Zepzelca Drug Information

Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions are listed in Table 1. Permanently discontinue ZEPZELCA in patients who require a dose interruption of greater than two weeks and in patients who are unable to tolerate 2 mg/m 2 every 21 days. Table 1: Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

Table 2: s for Use with Strong and Moderate CYP3A Inhibitors Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration of ZEPZELCA with a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ZEPZELCA by 50%. After discontinuation of a strong or moderate CYP3A inhibitor for 5 half-lives of the inhibitor, increase the ZEPZELCA dose to the dose used before starting the inhibitor.

Dosage Modifications for Patients with Severe and Moderate Hepatic Impairment Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × Upper Limit of Normal (ULN)). In patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN and any AST), the recommended dosage of ZEPZELCA is 1.6 mg/m 2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.

Recommended Prophylactic Medications

ZEPZELCA as a Single Agent 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) ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs • To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF). • To reduce the risk of nausea, administer the following pre-infusion medications for antiemetic prophylaxis prior to Cycle 1 and consider administering for subsequent cycles: ⸰ Corticosteroids (dexamethasone 8 mg or equivalent intravenously) ⸰ Serotonin antagonists (ondansetron 8 mg or equivalent intravenously)

Preparation, Administration and Storage ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures 1. 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, free of visible particles. • Calculate the required volume of reconstituted solution as follows: • 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 • Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement. • 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. o 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: o Containers: Polyolefin containers (polyethylene, polypropylene and mixtures). o Infusion sets: Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene). o Implantable venous access systems: 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.

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase - tqjs • Administer either atezolizumab or atezolizumab and hyaluronidase-tqjs first, then administer ZEPZELCA. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information. 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 to 8ºC (36ºF to 46ºF) conditions. volume calculation

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 safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ZEPZELCA in combination with intravenous atezolizumab in the IMforte study, in 242 patients with extensive stage small cell lung cancer (ES-SCLC) whose disease had not progressed after initial therapy with atezolizumab, carboplatin, and etoposide. The most common adverse reactions (≥ 30%), including laboratory abnormalities, in patients who received ZEPZELCA with atezolizumab were decreased lymphocytes, decreased platelets, decreased hemoglobin, decreased neutrophils, nausea, and fatigue/asthenia.

The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflects exposure to ZEPZELCA as a single agent at a dose of 3.2 mg/m 2 intravenously every 21 days in 554 patients with advanced solid tumors. The most common adverse reactions for ZEPZELCA as a single agent, (Study B-005), including laboratory abnormalities, (≥ 20%) are leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea. Extensive-Stage Small Cell Lung Cancer (IMforte) The safety of ZEPZELCA in combination with intravenous (IV) atezolizumab was evaluated in IMforte.

Primary prophylaxis of G-CSF was administered to 84% of patients. Serious adverse reactions occurred in 31% of patients receiving ZEPZELCA in combination with atezolizumab. Permanent discontinuation of ZEPZELCA due to an adverse reaction occurred in 5% of patients.

The adverse reaction resulting in permanent discontinuation in ≥ 1% of patients who received ZEPZELCA was decreased neutrophil count. Dosage interruptions of ZEPZELCA due to an adverse reaction occurred in 25%. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia, fatigue, decreased neutrophil count, and decreased platelet count.

Dose reductions of ZEPZELCA due to an adverse reaction occurred in 15% of patients. Adverse reactions which required dosage reduction in ≥ 2% of patients included decreased platelet count, fatigue, nausea and vomiting. Table 3 summarizes the adverse reactions in IMforte.

Table 3: Adverse Reactions (≥ 10%) in Patients with ES-SCLC Who Received ZEPZELCA in Combination with Intravenous Atezolizumab in IMforte 2 Clinically relevant adverse reactions in < 10% of patients who received ZEPZELCA in combination with intravenous atezolizumab included pneumonia, phlebitis, extravasation resulting in skin necrosis, hypersensitivity, and increased creatine phosphokinase. Table 4 summarizes the laboratory abnormalities in IMforte. Table 4: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with ES‑SCLC Who Received ZEPZELCA in Combination with Intravenous Atezolizumab in IMforte 0 Metastatic Small Cell Lung Cancer (SCLC) (Study B-005) The safety of ZEPZELCA was evaluated in a cohort of 105 patients with previously treated SCLC in Study B-005.

All patients in this study received a pre-specified anti-emetic regimen consisting of a corticosteroid and serotonin antagonist. Patients could receive G-CSF for secondary prophylaxis (i.e., after patients had an initial decrease in WBC), but not primary prophylaxis. Among patients who received ZEPZELCA, 29% were exposed for 6 months or longer and 6% were exposed for greater than one year.

Serious adverse reactions occurred in 34% of patients who received ZEPZELCA. Serious adverse reactions in ≥ 3% of patients included pneumonia, febrile neutropenia, neutropenia, respiratory tract infection, anemia, dyspnea, and thrombocytopenia. Permanent discontinuation due to an adverse reaction occurred in two patients (1.9%) who received ZEPZELCA.

Adverse reactions resulting in permanent discontinuation in ≥ 1% of patients who received ZEPZELCA, which included peripheral neuropathy and myelosuppression. Adverse reactions requiring dosage interruption in ≥ 3% of patients who received ZEPZELCA included neutropenia, and hypoalbuminemia. Adverse reactions requiring dosage reductions in ≥ 3% of patients who received ZEPZELCA included neutropenia, febrile neutropenia and fatigue.

Table 5 summarizes the adverse reactions in the SCLC cohort of Study B-005. Table 5: Adverse Reactions (≥ 10%) in Patients with SCLC Who Received ZEPZELCA in Study B-005 1 Clinically relevant adverse reactions in < 10% of patients who received ZEPZELCA include dysgeusia, febrile neutropenia and pneumonitis. Table 6 summarizes the laboratory abnormalities in Study B-005.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZEPZELCA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General disorders and administration site conditions: Extravasation including tissue necrosis requiring debridement.

Musculoskeletal and connective tissue disorders: Rhabdomyolysis. Metabolism and nutrition disorders: Tumor lysis syndrome.

Effect of Other Drugs on ZEPZELCA Strong and Moderate CYP3A Inhibitors Coadministration of ZEPZELCA with a strong or a moderate CYP3A inhibitor increases lurbinectedin systemic exposure, which may increase the incidence and severity of adverse reactions to ZEPZELCA. Avoid grapefruit and Seville oranges during ZEPZELCA treatment, as these contain strong or moderate inhibitors of CYP3A. If coadministration cannot be avoided, reduce the dose of ZEPZELCA.

Strong CYP3A Inducers Avoid coadministration of ZEPZELCA with strong CYP3A inducers. Coadministration of ZEPZELCA with a strong CYP3A inducer may decrease lurbinectedin systemic exposure, which may decrease the efficacy of ZEPZELCA.

Pregnancy Risk Summary 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/m 2 clinical dose) to pregnant rats during the period of organogenesis caused embryolethality (see Data).

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 respectively.

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