lurbinectedin 4 MG Injection

INDICATIONS AND USAGE ZEPZELCA is an alkylating drug indicated: • in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, for the maintenance treatment of adult patients with extensive-stage small cell lung cancer whose disease has not progressed after first-line induction therapy with atezolizumab or atezolizumab and hyaluronidase-tqjs, carboplatin and etoposide. ( 1.1 ) • For the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. ( 1.2 ) 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). ( 1.2 ) 1.1 Extensive-Stage Small Cell Lung Cancer ZEPZELCA, in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, is indicated for the maintenance treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has not progressed after first-line induction therapy with atezolizumab or atezolizumab and hyaluronidase-tqjs, carboplatin and etoposide. 1.2 Metastatic Small Cell Lung Cancer 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 [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

DOSAGE AND ADMINISTRATION • Recommended Dosage : 3.2 mg/m 2 administered intravenously every 21 days until disease progression or unacceptable toxicity. • Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement ( 5.3 ) • Administer ZEPZELCA as an intravenous infusion over 60 minutes. • To reduce the risk of nausea, administer corticosteroids and serotonin agonists prior to Cycle 1 and consider use for subsequent cycles. ( 2.5 ) • 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) [Refer to Prescribing Information]. • Moderate Hepatic Impairment : Recommended dosage is 1.6 mg/m 2 administered intravenously every 21 days until disease progression or unacceptable toxicity. ( 2.4 , 8.6 ) • Severe Hepatic Impairment : Avoid use of ZEPZELCA. If use cannot be avoided, the recommended dosage is 1.6 mg/m 2 administered intravenously every 21 days until disease progression or unacceptable toxicity. ( 2.4 , 8.6 ) 2.1 Recommended Dosage The recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m 2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity [see Dosage and Administration (2.4) ]. Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm 3 and platelet count is at least 100,000/mm 3 . ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs When administering ZEPZELCA on the same day as atezolizumab or atezolizumab and hyaluronidase-tqjs, administer the chosen atezolizumab drug first. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information. If discontinuation of atezolizumab or atezolizumab and hyaluronidase-tqjs is required due to an immune-related severe adverse event, treatment with ZEPZELCA may be continued at the same dose as a single agent. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA. 2.2 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: Dose Reduction for ZEPZELCA for Adverse Reactions Dose Reduction Total Dose First Second 2.6 mg/m 2 every 21 days 2 mg/m 2 every 21 days Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2. Table 2: Dosage Modifications for ZEPZELCA for Adverse Reactions a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b Patients who have not received primary prophylaxis of G-CSF with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm 3 ) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction. Adverse Reaction Severity a Dosage Modification Neutropenia b [see Warnings and Precautions (5.1) ] Grade 4 or Any grade febrile neutropenia • Withhold ZEPZELCA until absolute neutrophil count (ANC) is ≥ 1500/mm 3 • Resume ZEPZELCA at a reduced dose Thrombocytopenia [see Warnings and Precautions (5.1) ] Grade 3 with bleeding or Grade 4 • Withhold ZEPZELCA until platelet ≥ 100,000/mm 3 • Resume ZEPZELCA at reduced dose Hepatotoxicity [see Warnings and Precautions (5.2) ] Grade 2 • Withhold ZEPZELCA until Grade ≤ 1 • Resume ZEPZELCA at same dose Grade ≥ 3 • Withhold ZEPZELCA until Grade ≤ 1 • Resume ZEPZELCA at reduced dose or permanently discontinue Rhabdomyolysis [see Warnings and Precautions (5.4) ] Grade 2 • Withhold ZEPZELCA until Grade ≤ 1 • Resume ZEPZELCA at same dose Grade ≥ 3 • Permanently discontinue ZEPZELCA Other Adverse Reactions [see Adverse Reactions (6.1) , Postmarketing (6.2) ] Grade 2 • Withhold ZEPZELCA until Grade ≤ 1 • Resume ZEPZELCA at same dose Grade ≥ 3 • Withhold ZEPZELCA until Grade ≤ 1 • Resume ZEPZELCA at reduced dose or permanently discontinue 2.3 Dosage Modifications 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% [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . 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 . 2.4 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)). If administration of ZEPZELCA cannot be avoided, the recommended dosage is 1.6 mg/m 2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity [see Use In Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 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 . 2.5 Recommended Prophylactic Medications ZEPZELCA as a Single Agent Consider administering the following pre-infusion medications for antiemetic prophylaxis [see Adverse Reactions (6.1) ] : • 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) [Refer to Prescribing Information] . • 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 [see Adverse Reactions (6.1) ] : ⸰ Corticosteroids (dexamethasone 8 mg or equivalent intravenously) ⸰ Serotonin antagonists (ondansetron 8 mg or equivalent intravenously) 2.6 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 [see Warnings and Precautions (5.3) ] . • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. I

WARNINGS AND PRECAUTIONS • Myelosuppression : Monitor blood counts prior to each administration. Initiate treatment with ZEPZELCA only if baseline neutrophil count is ≥ 1,500 cells/mm 3 and platelet count is ≥ 100,000/mm 3 . For neutrophil count less than 500 cells/mm 3 or any value less than lower limit of normal, administer G-CSF. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity. ( 5.1 ) • Hepatotoxicity : Monitor liver function tests prior to initiating ZEPZELCA, periodically during treatment and as clinically indicated. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity. ( 5.2 ) • Extravasation Resulting in Tissue Necrosis : Consider use of a central venous catheter to reduce the risk of extravasation. Monitor patients for signs and symptoms of extravasation during the ZEPZELCA infusion. If extravasation occurs, immediately discontinue the infusion, remove the infusion catheter, and monitor for signs and symptoms of tissue necrosis. ( 5.3 ) • Rhabdomyolysis : Monitor creatine phosphokinase (CPK) prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity. ( 5.4 ) • Embryo-Fetal Toxicity : Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use an effective method of contraception. ( 5.5 ) 5.1 Myelosuppression ZEPZELCA can cause severe and fatal myelosuppression including febrile neutropenia and sepsis, thrombocytopenia and anemia. Administer ZEPZELCA only to patients with baseline neutrophil count of at least 1,500 cells/mm 3 and platelet count of at least 100,000/mm 3 . 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) [refer to Prescribing Information] . Monitor blood counts including neutrophils, red blood cells and platelets prior to each ZEPZELCA administration. For neutrophil count less than 500 cells/mm 3 or any value less than lower limit of normal, administer G-CSF. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity [see Dosage and Administration (2.2) ] . ZEPZELCA with Intravenous Atezolizumab In the IMforte study [see Adverse Reactions (6.1) ] , primary prophylaxis of G-CSF was administered to 84% of patients. Based on laboratory values, decreased neutrophils occurred in 36%, including 18% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. The median time to onset of Grade 3 and 4 decreased neutrophil cells was 31 days and a median duration of 10 days. Febrile neutropenia occurred in 1.7%. Sepsis occurred in 1%. There were 7 fatal infections: pneumonia (n=3), sepsis (n=3), and febrile neutropenia (n=1). Based on laboratory values, decreased platelets occurred in 54%, including 15% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. The median time to onset of Grade 3 and 4 decreased platelet cells was 31 days and a median duration of 12 days. Based on laboratory values, decreased hemoglobin occurred in 51%, including 13% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. The median time to onset of Grade 3 and 4 decreased hemoglobin was 64 days and a median duration of 8 days. ZEPZELCA as a Single Agent In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA as a single agent [see Adverse Reactions (6.1) ] , Grade 3 or 4 neutropenia occurred in 41% of patients, with a median time to onset of 15 days and a median duration of 7 days. Febrile neutropenia occurred in 7% of patients. Sepsis occurred in 2% of patients and was fatal in 1% (all cases occurred in patients with solid tumors other than SCLC). Grade 3 or 4 thrombocytopenia occurred in 10%, with a median time to onset of 10 days and a median duration of 7 days. Grade 3 or 4 anemia occurred in 17% of patients. 5.2 Hepatotoxicity ZEPZELCA can cause hepatotoxicity which may be severe. 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 [see Dosage and Administration (2.2) ]. ZEPZELCA with Intravenous Atezolizumab In the IMforte study [see Adverse Reactions (6.1) ] , based on laboratory values, increased alanine aminotransferase (ALT) occurred in 25%, including 3% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. Increased aspartate aminotransferase (AST) occurred in 24% including 3% Grade 3 or Grade 4. The median time to onset of Grade ≥ 3 elevation in transaminases was 52 days (range: 6 to 337). ZEPZELCA as a Single Agent In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA as a single agent [see Adverse Reactions (6.1) ] , Grade 3 elevations of ALT and AST were observed in 6% and 3% of patients, respectively, and Grade 4 elevations of ALT and AST were observed in 0.4% and 0.5% of patients, respectively. The median time to onset of Grade ≥ 3 elevation in transaminases was 8 days (range: 3 to 49), with a median duration of 7 days. 5.3 Extravasation Resulting in Tissue Necrosis Extravasation of ZEPZELCA can cause skin and soft tissue injury, including necrosis requiring debridement. Consider use of a central venous catheter to reduce the risk of extravasation, particularly in patients with limited venous access. Monitor patients for signs and symptoms of extravasation during the ZEPZELCA infusion. If extravasation occurs, immediately discontinue the infusion, remove the infusion catheter, and monitor for signs and symptoms of tissue necrosis. The time to onset of necrosis after extravasation may vary. ZEPZELCA with Intravenous Atezolizumab In the IMforte study [see Adverse Reactions (6.1 )] , extravasation resulting in skin necrosis occurred in one patient who received ZEPZELCA in combination with atezolizumab. 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. 5.4 Rhabdomyolysis Rhabdomyolysis has been reported in patients treated with ZEPZELCA. Monitor creatine phosphokinase (CPK) prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold or reduce the dose based on severity [see Dosage and Administration (2.2) ] . ZEPZELCA with Intravenous Atezolizumab In the IMforte study [see Adverse Reactions (6.1 )] , among 235 patients who had a creatine phosphokinase laboratory evaluation, increased creatine phosphokinase occurred in 9% who received ZEPZELCA in combination with atezolizumab. 5.5 Embryo-Fetal Toxicity Based on animal data and its mechanism of action ZEPZELCA can cause fetal harm when administered to a pregnant woman. Intravenous administration of a single dose of lurbinectedin (approximately 0.2 times the 3.2 mg/m 2 clinical dose) to pregnant animals during the period of organogenesis caused 100% embryolethality in rats. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the last dose [see Use in Specific Populations (8.1 , 8.3 )] .

CONTRAINDICATIONS None. None. ( 4 )

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.