BRIEF SUMMARY

LONCASTUXIMAB - TESIRINE- (Apr 2021)

Indn-     To treat certain types of relapsed or refractory large B- cell lymphoma  

Comp- For injection: 10 mg of loncastuximab tesirine-lpyl as a lyophilized powder in a single-dose vial for reconstitution and further dilution.                                                     The recommended dosage is:  0.15 mg/kg every 3 weeks for 2 cycles. ? 0.075 mg/kg every 3 weeks for subsequent cycles.

ADR- Most common adverse reactions, including laboratory abnormalities, are thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

CI-  None

WARNINGS-

 Effusion and Edema: Monitor for the development of pleural effusion, pericardial effusion, ascites, peripheral edema, and general edema. Consider diagnostic imaging when symptoms develop or worsen.

Myelosuppression: Monitor blood cell counts. Withhold, reduce, or discontinue  based on severity.

Pat Inform-

Effusion and Edema: Advise patients to contact their healthcare provider if they experience swelling, weight gain, shortness of breath, or difficult, labored breathing 

 Myelosuppression: Advise patients to immediately contact their healthcare provider for a fever of 100.4°F (38°C) or greater, or signs or symptoms of bruising or bleeding. Advise patients of the need for periodic monitoring of blood counts

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

U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 18

Name of the Drug-    ZYNLONTS

Active Ingredient -   Loncastuximab trsirine-lpyl

Pharmacological Classification-   To treat certain types of relapsed or refractory                                                                large B- cell lymphoma                                                                                                                                                                                                                                              

Date of Approval-          4/23/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                           ZYNLONTA safely and effectively.                                                                                    See full prescribing information for ZYNLONTA. ZYNLONTA™ (loncastuximab tesirine-lpyl) for injection, for intravenous use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE- 

 ZYNLONTA is a CD19-directed antibody and alkylating agent conjugate indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

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

DOSAGE AND ADMINISTRATION-

 ZYNLONTA is an intravenous infusion over 30 minutes on Day 1 of each cycle (every 3 weeks).

The recommended dosage is: 0.15 mg/kg every 3 weeks for 2 cycles. ? 0.075 mg/kg every 3 weeks for subsequent cycles.

 Premedicate with dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before ZYNLONTA.

See Full Prescribing Information for instructions on preparation and administration.

ADVERSE REACTIONS- 

 Most common (=20%) adverse reactions, including laboratory abnormalities, are thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

CONTRAINDICATIONS- 

 None

WARNINGS AND PRECAUTIONS-

 Effusion and Edema: Monitor for the development of pleural effusion, pericardial effusion, ascites, peripheral edema, and general edema. Consider diagnostic imaging when symptoms develop or worsen.

Myelosuppression: Monitor blood cell counts. Withhold, reduce, or discontinue ZYNLONTA based on severity.

Infections: Monitor for infection and treat promptly.

 Cutaneous Reactions: Monitor patients for new or worsening cutaneous reactions, including photosensitivity reactions.

Dermatologic consultation should be considered.

 Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception.

DOSAGE AND ADMINISTRATION-

 ZYNLONTA is an intravenous infusion over 30 minutes on Day 1 of each cycle (every 3 weeks).

The recommended dosage is: ? 0.15 mg/kg every 3 weeks for 2 cycles. ? 0.075 mg/kg every 3 weeks for subsequent cycles.

 Premedicate with dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before ZYNLONTA.

See Full Prescribing Information for instructions on preparation and administration.

DOSAGE FORMS AND STRENGTHS-                                                                              

 For injection: 10 mg of loncastuximab tesirine-lpyl as a lyophilized powder in a single-dose vial for reconstitution and further dilution.

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information). 

Effusion and Edema: Advise patients to contact their healthcare provider if they experience swelling, weight gain, shortness of breath, or difficult, labored breathing 

 Myelosuppression: Advise patients to immediately contact their healthcare provider for a fever of 100.4°F (38°C) or greater, or signs or symptoms of bruising or bleeding. Advise patients of the need for periodic monitoring of blood counts

 Infections: Advise patients to contact their healthcare provider for signs or symptoms of infection, including fever, chills, weakness and/or difficulty breathing

 Cutaneous Reactions: Advise patients that skin reaction or rash can occur. Patients should be directed to minimize or avoid exposure to direct natural or artificial sunlight, including sunlight exposure through glass windows.

Patients should be instructed to protect skin from exposure to sunlight by wearing sun-protective clothing and/or the use of sunscreen products

 Embryo-Fetal Toxicity: - Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with ZYNLONTA

  Advise male patients with female partners of reproductive potential, to use effective contraception during treatment with ZYNLONTA and for 6 months after the last dose

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

Manufactured by: ADC Therapeutics SA Route de la Corniche 3B 1066 Epalinges, Switzerland U.S. license No. 2166 Distributed by: ADC Therapeutics America Murray Hill, New Jersey 07974 For more information, go to www.ZYNLONTA.com or call 1-855-690-0340

 CLINICAL PHARMACOLOGY

1. Mechanism of Action -                                                                                        Loncastuximab tesirine-lpyl is an antibody-drug conjugate (ADC) targeting CD19.

The monoclonal IgG1 kappa antibody component binds to human CD19, a transmembrane protein expressed on the surface of cells of B-lineage origin.

The small molecule component is SG3199, a PBD dimer and alkylating agent. Upon binding to CD19, loncastuximab tesirine-lpyl is internalized followed by release of SG3199 via proteolytic cleavage. The released SG3199 binds to the DNA minor groove and forms highly cytotoxic DNA interstrand crosslinks, subsequently inducing cell death. Loncastuximab tesirine-lpyl had anticancer activity in animal models of lymphoma.

2. Pharmacodynamics-                                                                                                  Higher loncastuximab tesirine-lpyl exposure in Cycle 1 was associated with higher incidence of some Grade =2 adverse reactions, including skin and nail reactions, liver function test abnormalities and increased gamma-glutamyltransferase.

Cardiac Electrophysiology -At the maximum recommended therapeutic dose of 0.15 mg/kg during Cycle 1 and Cycle 2, loncastuximab tesirine-lpyl does not cause large mean increases (i.e., >20 msec) in the QTc interval.

3 Pharmacokinetics-                                                                                                        . Loncastuximab tesirine-lpyl steady state Cmax was 28.2% lower than the Cmax after the first dose. The time to reach steady state was 210 days.

Distribution- The mean (CV%) of loncastuximab tesirine-lpyl volume of distribution was 7.11 (26.6%) L.

Elimination- The mean (CV%) of loncastuximab tesirine-lpyl clearance decreased with time from 0.499 L/day (89.3%) after a single dose to 0.275 L/day (38.2%) at steady state.

The mean (standard deviation) half-life of loncastuximab tesirine-lpyl was 20.8 (7.06) days at steady state.

Metabolism -The monoclonal antibody portion of loncastuximab tesirine-lpyl is expected to be metabolized into small peptides by catabolic pathways. The small molecule cytotoxin, SG3199, is metabolized by CYP3A4/5 in vitro.

Excretion- The major excretion pathways of SG3199 have not been studied in humans. SG3199 is expected to be minimally renally excreted

Specific Populations- No clinically significant differences in the pharmacokinetics of loncastuximab tesirine-lpyl were observed based on age (20-94 years), sex, race (White vs. Black), body weight (42.1 to 160.5 kg), ECOG status (0 to 2) or mild to moderate renal impairment (CLcr 30 to <90 mL/min using the Cockcroft-Gault equation).

The effect of severe renal impairment (CLcr 15 to 29 mL/min), and end-stage renal disease with or without hemodialysis on loncastuximab tesirine-lpyl pharmacokinetics is unknown.

Patients with Hepatic Impairment- Mild hepatic impairment (total bilirubin = ULN and AST > ULN, or total bilirubin >1 to 1.5 × ULN and any AST) may increase the exposure of unconjugated SG3199, however there was no clinically significant effect on loncastuximab tesirine-lpyl pharmacokinetics.

The effect of moderate (total bilirubin >1.5 to =3 × ULN and any AST) or severe (total bilirubin >3 ULN and any AST) hepatic impairment on loncastuximab tesirine-lpyl pharmacokinetics is unknown.

Drug Interaction Studies-                                                                                                 In Vitro Studies Cytochrome P450 (CYP) Enzymes: SG3199 does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 at clinically relevant unconjugated SG3199 concentrations.

Transporter Systems: SG3199 is a substrate of P-glycoprotein (P-gp), but not a substrate of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP)1B1, or organic cation transporter (OCT)1. SG3199 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, OCT2, OCT1, multi-antimicrobial extrusion protein (MATE)1, MATE2-K, or bile salt export pump (BSEP) at clinically relevant unconjugated SG3199 concentrations.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                         Based on its mechanism of action, ZYNLONTA can cause embryo-fetal harm when administered to a pregnant woman, because it contains a genotoxic compound (SG3199) and affects actively dividing cells 

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

No animal reproduction studies were conducted with ZYNLONTA. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

2. Lactation Risk Summary-                                                                                                 There is no data on the presence of loncastuximab tesirine-lpyl or SG3199 in human milk, the effects on the breastfed child, or milk production.

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

3 Females and Males of Reproductive Potential -                                                       ZYNLONTA can cause fetal harm when administered to pregnant women

Pregnancy Testing- Pregnancy testing is recommended for females of reproductive potential prior to initiating ZYNLONTA.

Contraception Females -Advise women of reproductive potential to use effective contraception during treatment and for 9 months after the last dose.

Males- Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during the treatment with ZYNLONTA and for 6 months after the last dose 

Infertility- Males- Based on the results from animal studies, ZYNLONTA may impair fertility in males.

4 Pediatric Use-                                                                                                               Safety and effectiveness of ZYNLONTA in pediatric patients have not been established.

5. Geriatric Use -                                                                                                               Of the 145 patients with large B-cell lymphoma who received ZYNLONTA in clinical trials, 55% were 65 years of age and older, while 14% were 75 years of age and older 

No overall differences in safety or effectiveness were observed between these patients and younger patients.

6. Hepatic Impairment-                                                                                                   No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin = upper limit of normal [ULN] and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 × ULN and any AST).

Monitor patients with mild hepatic impairment for potential increased incidence of adverse reactions and modify the ZYNLONTA dosage in the event of adverse reactions 

ZYNLONTA has not been studied in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST)