DRUG INTERACTIONS-(summary)-

For certain cytochrome P450 (CYP) substrates, minimal changes in the substrate concentration may lead to serious adverse reactions.

Monitor for toxicity or drug concentrations of such CYP substrates when co-administered with TALVEY. Talquetamab-tgvs causes release of cytokines  that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates.

Increased exposure of CYP substrates is more likely to occur from initiation of the TALVEY step-up dosing schedule up to 14 days after the first treatment dose and during and after CRS

SUMMARY-

TALQUETAMAB- (Aug 2023)

Indication- to treat adults with relapsed or refractory   multiple myeloma

Dose- First treatment dose 0.4 mg/kg Weekly One week after first treatment dose and weekly thereafter. Subsequent treatment doses 0.4 mg/kg once weekly a Based on actual body weight.   

ADR-  most common adverse reactions  are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain    

CI -none     

Pat.inform-  Counsel patients to seek medical attention should signs or symptoms of CRS occur. Advise patients that they should be hospitalized for 48 hours after administration of all doses within the  step-up dosing schedule

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 32

Name-                      TALVEY

Acive  Ingredient -  Talquetamam tgus

Pharmacological clssificiation-        To treat adults with relapsed or refractory                                                                       multiple myeloma who have received at least                                                                 four linesof therapies                                                                                                                                                                   

  Date of Approval-         8/9/2023

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                  TALVEY safely and effectively.

See full prescribing information for TALVEY. TALVEY™ (talquetamab-tgvs) injection, for subcutaneous use

Initial U.S. Approval: 2023

WARNING:

CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY, including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

See full prescribing information for complete boxed warning.

Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TALVEY. Initiate TALVEY treatment with step-up dosing to reduce the risk of CRS.

Withhold TALVEY until CRS resolves or permanently discontinue based on severity. 

Neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), and serious and life-threatening or fatal reactions, can occur in patients receiving TALVEY.

Monitor patients for signs or symptoms of neurologic toxicity, including ICANS, during treatment. Withhold or permanently discontinue TALVEY based on severity.

 TALVEY is available only through a restricted program called the TECVAYLI and TALVEY Risk Evaluation and Mitigation Strategy (REMS).

INDICATIONS AND USAGE

 TALVEY is a bispecific GPRC5D-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

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.

CONTRAINDICATIONS

 None. 

WARNINGS AND PRECAUTIONS-

 • Oral Toxicity and Weight Loss: Monitor for oral toxicity and weight loss. Withhold or permanently discontinue based on severity.

 • Infections: Can cause serious, life-threatening, or fatal infections. Monitor for signs and symptoms of infection; treat appropriately. Withhold or consider permanent discontinuation based on severity.

 • Cytopenias: Monitor complete blood counts.

 • Skin Toxicity: Monitor for skin toxicity, including rash progression, for early intervention and treat appropriately. Withhold as recommended based on severity.

 • Hepatotoxicity: Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold or consider permanent discontinuation based on severity.

 • Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.

DOSAGE AND ADMINISTRATION

 • For subcutaneous injection.                                                                                             • Patients should be hospitalized for 48 hours after all doses within the stepup dosing schedule.                                                                                                                             • Administer pretreatment medications as recommended.                                                 • See Full Prescribing Information for instructions on preparation and administration.

 TALVEY Weekly Dosing Schedule

 Dosing schedule Day Dosea Step-up dosing schedule Day 1 Step-up dose 1 0.01 mg/kg Day 4b Step-up dose 2 0.06 mg/kg Day 7b

First treatment dose 0.4 mg/kg Weekly dosing schedule One week after first treatment dose and weekly thereafter

Subsequent treatment doses 0.4 mg/kg once weekly a Based on actual body weight.   

 b Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. 

 c Maintain a minimum of 6 days between weekly doses.

d Maintain a minimum of 12 days between biweekly (every 2 weeks) doses.

DOSAGE FORMS AND STRENGTHS

- Injection • 3 mg/1.5 mL (2 mg/mL) in a single-dose vial

 • 40 mg/mL in a single-dose vial 

TALVEY Biweekly (Every 2 Weeks) Dosing Schedule

 Dosing schedule Day Dosea

Step-up dosing schedule Day 1 Step-up dose 1 0.01 mg/kg Day 4b Step-up dose 2 0.06 mg/kg Day 7b Step-up dose 3 0.4 mg/kg Day 10c

First treatment dose 0.8 mg/kg Biweekly (every 2 weeks) dosing schedule Two weeks after first treatment dose and every 2 weeks thereafterd

Subsequent treatment doses 0.8 mg/kg every 2 weeks a Based on actual body weight.

b Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions.

c Dose may be administered between 2 to 7 days after step-up dose 3.

d Maintain a minimum of 12 days between biweekly (every 2 weeks) doses.

DOSAGE FORMS AND STRENGTHS

- Injection • 3 mg/1.5 mL (2 mg/mL) in a single-dose vial

 • 40 mg/mL in a single-dose vial 

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Cytokine Release Syndrome (CRS)-

 Discuss the signs and symptoms associated with CRS including, but not limited to, pyrexia, hypotension, chills, hypoxia, headache, and tachycardia

 Counsel patients to seek medical attention should signs or symptoms of CRS occur.

Advise patients that they should be hospitalized for 48 hours after administration of all doses within the TALVEY step-up dosing schedule

Neurologic Toxicity, including ICANS-

Discuss the signs and symptoms associated with neurologic toxicity, including ICANS including headache, encephalopathy, sensory neuropathy, motor dysfunction, ICANS, confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

Counsel patients to seek medical attention should signs or symptoms of ICANS occur.

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 neurologic toxicity symptoms, until symptoms resolve

.TECVAYLI and TALVEY REMS TALVEY is available only through a restricted program called the 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.

Oral Toxicity and Weight Loss -

Discuss the signs and symptoms of oral toxicities including dysgeusia, dry mouth, dysphagia, and stomatitis.

Counsel patients to seek medical attention should signs or symptoms of oral toxicity occur.

Advise patients that they may experience weight loss and to report weight loss.

Advise patients that they may be referred to a nutritionist for consultation

 Infections-

 Discuss the signs and symptoms of serious infections

 Discuss the signs and symptoms associated with neutropenia and thrombocytopenia

 Skin Toxicity-

 Discuss the signs and symptoms of skin reactions

Hepatotoxicity -

Advise patients that liver enzyme 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. .

Embryo-Fetal Toxicity-

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 TALVEY and for 3 months after the last dose

Lactation

Advise women not to breastfeed during treatment with TALVEY and for 3 months after the last dose 

Manufactured by: Janssen Biotech, Inc. Horsham, PA 19044, USA U.S. License Number 1864 For patent information: www.janssenpatents.com © 2023 Janssen Pharmaceutical Companies

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

 Talquetamab-tgvs is a bispecific T-cell engaging antibody that binds to the CD3 receptor expressed on the surface of T-cells and G protein-coupled receptor class C group 5 member D (GPRC5D) expressed on the surface of multiple myeloma cells and non-malignant plasma cells, as well as healthy tissues such as epithelial cells in keratinized tissues of the skin and tongue. In vitro, talquetamab-tgvs activated T-cells caused the release of proinflammatory cytokines and resulted in the lysis of multiple myeloma cells.

Talquetamab-tgvs had anti-tumor activity in mouse models of multiple myeloma.

2. Pharmacodynamics -

Serum concentrations of cytokines (IL-6, IL-10, TNF-a, and IFN-?) and IL-2R were measured before and after administration of each step-up dose, the first three treatment doses at 0.4 mg/kg once weekly, and the first two treatment doses at 0.8 mg/kg every two weeks. Increased concentrations of IL-6, IL-10, and IL-2R were observed during this period.

Higher talquetamab-tgvs exposures (i.e., AUC and Cmax) are associated with higher incidence of some adverse reactions (including oral toxicity, nail toxicity, and skin reactions).

The exposureresponse relationships for effectiveness and the time course of pharmacodynamic response of talquetamab-tgvs have not been fully characterized.

3. Pharmacokinetics-

The Cmax and AUCtau of talquetamab-tgvs after subcutaneous administration increased proportionally over a dose range of 0.005 to 0.8 mg/kg weekly (0.01 to 2 times the recommended 0.4 mg/kg weekly treatment dose) and 0.8 to 1.2 mg/kg every two weeks (1 to 1.5 times the recommended 0.8 mg/kg every 2 weeks treatment dose). Ninety percent of steady state exposure was achieved 16 weeks after the first treatment dose for both regimens.

Absorption The geometric mean (coefficient of variation [CV] %) bioavailability of talquetamab-tgvs was 59% (22%) when administered subcutaneously.

Distribution

The geometric mean (CV%) volume of distribution of talquetamab-tgvs was 10.1 L (25%).

Elimination-

Talquetamab-tgvs clearance decreases over time, with a mean (CV%) maximal reduction from the first treatment dose to 16 weeks after the first treatment dose of 40% (56%).

The geometric mean (CV%) clearance is 0.90 L/day (63%) at 16 weeks after the first treatment dose.

The mean (CV%) terminal half-life was 8.4 (41%) days after the first treatment dose and 12.2 (49%) days at 16 weeks after the first treatment dose.

Metabolism -

Talquetamab-tgvs is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations-

 The volume of distribution and clearance of talquetamab-tgvs increased with increasing bodyweight (40 kg to 143 kg). 

There were no clinically significant differences in the pharmacokinetics of talquetamab-tgvs based on age (33 to 86 years), sex, race (White, Black or African American), ethnicity (Not Hispanic/Latino, Hispanic/Latino), mild or moderate renal impairment (creatinine clearance [CLcr] by Cockcroft-Gault equation: 30 to 89 mL/min) or mild (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) or moderate (total bilirubin greater than 1.5 to less than 3 times ULN with any AST) hepatic impairment.

The effects of severe renal impairment (CLcr less than 30 mL/min) or severe hepatic impairment (total bilirubin greater than 3 times ULN with any AST) on the pharmacokinetics of talquetamab-tgvs are unknown.

6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

1 Pregnancy Risk Summary-

Based on the mechanism of action, TALVEY may cause fetal harm when administered to a pregnant woman.

There are no available data on the use of TALVEY in pregnant women to evaluate for a drug associated risk.

No animal reproductive or developmental toxicity studies have been conducted with talquetamab-tgvs. Talquetamab-tgvs causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance.

Human immunoglobulin G (IgG) is known to cross the placenta; therefore, TALVEY has the potential to be transmitted from the mother to the developing fetus.

Advise women of the potential risk to the fetus.

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.

2. Lactation Risk Summary-

 There is no information regarding the presence of talquetamab-tgvs in human milk, the effect on the breastfed child, or the effect 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 TALVEY are unknown.

Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TALVEY and for 3 months after the last dose.

3. Females and Males of Reproductive Potential-

TALVEY may cause fetal harm when administered to a pregnant woman

Pregnancy Testing-                                                                                                            Verify pregnancy status of females of reproductive potential prior to initiating TALVEY.

Contraception-

Females Advise females of reproductive potential to use effective contraception during treatment with TALVEY and for 3 months after the last dose.

4 Pediatric Use-

The safety and efficacy of TALVEY have not been established in pediatric patients.

5 Geriatric Use-

There were 339 patients in the clinical trial for relapsed or refractory multiple myeloma. Of the total number of TALVEY-treated patients in the study, 178 (53%) patients were 65 years of age and older, while 57 (17%) patients were 75 years of age and older.

No overall differences in safety or effectiveness were observed in patients 65 to less than 74 years of age compared to younger patients.

There was a higher rate of fatal adverse reactions in patients 75 years of age or older compared to younger patients [see Adverse Reactions (6.1)].

Clinical studies did not include sufficient numbers of patients 75 years of age or over to determine whether they respond differently from younger patients.