DRUG INTERACTIONS -(details).

For certain CYP substrates, minimal changes in the concentration may lead to serious adverse reactions.

Monitor for toxicity or drug concentrations of such CYP substrates when co-administered with EPKINLY. Epcoritamab-bysp causes release of cytokines [see Clinical Pharmacology (12.2)] that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates.

Increased exposure of CYP substrates is more likely to occur after the first dose of EPKINLY on Cycle 1 Day 1 and up to 14 days after the first 48 mg dose on Cycle 1 Day 15, and during and after CRS

BRIEF SUMMARY-

EPCORITAMAB- (May 2023)

Indication-  To treat relapsed or refractory diffuse large B- cell lymphoma                         

 Dosage-  For subcutaneous injection only. Dosage  1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 First full dose 48 mg 22 48 mg Cycles 2 and 3 1, 8, 15 and 22 48 mg Cycles 4 to 9 1 and 15 48 mg Cycle 10 and beyond 1 48 mg a Cycle = 28 days                 

ADR-   most common (= 20%) adverse reactions are cytokine release syndrome, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. 

CI-  None.

 WARNINGS - Infections: Can cause serious or fatal infections. Monitor patients for signs or symptoms of infection, including opportunistic infections, and treat appropriately.

Pat inform- inform patients of the risk of CRS, and to immediately contact their healthcare provider should signs and symptoms associated with CRS (e.g., pyrexia, hypotension, hypoxia, chills, tachycardia, headache, and dyspnea) occur at any time

================================================================

U.S. FDA APPROVED  DRUGS DURING 2023

Sr.No-  18

 ADVERSE REACTIONS-

 The most common (= 20%) adverse reactions are cytokine release syndrome, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (= 10%) are decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets. 

CONTRAINDICATION-

 None.

 WARNINGS AND PRECAUTIONS -

 • Infections: Can cause serious or fatal infections. Monitor patients for signs or symptoms of infection, including opportunistic infections, and treat appropriately.

 • Cytopenias: Monitor complete blood cell counts during treatment.

 • 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-

DOSAGE FORMS AND STRENGTHS-

 • Injection: 4 mg/0.8 mL in a single-dose vial. Dilute prior to use.

 • Injection: 48 mg/0.8 mL in a single-dose vial.

• Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg.

 • Administer premedications and prophylaxis as recommended.

 • Dosages of EPKINLY 0.16 mg and 0.8 mg require dilution prior to administration.

 • See Full Prescribing Information for instructions on preparation and administration.

PATIENT COUNSELING INFORMATION -

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

 Cytokine Release Syndrome (CRS)-

 Inform patients of the risk of CRS, and to immediately contact their healthcare provider should signs and symptoms associated with CRS (e.g., pyrexia, hypotension, hypoxia, chills, tachycardia, headache, and dyspnea) occur at any time.

Advise patients that they should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg.

Advise patients who experience symptoms that impair consciousness not to drive and refrain from operating heavy or potentially dangerous machinery until events resolve 

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) -

Advise patients of the risk of ICANS, to immediately contact their healthcare provider for signs and symptoms associated with ICANS, which may manifest, for example, as confusional state, lethargy, tremor, dysgraphia, aphasia, and non-convulsive status epilepticus, and that the onset of events may be delayed.

Advise patients who experience symptoms of ICANS that impair consciousness to refrain from driving or operating heavy or potentially dangerous machinery until symptoms of ICANS resolve.

Infections -

Advise patients of the risk of serious infections, and to contact their healthcare professional for signs or symptoms of serious infection

Cytopenias-

Discuss the signs and symptoms associated with cytopenias, including neutropenia and febrile neutropenia, anemia, and thrombocytopenia.

 Embryo-Fetal Toxicity-

Advise pregnant women 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 EPKINLY and for 4 months after the last dose.

Lactation-

Advise women not to breastfeed during treatment with EPKINLY and for 4 months after the last dose..

Marketed by: Genmab US, Inc. Plainsboro, NJ 08536 Reference ID: 5176689 and AbbVie Inc. North Chicago, IL 60064 EPKINLY is a trademark owned by Genmab A/S ©2023 Genmab A/S Reference ID:

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-

 Epcoritamab-bysp is a T-cell engaging bispecific antibody that binds to the CD3 receptor expressed on the surface of T-cells and CD20 expressed on the surface of lymphoma cells and healthy B-lineage cells.

In vitro, epcoritamab-bysp activated T-cells, caused the release of proinflammatory cytokines, and induced lysis of B-cells

2. Pharmacodynamics-

 Circulating B Cell Count Circulating B cells decreased to undetectable levels (< 10 cells/microliter) after administration of the approved recommended dosage of EPKINLY in patients who had detectable B cells at  treatment initiation by Cycle 1 Day 15 (after the first full dose of 48 mg) and the depletion was sustained while patients remained on treatment.

3. Pharmacokinetics-

Pharmacokinetic (PK) parameters were evaluated at the approved recommended dosage (48 mg) and are presented as geometric mean (CV%) unless otherwise specified.

Absorption-

The median (range) Tmax of epcoritamab-bysp after the first full dose and end of the weekly dosing regimen (end of Cycle 3) treatment doses were 4 (0.3 to 7) days and 2.3 (0.3 to 3.2) days, respectively.

Distribution-

The apparent total volume of distribution is 25.6 L (82%). Reference ID: 5176689

Elimination-

 The half-life of full dose epcoritamab-bysp (48 mg) was approximately 22 days (58%) at the end of Cycle 3, with apparent total clearance of approximately 0.53 L/day (40%) after the end of Cycle 3.

Metabolism-

Epcoritamab-bysp is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations-

No clinically significant differences in the PK of epcoritamab-bysp were observed based on age (20 to 89 years), sex, race (White or Asian), mild to moderate renal impairment (creatinine clearance [CLcr] 30 to < 90 mL/min as estimated by Cockcroft-Gault formula), and mild hepatic impairment (total bilirubin = ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and any AST) after accounting for differences in bodyweight.

The effects of severe renal impairment (CLcr 15 to < 30 mL/min), end-stage renal disease (CLcr < 15 mL/min), or moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST) on the PK of epcoritamab-bysp are unknown.

Body Weight In patients who received the recommended dosage of EPKINLY, Cycle 1 median average concentration was 13% lower in the higher body weight (BW) group (85 to 144 kg) and 37% higher in the lower BW group (39 to 65 kg) compared to patients with BW of 65 to less than 85 kg.

Drug Interaction Studies-

No clinical studies evaluating the drug interaction potential of epcoritamab-bysp have been conducted.

6 Immunogenicity-

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 (ADA) in the study described below with the incidence of ADA in other studies, including those of epcoritamab-bysp.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

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

There are no available data on the use of EPKINLY in pregnant women to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies have been conducted with epcoritamab-bysp.

Epcoritamab-bysp causes T-cell activation and cytokine release

; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD20 on B-cells and the finding of B-cell depletion in non-pregnant animals, epcoritamab-bysp can cause B-cell lymphocytopenia in infants exposed to epcoritamab-bysp in-utero.

Human immunoglobulin G (IgG) is known to cross the placenta; therefore,

EPKINLY 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 epcoritamab-bysp in human milk, the effect on the breastfed child, or milk production.

Because maternal IgG is present in human milk, and there is potential for epcoritamab-bysp absorption leading to serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with EPKINLY and for 4 months after the last dose.

3. Females and Males of Reproductive Potential-

 EPKINLY may cause fetal harm when administered to a pregnant woman 

Pregnancy Testing-

Verify pregnancy status in females of reproductive potential prior to initiating EPKINLY.

Contraception Females-

Advise females of reproductive potential to use effective contraception during treatment with EPKINLY and for 4 months after the last dose.

4. Pediatric Use-

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

5. Geriatric Use-

In patients with relapsed or refractory LBCL who received EPKINLY in the clinical trial, 49% were 65 years of age or older, and 19% were 75 years of age or older.

No clinically meaningful differences in safety or efficacy were observed between patients 65 years of age or older compared with younger adult patients.