECVAYLI 1.5 mg/kg, subcutaneously once weekly.
Among patients who received TECVAYLI, 47% were exposed for 6 months or longer
and 7% were exposed for one year or longer.
.
. .
Table 14: Adverse
Reactions (greater than or equal to 10%) in Patients with Multiple Myeloma Who
Received TECVAYLI in MajesTEC-1
Additions and/or revisions to the key (legend)
section of table; please refer to label for complete information.
. . .
7
Drug Interactions
Additions
and/or revisions underlined:
TECVAYLI
causes release of cytokines [see Clinical
Pharmacology (12.2)] that may suppress activity of certain
cytochrome P450 (CYP) enzymes, resulting in increased exposure of CYP
substrates, which may increase the risk of adverse reactions of the CYP
substrates. The highest risk of drug-drug interaction is expected to occur after
initiation of TECVAYLI step-up dosing schedule up to 7 days after the first
treatment dose and during and after CRS [see
Warnings and Precautions (5.1)].
Monitor
for toxicity and/or concentrations of CYP substrates where minimal increases
in concentration may lead to serious adverse reactions. Consider
decreasing the dosage of the concomitant CYP substrate as needed.
8
Use in Specific Populations
8.5
Geriatric Use
Additions
and/or revisions underlined:
- 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. The study did not include a sufficient number of
patients 75 years of age or older to assess whether there are differences in
safety or effectiveness.
- Of
the 291 patients with relapsed or refractory multiple myeloma treated with
TECVAYLI at the recommended dosage in combination with daratumumab
hyaluronidase-fihj in MajesTEC-3, 51% were younger than 65 years of age, 39%
were 65 to 74 years of age, and 11% were 75 years of age or older. No overall
differences in effectiveness were observed between patients 65 to 74 years of
age compared to younger patients. The study did not include a sufficient number
of patients 75 years of age or older to assess whether there are differences in
effectiveness compared to younger patients. There was a higher incidence of
serious adverse reactions in patients 75 years of age or older (83%) and in
patients 65 to 74 years of age (77%) as compared to patients younger than 65
years of age (63%).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION
GUIDE
Extensive changes; please refer to
label for complete information.
PATIENT
COUNSELING INFORMATION
Additions
and/or revisions underlined:
.
. .
Cytokine
Release Syndrome (CRS)
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
any signs or symptoms of CRS. Advise patients that they will be hospitalized
for 48 hours after administration of both step-up dose 1 and step-up dose 2.
Advise patients to remain within proximity of a healthcare facility and that
they will be monitored daily for 48 hours after the first treatment dose
within the TECVAYLI step-up dosing schedule [see
Dosage and Administration (2.5) and Warnings and Precautions (5.1)].
Neurologic
Toxicity including ICANS
Discuss
the signs and symptoms associated with neurologic toxicity, including ICANS,
including headache, confusion, dysgraphia, decreased level of consciousness,
aphasia, apraxia, somnolence, disorientation, motor dysfunction,
neuropathy, or encephalopathy. Advise patients to immediately contact their
healthcare provider if they experience any signs or symptoms of neurologic
toxicity, including ICANS. 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, including ICANS symptoms until
neurologic toxicity resolves [see Dosage
and Administration (2.5) and Warnings and Precautions (5.2)].
TECVAYLI
and TALVEY REMS
TECVAYLI
is available only through a restricted program called TECVAYLI and TALVEY REMS.
Inform patients that they will be given a Patient Wallet Card that they should
carry with them at all times and show to all of their healthcare providers.
This card describes signs and symptoms of CRS and neurologic toxicity, including
ICANS which, if experienced, should prompt the patient to immediately seek
medical attention [see Warnings and
Precautions (5.3)].
.
. .
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