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ZEPZELCA® (lurbinectedin) for injection

ZEPZELCA is an alkylating drug. The chemical name of ZEPZELCA (lurbinectedin) is (1’R,6R,6aR,7R,13S,14S,16R)-8,14-dihydroxy-6’,9-dimethoxy-4,10,23-trimethyl-19-oxo-2’,3’,4’,6,7,9’,12,13,14,16-decahydro-6aH-spiro[7,13-azano-6,16-(epithiopropanooxymethano) [1,3]dioxolo[7,8]isoquinolino[3,2-b][3]benzazocine-20,1’-pyrido[3,4-b]indol]-5-yl acetate. The molecular formula is C₄₁H₄₄N₄O₁₀S. The molecular weight is 784.87g/mol.

ZEPZELCA for injection 4 mg is supplied as a lyophilized powder in a single-dose vial for reconstitution for intravenous use. The ZEPZELCA lyophilized formulation is comprised of 4 mg lurbinectedin, sucrose (800 mg), lactic acid (22.1 mg), and sodium hydroxide (5.1 mg).

Before use, the lyophilizate is reconstituted by addition of 8 mL Sterile Water for Injection USP, yielding a solution containing 0.5 mg/mL lurbinectedin (the calculated concentration is 0.47 mg/mL based on the final volume of 8.5 mL).

INDICATIONS AND USAGE

ZEPZELCA is indicated for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

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

Mechanism of Action

Lurbinectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.

Lurbinectedin inhibited human monocyte activity in vitro and reduced macrophage infiltration in implanted tumors in mice.

DOSAGE AND ADMINISTRATION

The recommended dosage of ZEPZELCA is 3.2 mg/m2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.

Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm³

and platelet count is at least 100,000/mm³.

Premedication

Consider administering the following pre-infusion medications for antiemetic prophylaxis:

Corticosteroids (dexamethasone 8 mg intravenously or equivalent)
Serotonin antagonists (ondansetron 8 mg intravenously or equivalent)

Preparation, Administration and Storage

ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures.

Preparation

Inject 8 mL of Sterile Water for Injection USP into the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution.
Visually inspect the solution for particulate matter and discoloration. The reconstituted solution is a clear, colorless or slightly yellowish solution, essentially free of visible particles.
Calculate the required volume of reconstituted solution as follows:

Volume (mL) = (Body Surface Area (m²) x Individual Dose (mg/m²))/0.5 mg/mL

For administration through a central venous line, withdraw the appropriate amount of reconstituted solution from the vial and add to an infusion container containing at least 100 mL of diluent (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
For administration through a peripheral venous line, withdraw the appropriate amount of reconstituted solution from the vial and add to an infusion container containing at least 250 mL of diluent (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).

Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, Polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.

Do not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.

Compatibility with other intravenous administration materials and the diluted

ZEPZELCA solution has been demonstrated in the following materials:

Polyolefin containers (polyethylene, polypropylene and mixtures).
Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene).
Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.

Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.

Storage of Infusion Solution

If not used immediately after reconstitution or dilution, the ZEPZELCA solution can be stored prior to administration for up to 24 hours following reconstitution, including infusion time, at either room temperature/ ambient light or under refrigeration at 2ºC-8ºC (36ºF-46ºF) conditions.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Myelosuppression: ZEPZELCA can cause myelosuppression.

Administer ZEPZELCA only to patients with baseline neutrophil count of at least 1,500 cells/mm³ and platelet count of at least 100,000/mm³. Monitor blood counts including neutrophil count and platelet count prior to each administration. For neutrophil count less than 500 cells/mm3 or any value less than lower limit of normal, the use of G-CSF is recommended.

Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity.

Hepatotoxicity: ZEPZELCA can cause hepatotoxicity.

Monitor liver function tests prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity.

Extravasation Resulting in Tissue Necrosis: Extravasation of ZEPZELCA resulting in skin and soft tissue injury, including necrosis requiringdebridement, can occur. Consider use of a central venous catheter to reduce the risk ofextravasation, particularly in patients with limited venous access. Monitor patients for signs andsymptoms of extravasation during the ZEPZELCA infusion. If extravasation occurs, immediatelydiscontinue the infusion, remove the infusion catheter, and monitor for signs and symptoms oftissue necrosis. The time to onset of necrosis after extravasation may vary.

Administer supportive care and consult with an appropriate medical specialist as needed for signs and symptoms of extravasation. Administer subsequent infusions at a site that was not affected by extravasation.

Rhabdomyolysis: Rhabdomyolysis has been reported in patients treated with ZEPZELCA. Monitor creatinephosphokinase (CPK) prior to initiating ZEPZELCA and periodically during treatment asclinically indicated. Withhold or reduce the dose based on severity.

Embryo-Fetal Toxicity: Based on animal data and its mechanism of action ZEPZELCA can cause fetal harm whenadministered to a pregnant woman. Intravenous administration of a single dose of lurbinectedin(approximately 0.2 times the 3.2 mg/m² clinical dose) to pregnant animals during the period oforganogenesis caused 100% embryolethality in rats. Advise pregnant women of the potential riskto a fetus. Advise female patients of reproductive potential to use effective contraception duringtreatment with ZEPZELCA and for 6 months after the final dose. Advise male patients withfemale partners of reproductive potential to use effective contraception during treatment withZEPZELCA and for 4 months after the final dose.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data and its mechanism of action, ZEPZELCA can cause fetal harm when administered to a pregnant woman. There are no available data to inform the risk of ZEPZELCA use in pregnant women. Intravenous administration of a single lurbinectedin dose (approximately 0.2 times the 3.2 mg/m² clinical dose) to pregnant rats during the period of organogenesis caused embryolethality.

Advise pregnant women of the potential risk to a fetus.

Lactation: There are no data on the presence of lurbinectedin in human milk or its effects on the breastfedchild or on milk production. Because of the potential for serious adverse reactions from ZEPZELCA in breastfed children, advise women not to breastfeed during treatment with ZEPZELCA and for 2 weeks after the final dose.

Pediatric Use: The safety and effectiveness of ZEPZELCA in pediatric patients have not been established.

Geriatric Use: Of the 105 patients with SCLC administered ZEPZELCA in clinical studies, 37 (35%) patientswere 65 years of age and older, while 9 (9%) patients were 75 years of age and older. No overalldifference in effectiveness was observed between patients aged 65 and older and youngerpatients.

Hepatic Impairment: The effect of moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST)on the pharmacokinetics of lurbinectedin has not been studied. No dose adjustment ofZEPZELCA is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULNand AST > ULN, or total bilirubin 1.0-1.5 × ULN and any AST)

ZEPZELCA® (lurbinectedin) for injection

ZEPZELCA® (lurbinectedin) for injection