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Linvoseltamab-gcpt, a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, is a recombinant human immunoglobulin (Ig)G4 antibody. Linvoseltamab-gcpt is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspen- sion culture. The molecular weight of linvoseltamab-gcpt is approximately 146 kDa.
LYNOZYFIC (linvoseltamab-gcpt) injection for intravenous use is a sterile, preservative- free, clear to slightly opalescent, colorless to pale yellow solution with a pH 6.0.
Each LYNOZYFIC 5 mg/2.5 mL vial contains 5 mg of linvoseltamab-gcpt. Each mL contains 2 mg of linvoseltamab-gcpt, histidine (0.7 mg), L-histidine hydrochloride mono- hydrate (1.1 mg), polysorbate 80 (1 mg), sucrose (100 mg), and Water for Injection, USP.
Each LYNOZYFIC 200 mg/10 mL vial contains 200 mg of linvoseltamab-gcpt. Each mL contains 20 mg of linvoseltamab-gcpt, histidine (0.7 mg), L-histidine hydrochloride monohydrate (1.1 mg), polysorbate 80 (1 mg), sucrose (100 mg), and Water for Injection, USP.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of LYNOZYFIC was evaluated in LINKER-MM1 [see Clinical Studies (14)]. Patients (n=117) received LYNOZYFIC as step-up doses of 5 mg on Day 1 and 25 mg on Day 8, and the first treatment dose of 200 mg on Day 15. Patients then received 200 mg intravenously once weekly from Week 4 to Week 13, followed by 200 mg every 2 weeks from Week 14. In the Phase 2 portion of the study, patients who achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg were able to receive every 4-week dosing. The median duration of treatment was 47 weeks (range 1, 151); 55% of patients were exposed for 9 months or longer and 36% were exposed for 1 year or longer.
The median age of patients who received LYNOZYFIC was 70 years (range: 37 to 91 years); 55% were male; 71% were White, 17% were Black or African American, and 9% were Asian.
Serious adverse reactions occurred in 74% of patients who received LYNOZYFIC. Serious adverse reactions that occurred in >5% of patients included cytokine release syndrome (27%), pneumonia (13%), COVID-19 (7%), and acute kidney injury (5%). Fatal adverse reactions occurred in 7% of patients, and included sepsis (3.4%), chronic kidney disease (0.9%), pneumonia (0.9%), tumor lysis syndrome (0.9%), and encephalopathy (0.9%).
Permanent discontinuation of LYNOZYFIC due to adverse reactions occurred in 16% of patients. Adverse reactions leading to discontinuation that occurred in at least 2 patients included sepsis, pneumonia, and encephalopathy.
Dosage interruptions or delays of LYNOZYFIC due to adverse reactions occurred in 74% of patients. Adverse reactions which required a dosage interruption or delay in >10% of patients included neutropenia (29%), upper respiratory tract infection (18%), pneumonia (15%), and COVID-19 infection (11%).
The most common adverse reactions (≥20%) were musculoskeletal pain, cytokine release syndrome, cough, upper respiratory tract infection, diarrhea, fatigue, pneumonia, nausea, headache, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased lymphocyte count, decreased neutrophil count, decreased hemoglobin, and decreased white blood cell count.
Table 7 summarizes the adverse reactions in LINKER-MM1.
Table 7: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Multiple Myeloma Who Received LYNOZYFIC in LINKER-MM1
|
Adverse Reaction |
LYNOZYFIC (N=117) |
|
|
All Grades (%) |
Grade 3 or 4 (%) |
|
|
Musculoskeletal and connective tissue disorders |
||
|
Musculoskeletal pain* |
53 |
3.4# |
|
Immune system disorders |
||
|
Cytokine release syndrome |
46 |
0.9# |
|
Hypogammaglobulinemia |
13 |
0.9# |
|
Respiratory, thoracic and mediastinal disorders |
||
|
Cough* |
39 |
0 |
|
Dyspnea* |
21 |
0.9# |
|
Nasal congestion |
16 |
0 |
|
Infections and infestations |
||
|
Upper respiratory tract infection* |
35 |
6# |
|
Pneumoniaa,± |
28 |
21 |
|
COVID-19 |
17 |
5 |
|
Urinary tract infections* |
16 |
8# |
|
Sepsis |
10 |
6 |
|
Gastrointestinal disorders |
||
|
Diarrhea |
35 |
1.7# |
|
Nausea |
23 |
0 |
|
Vomiting |
19 |
0 |
|
Constipation |
17 |
0 |
|
General disorders and administration site conditions |
||
|
Fatigue* |
34 |
0 |
|
Edema* |
19 |
0.9# |
|
Pyrexia |
17 |
0 |
|
Nervous system disorders |
||
|
Headache* |
22 |
0.9# |
|
Encephalopathy±,b |
18 |
3.4 |
|
Sensory Neuropathy* |
13 |
0.9 |
|
Metabolism and nutrition disorders |
||
|
Decreased appetite |
15 |
0.9# |
|
Skin and subcutaneous tissue disorders |
||
|
Rashc |
15 |
1.7# |
|
Psychiatric disorders |
||
|
Insomnia |
13 |
0 |
|
Vascular disorders |
||
|
Hypertension |
10 |
4.3# |
|
* Includes other related terms. |
||
Clinically significant adverse reactions that occurred in <10% of patients treated with LYNOZYFIC included IRR, motor dysfunction, febrile neutropenia, ICANS, CMV infection, and PML.
Table 8 summarizes the laboratory abnormalities in LINKER-MM1.
Table 8: Select Laboratory Abnormalities (≥5% for Grade 3 or 4) That Worsened from Baseline in Patients with Multiple Myeloma Treated with LYNOZYFIC in LINKER-MM1
|
Laboratory Abnormalitya |
LYNOZYFIC (N=117)b |
|
|
All Grades (%) |
Grades 3 or 4 (%) |
|
|
Hematology |
||
|
Lymphocyte count decreased |
97 |
92 |
|
Hemoglobin decreased |
72 |
42 |
|
Platelet count decreased |
64 |
19 |
|
White blood cell count decreased |
63 |
31 |
|
Neutrophil count decreased |
62 |
47 |
|
Chemistry |
||
|
Aspartate aminotransferase increased |
61 |
10 |
|
Phosphorus decreased |
55 |
24 |
|
Creatinine increased |
47 |
7 |
|
Alanine aminotransferase increased |
46 |
6 |
|
a Laboratory tests were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Version 5.0. |
||
Monitor for toxicity unless otherwise recommended in the Prescribing Information of certain CYP substrates where minimal changes in the concentration may lead to serious adverse reactions when used concomitantly with LYNOZYFIC.
Linvoseltamab-gcpt causes the release of cytokines [see Clinical Pharmacology (12.2)] that may suppress cytochrome P450 (CYP) enzyme activity. Concomitant use with LYNOZYFIC increases CYP substrate exposure which may increase the risk of adverse reactions related to these substrates. Increased CYP substrate exposure is more likely to occur from initiation of the LYNOZYFIC step-up dosing schedule up to 14 days after the first 200 mg dose, and during and after CRS [see Warnings and Precautions (5.1)].
Included as part of the PRECAUTIONS section.
LYNOZYFIC can cause cytokine release syndrome (CRS), which can be serious or life- threatening.
In LINKER-MM1, CRS occurred in 46% (54/117) of patients who received LYNOZYFIC at the recommended dose, with Grade 1 CRS occurring in 35% (41/117) of patients, Grade 2 in 10% (12/117), and Grade 3 in 0.9% (1/117) [see Adverse Reactions (6.1)]. Thirty-eight percent (45/117) of patients had CRS following step-up dose 1, including 1 patient who experienced Grade 3 CRS; 8% (9/117) had an initial CRS event following a subsequent dose. Seventeen percent (19/113) of patients developed CRS after step-up dose 2, 10% (11/111) developed CRS after the first full 200 mg dose of LYNOZYFIC, and 3.6% (4/110) developed CRS after the second full dose. Recurrent CRS occurred in 20% (23/117) of patients. The median time to onset of CRS from the end of infusion was 11 (range: -1 to 184) hours after the most recent dose with a median duration of 15 (range: 1 to 76) hours.
Clinical signs and symptoms of CRS included, but were not limited to pyrexia, chills, hypoxia, tachycardia, and hypotension.
Administer pretreatment medications and initiate therapy according to LYNOZYFIC step-up dosing to reduce the incidence and severity of CRS [see Dosage and Administration (2.2) and Dosage and Administration (2.3)].
Monitor patients for signs and symptoms of CRS after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur.
At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold LYNOZYFIC until CRS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity [see Dosage and Administration (2.5)].
Infusion Related Reactions
Infusion-related reactions (IRR) may be clinically indistinguishable from manifestations of CRS. In the patients who were treated with the recommended step-up dosing regimen and pretreatment medications [see Dosage and Administration (2.2) and Dosage and Administration (2.3)], the rate of IRR was 9% [11/117 including Grade 2 IRR (4.3%) and Grade 3 IRR (1.7%)]. For IRR, interrupt or slow the rate of infusion or permanently discontinue LYNOZYFIC based on severity of reaction [see Dosage and Administration (2.5)].
LYNOZYFIC is available only through a restricted program under a REMS [see Warnings and Precautions (5.3)].
LYNOZYFIC can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS) [see Adverse Reactions (6.1)].
In LINKER-MM1, neurologic toxicity occurred in 54% of patients, with Grade 3 or 4 neurologic toxicity occurring in 8%, at the recommended dose [see Adverse Reactions (6.1)]. Neurologic toxicities included ICANS, depressed level of consciousness, encephalopathy, and toxic encephalopathy.
ICANS occurred in 8% of patients who received LYNOZYFIC with the recommended dosing regimen, including Grade 3 events in 2.6%. Most patients experienced ICANS following step-up dose 1 (5%). Two patients (1.8%) experienced initial ICANS following step-up dose 2 and one patient developed the first occurrence of ICANS following a subsequent full dose of LYNOZYFIC. Recurrent ICANS occurred in one patient. The median time to onset of ICANS was 1 (range: 1 to 4) day after the most recent dose with a median duration of 2 (range: 1 to 11) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.
The most common clinical signs and symptoms of ICANS are confusion, depressed level of consciousness, and lethargy. Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient; provide supportive therapy and consider further management per current practice guidelines. Withhold LYNOZYFIC until ICANS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity [see Dosage and Administration (2.5)]. Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time.
Due to the potential for neurologic toxicity, including ICANS, patients receiving LYNOZYFIC are at risk of confusion and depressed consciousness. Advise patients to refrain from driving, or operating heavy or potentially dangerous machinery, for 48 hours after completion of each of the step-up doses [see Dosage and Administration (2.2)] and in the event of new onset of any neurological symptoms, until symptoms resolve.
LYNOZYFIC is available only through a restricted program under a REMS [see Warnings and Precautions (5.3)].
LYNOZYFIC is available only through a restricted program under a REMS called the LYNOZYFIC REMS because of the risks of CRS and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1, 5.2)].
Notable requirements of the LYNOZYFIC REMS include the following:
Further information about the LYNOZYFIC REMS program is available at lynozyficREMS.com or by telephone at 1-855-212-6391.
LYNOZYFIC can cause serious, life-threatening, or fatal infections.
In patients who received LYNOZYFIC at the recommended dose in LINKER-MM1, serious infections, including opportunistic infections, occurred in 42% of patients, with Grade 3 or 4 infections in 38% and fatal infections in 4% [see Adverse Reactions (6.1)]. The most common serious infection reported (≥10%) were pneumonia and sepsis. Two cases of progressive multifocal leukoencephalopathy (PML) occurred in patients receiving LYNOZYFIC.
Monitor patients for signs and symptoms of infection and immunoglobulin levels prior to and during treatment with LYNOZYFIC and treat appropriately. Administer prophylactic antimicrobials, antibiotics, antifungals, antivirals, vaccines, and subcutaneous or intravenous immunoglobulin (IVIG) according to guidelines, including prophylaxis for PJP and herpesviruses [see Dosage and Administration (2.3)].
Withhold LYNOZYFIC or consider permanent discontinuation of LYNOZYFIC based on severity of the infection [see Dosage and Administration (2.5)].
LYNOZYFIC can cause neutropenia and febrile neutropenia.
In patients who received LYNOZYFIC at the recommended dose in LINKER-MM1, decreased neutrophil count occurred in 62% of patients with Grade 3 or 4 decreased neutrophil count in 47%. Febrile neutropenia occurred in 8% of patients [see Adverse Reactions (6.1)].
Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local guidelines. Monitor patients with neutropenia for signs of infection. Withhold LYNOZYFIC based on severity [see Dosage and Administration (2.5)].
LYNOZYFIC can cause hepatotoxicity.
In LINKER-MM1, elevated ALT occurred in 46% of patients, with Grade 3 or 4 ALT elevation occurring in 6%; elevated AST occurred in 61% of patients, with Grade 3 or 4 AST elevation occurring in 10% of patients who received the recommended dose.
Grade 3 or 4 total bilirubin elevations occurred in 1.7% of patients [see Adverse Reactions (6.1)]. Liver enzyme elevation can occur with or without concurrent CRS.
Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold LYNOZYFIC or consider permanent discontinuation of LYNOZYFIC based on severity [see Dosage and Administration (2.5)].
Based on its mechanism of action, LYNOZYFIC 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 LYNOZYFIC and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
No carcinogenicity or genotoxicity studies have been conducted with linvoseltamab-gcpt.
No animal studies have been performed to evaluate the effects of linvoseltamab-gcpt on fertility.
No information provided.
No information provided.
Linvoseltamab-gcpt is a bispecific T-cell engaging antibody that binds to the CD3 receptor expressed on the surface of T-cells and B-cell maturation antigen (BCMA) expressed on the surface of multiple myeloma cells and some healthy B-lineage cells.
In vitro, linvoseltamab-gcpt activated T-cells, caused the release of various proinflamma- tory cytokines, and resulted in the lysis of multiple myeloma cells. Linvoseltamab-gcpt had anti-tumor activity in mouse models of multiple myeloma.
The 200 mg once weekly dosing regimen was associated with better objective response rate and complete response rate when compared to the 50 mg once weekly (0.25 times the recommended dosage) dosing regimen in patients with relapsed or refractory multiple myeloma.
Linvoseltamab-gcpt exposure-response relationships have not been fully characterized.
Transient elevation of circulating cytokines (IL-2, IL-6, and IFN- ) was primarily observed during the step-up dose regimen and the first full 200 mg dose. The highest elevation of cytokines was generally observed 4 hours after each infusion and generally returned to baseline prior to the next dose. Limited cytokine release was observed following subsequent doses.
Pharmacokinetic (PK) parameters were evaluated at the recommended dosage in patients with relapsed or refractory multiple myeloma and arepresented as geometric mean (CV%) unless otherwise specified.
Linvoseltamab-gcpt PK exposures following useof the recommended dosing schedule are presented in Table 9. Linvoseltamab-gcpt Ctrough increased more than proportionally over a dose range of 96 mg to 800 mg (0.48 to 4 times the recommended full dose). Linvoseltamab-gcpt maximum concentration (127 mg/L [51%]) is achieved after the first dose of the every-2-weeks dosing regimen (i.e., the 12th dose of 200 mg).
Table 9: Geometric Mean (CV%) Exposure Following the Recommended Dosage for Linvoseltamab-gcpt
|
Dosing Period |
Cmax (mg/L) |
Ctrough (mg/L) |
Cavg (mg /L) |
|
First 200 mg weekly dose |
52.7 (37.2) |
15.5 (64.8) |
27.4 (34.2) |
|
End of 200 mg weekly dosing (11th dose of 200 mg) |
124 (50.4) |
61.8 (123) |
84.6 (74.6) |
|
End of 200 mg every 2 weeks dosing (16th dose of 200 mg) |
97.9 (52.7) |
30.2 (213) |
51.9 (95.3) |
|
Steady statea with 200 mg every 4 weeks dosing |
64.8 (45.1) |
6.3 (362) |
20.5 (84.6) |
|
a Steady state values are approximated at Week 28. |
|||
Linvoseltamab-gcpt volume of distribution (Vd) is 7.05 L (33.6%).
Linvoseltamab-gcpt clearance is 0.68 L/day (52.2%) at baseline and 0.43 L/day (83.8%) at steady state.
Linvoseltamab-gcpt clearance decreases over time because its elimination is mediated by two parallel processes: a linear, non-saturable catabolic process and a nonlinear, saturable target-mediated pathway. Patients who discontinue linvoseltamab-gcpt are expected to have a 97% reduction from Cmax at a median (5th to 95th percentile) time of 77.7 (18 to 154) days after last dose.
Metabolism
Linvoseltamab-gcpt is expected to be metabolized into small peptides by catabolic pathways.
No clinically significant differences in the pharmacokinetics of linvoseltamab-gcpt were observed based on age (37 to 91 years), weight (44 to 172 kg), sex, race (White, Asian, or Black), ethnicity (Hispanic/Latino or not Hispanic/Latino), mild to moderate renal impairment (creatinine clearance [CrCL] 30 to 89 mL/min, by Cockcroft-Gault [C-G] equation), or mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST).
The effect of severe renal impairment (CrCL 15 to 29 mL/min), end-stage renal disease (CrCL less than 15 mL/min), and moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN with any AST) on the pharmacokinetics of linvoseltamab-gcpt is unknown.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies, including those of linvoseltamab-gcpt.
During treatment in LINKER-MM1 (evaluated through 30 months) [see Clinical Studies (14)], 1% (2/192) of LYNOZYFIC-treated patients developed anti-linvoseltamab-gcpt antibodies. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of linvoseltamab products is unknown.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients that they should be hospitalized for 24 hours after administration of the first and second step-up doses of LYNOZYFIC [see Dosage and Administration (2.2)]. Inform patients of the risk of CRS, and discuss the signs and symptoms associated with CRS, including fever, chills, hypoxia, tachycardia, and hypotension. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Warnings and Precautions (5.1)].
Discuss the signs and symptoms associated with neurologic toxicity, including ICANS, including confusion, depressed level of consciousness, and lethargy. 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, for 48 hours after completion of each of the step-up doses or if they experience new onset of neurologic toxicity symptoms until the symptoms resolve [see Warnings and Precautions (5.2)].
LYNOZYFIC is available only through a restricted program called the LYNOZYFIC 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 symptoms of CRS and neurologic toxicity, including ICANS which, if experienced, should prompt the patient to seek immediate medical attention [see Warnings and Precautions (5.3)].
Advise patients of the risk of serious infections. Instruct patients to immediately report infection-related signs or symptoms of infection (e.g., fever, chills, weakness) [see Warnings and Precautions (5.4)].
Discuss the signs and symptoms associated with neutropenia and febrile neutropenia [see Warnings and Precautions (5.5)].
Advise patients that liver enzymes elevations may occur and that they should report symptoms that may indicate liver toxicity, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.6)].
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant. Advise females of reproductive potential to use effective contraception during treatment with LYNOZYFIC and for 3 months after the last dose [see Warnings and Precautions (5.7), Use in Specific Populations (8.1, 8.3)].
Advise women not to breastfeed during treatment with LYNOZYFIC and for 3 months after the last dose [see Use in Specific Populations (8.2)].
 |
Manufactured by:
Regeneron Pharmaceuticals, Inc.
777 Old Saw Mill River Road
Tarrytown, NY 10591-6707
U.S. License No. 1760
LYNOZYFIC is a trademark of Regeneron Pharmaceuticals, Inc.
©2025 Regeneron Pharmaceuticals, Inc.
All rights reserved.
