Loncastuximab Tesirine

FDA Drug Information • Also known as: Zynlonta

Brand Names: Zynlonta
Dosage Form: INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type: DRUG FOR FURTHER PROCESSING

Description

11 DESCRIPTION Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating agent conjugate, consisting of a humanized IgG1 kappa monoclonal antibody conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxic alkylating agent, through a protease-cleavable valine-alanine linker. SG3199 attached to the linker is designated as SG3249, also known as tesirine. Loncastuximab tesirine-lpyl has an approximate molecular weight of 151 kDa. An average of 2.3 molecules of SG3249 are attached to each antibody molecule. Loncastuximab tesirine-lpyl is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis. ZYNLONTA (loncastuximab tesirine-lpyl) for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder, which has a cake-like appearance, for intravenous infusion after reconstitution and dilution. Each single-dose vial delivers 10 mg of loncastuximab tesirine-lpyl, L-histidine (2.8 mg), L-histidine monohydrochloride (4.6 mg), polysorbate 20 (0.4 mg), and sucrose (119.8 mg). After reconstitution with 2.2 mL Sterile Water for Injection, USP, the final concentration is 5 mg/mL with a pH of approximately 6.0. Chemical Structure

What Is Loncastuximab Tesirine Used For?

1 INDICATIONS AND USAGE ZYNLONTA is 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 [see Clinical Studies (14.1) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 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. ( 1 ) 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). ( 1 )

Dosage and Administration

2 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. ( 2.1 ) Premedicate with dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before ZYNLONTA. ( 2.2 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.4 ) 2.1 Recommended Dosage ZYNLONTA as an intravenous infusion administered over 30 minutes on Day 1 of each cycle (every 3 weeks). Administer intravenous infusion as follows: 0.15 mg/kg every 3 weeks for 2 cycles. 0.075 mg/kg every 3 weeks for subsequent cycles. 2.2 Recommended Premedication Unless contraindicated, administer dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before administering ZYNLONTA. If dexamethasone administration does not begin the day before ZYNLONTA, dexamethasone should begin at least 2 hours prior to administration of ZYNLONTA. 2.3 Dosage Modifications and Delays Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse Reactions Severity Dosage Modification Hematologic Adverse Reactions Neutropenia [see Warnings and Precautions (5.2) ] Absolute neutrophil count less than 1 × 10 9 /L Withhold ZYNLONTA until neutrophil counts returns to 1 × 10 9 /L or higher Thrombocytopenia [see Warnings and Precautions (5.2) ] Platelet count less than 50,000/mcL Withhold ZYNLONTA until platelet count returns to 50,000/mcL or higher Nonhematologic Adverse Reactions Edema or Effusion [see Warnings and Precautions (5.1) ] Grade 2 National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 or higher Withhold ZYNLONTA until the toxicity resolves to Grade 1 or less Pericardial Effusion [see Warnings and Precautions (5.1) ] Grade 2 Withhold ZYNLONTA until the toxicity resolves. Discontinue ZYNLONTA if effusion recurs Grade 3 or higher Discontinue ZYNLONTA Hepatotoxicity [ see Warnings and Precautions (5.4) ] Grade 3 or higher increase in AST or ALT or suspected DILI Withhold ZYNLONTA until toxicity resolves to Grade 1 or less, discontinue for confirmed DILI Other Adverse Reactions [see Warnings and Precautions (5.3) , (5.5) , Adverse Reactions (6.1) ] Grade 3 or higher Withhold ZYNLONTA until the toxicity resolves to Grade 1 or less Recommendations for Dosage Delays If dosing is delayed by more than 3 weeks due to toxicity related to ZYNLONTA, reduce subsequent doses by 50%. If toxicity reoccurs following dose reduction, consider discontinuation. Note: If toxicity requires dose reduction following the second dose of 0.15 mg/kg (Cycle 2), the patient should receive the dose of 0.075 mg/kg for Cycle 3. 2.4 Reconstitution and Administration Instructions Reconstitute and further dilute ZYNLONTA prior to intravenous infusion. Use appropriate aseptic technique. ZYNLONTA is a hazardous drug. Follow applicable special handling...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Effusion and Edema [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2)] Infections [see Warnings and Precautions (5.3) ] Hepatotoxicity, including DILI [see Warnings and Precautions(5.4) ] Cutaneous Reactions [see Warnings and Precautions (5.5) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ADC Therapeutics at 1-855-690-0340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to ZYNLONTA as a single agent at an initial dose of 0.15 mg/kg in 215 patients with DLBCL in studies ADCT-402-201 (LOTIS-2) and ADCT-402-101, which includes 145 patients from LOTIS-2 treated with 0.15 mg/kg × 2 cycles followed by 0.075 mg/kg for subsequent cycles. Among 215 patients who received ZYNLONTA, the median number of cycles was 3 (range 1 to 15) with 58% receiving three or more cycles and 30% receiving five or more cycles. In this pooled safety population of 215 patients, the most common (>20%) adverse reactions, including laboratory abnormalities, were thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain. Relapsed or Refractory Diffuse Large B-Cell Lymphoma LOTIS-2 The safety of ZYNLONTA was evaluated in LOTIS-2, an open-label, single-arm clinical trial that enrolled 145 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including high-grade B-cell lymphoma, after at least two prior systemic therapies [see Clinical Studies (14.1) ] . The trial required hepatic transaminases, including gamma-glutamyltransferase (GGT), ≤2.5 times upper limit of normal (ULN), total bilirubin ≤1.5 times ULN, and creatinine clearance ≥60 mL/min. Patients received ZYNLONTA 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles and received treatment until progressive disease or unacceptable toxicity. Among the 145 patients, the median number of cycles received was 3, with 34% receiving 5 or more cycles. The median age was 66 years (range 23 to 94), 59% were male, and 94% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Race was reported in 97% of patients; of these patients, 90% were White, 3% were Black, and 2% were Asian. Serious adverse reactions occurred in 28% of patients receiving ZYNLONTA. The most common serious adverse reactions that occurred in ≥2% receiving ZYNLONTA were febrile neutropenia, pneumonia, edema, pleural effusion, and sepsis. Fatal adverse reactions occurred in 1%, due to infection. Permanent treatment discontinuation due to an adverse reaction of ZYNLONTA occurred in 19% of patients. Adverse reactions resulting in permanent discontinuation of ZYNLONTA in ≥2% were gamma-glutamyltransferase increased, edema, and effusion. Dose reductions due to an adverse reaction of ZYNLONTA occurred in 8% of patients. Adverse reactions resulting in dose reduction of ZYNLONTA in ≥4% was gamma-glutamyltransferase increased. Dosage interruptions due to an adverse reaction occurred in 49% of patients receiving ZYNLONTA. Adverse reactions leading to interruption of ZYNLONTA in ≥5% were gamma-glutamyltransferase increased, neutropenia,...

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 )

Pregnancy and Breastfeeding

8.1 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 [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1) ] . 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. Data Animal Data Animal reproductive or developmental toxicity studies were not conducted with loncastuximab tesirine-lpyl. The cytotoxic component of ZYNLONTA, SG3199, crosslinks DNA, is genotoxic, and is toxic to rapidly dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ZYNLONTA (loncastuximab tesirine-lpyl) for injection is a sterile, preservative-free, white to off-white lyophilized powder, which has a cake-like appearance, supplied in a single-dose vial for reconstitution and further dilution. Each carton (NDC 79952-110-01) contains one 10 mg single-dose vial. Storage and Handling Store refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not use beyond the expiration date shown on the carton. Do not freeze. Do not shake. Special Handling ZYNLONTA is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Any unused drug product or waste material should be disposed in accordance with local requirements.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.