ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:oMyelosuppression [see Warnings and Precautions (5.1)]oHepatotoxicity [see Warnings and Precautions (5.2)]. oMyelosuppression [see Warnings and Precautions (5.1)]. oHepatotoxicity [see Warnings and Precautions (5.2)]. The most common adverse reactions, 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. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 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 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 ZEPZELCA as single agent at dose of 3.2 mg/m2 intravenously every 21 days in 554 patients with advanced solid tumors. Among 554 patients who received ZEPZELCA, including 105 patients with small cell lung cancer (SCLC) in PM1183-B-005-14 (Study B-005), 24% were exposed for months or longer and 5% were exposed for greater than one year. Small Cell Lung Cancer (SCLC)The safety of ZEPZELCA was evaluated in cohort of 105 patients with previously treated SCLC in Study B-005 [see Clinical Studies (14)]. Patients received ZEPZELCA 3.2 mg/m2 intravenously every 21 days. All patients in this study received pre-specified anti-emetic regimen consisting of 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 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.Dosage interruptions due to an adverse reaction occurred in 30.5% of patients who received ZEPZELCA. Adverse reactions requiring dosage interruption in >= 3% of patients who received ZEPZELCA included neutropenia, and hypoalbuminemia.Dose reductions due to an adverse reaction occurred in 25% of patients who received ZEPZELCA. Adverse reactions requiring dosage reductions in >= 3% of patients who received ZEPZELCA included neutropenia, febrile neutropenia and fatigue.The most common adverse reactions, including laboratory abnormalities, (>= 20%) were 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.Table summarizes the adverse reactions in the SCLC cohort of Study B-005.Table 3: Adverse Reactions (>=10%) in Patients With SCLC Who Received ZEPZELCA in Study B-005Adverse ReactionZEPZELCA(n=105)All Gradesa,b (%)Grades 3-4 (%)General disordersFatigue7712Pyrexia130Chest pain100Gastrointestinal disordersNausea370Constipation310Vomiting220Diarrhea204Abdominal painc 111Musculoskeletal and connective tissue disordersMusculoskeletal paind 334Metabolism and nutrition disordersDecreased appetite331Respiratory, thoracic and mediastinal disordersDyspnea316Coughe 200Infections and infestationsRespiratory tract infectionf 185Pneumoniag 107Nervous system disordersPeripheral neuropathyh 111Headache101aGraded per NCI CTCAE 4.0.bNo grade adverse reactions were reported.cIncludes abdominal pain, abdominal pain upper and abdominal discomfort.dIncludes musculoskeletal pain, back pain, arthralgia, pain in extremity, musculoskeletal chest pain, neck pain, bone pain and myalgia.eIncludes cough and productive cough.fIncludes upper respiratory tract infection, viral upper respiratory tract infection, respiratory tract infection and bronchitis.gIncludes pneumonia and lung infection.hIncludes neuropathy peripheral, neuralgia, paresthesia, peripheral sensory neuropathy, hypoesthesia, and hyperesthesia.Clinically relevant adverse reactions in 10% of patients who received ZEPZELCA include dysgeusia, febrile neutropenia and pneumonitis.Table summarizes the laboratory abnormalities in Study B-005.Table 4: Select Laboratory Abnormalities (>= 20%) Worsening from Baseline in Patients With SCLC Who Received ZEPZELCA in Study B-005Laboratory AbnormalityZEPZELCAa (n=105)All Gradesb (%)Grades 3-4 (%)HematologyDecreased leukocytes7929Decreased lymphocytes7943Decreased hemoglobin7410Decreased neutrophils7146Decreased platelets377ChemistryIncreased creatinine690Increased alanine aminotransferase664Increased glucose525Decreased albumin321Decreased sodium317Increased aspartate aminotransferase262Decreased magnesium220aThe denominator used to calculate the rate varied from 95 to 105 based on the number of patients with baseline value and at least one post-treatment value.bGraded per NCI CTCAE 4.0.. aGraded per NCI CTCAE 4.0.. bNo grade adverse reactions were reported.. cIncludes abdominal pain, abdominal pain upper and abdominal discomfort.. dIncludes musculoskeletal pain, back pain, arthralgia, pain in extremity, musculoskeletal chest pain, neck pain, bone pain and myalgia.. eIncludes cough and productive cough.. fIncludes upper respiratory tract infection, viral upper respiratory tract infection, respiratory tract infection and bronchitis.. gIncludes pneumonia and lung infection.. hIncludes neuropathy peripheral, neuralgia, paresthesia, peripheral sensory neuropathy, hypoesthesia, and hyperesthesia.. aThe denominator used to calculate the rate varied from 95 to 105 based on the number of patients with baseline value and at least one post-treatment value.. bGraded per NCI CTCAE 4.0.. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ZEPZELCA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.General and Administration Site Conditions: Extravasation (in rare cases tissue necrosis requiring debridement has occurred).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lurbinectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in bending of the DNA helix towards the major groove. Adduct formation triggers 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.. 12.2 Pharmacodynamics Lurbinectedin exposure-response relationships and the pharmacodynamic time-course for efficacy have not been fully characterized.Increased incidence of Grade neutropenia and Grade >= thrombocytopenia were observed with increased lurbinectedin exposure.Cardiac ElectrophysiologyNo large mean increase in QTc (i.e. 20 ms) was detected following treatment with ZEPZELCA at the recommended dose of 3.2 mg/m2.. 12.3 Pharmacokinetics Following the approved recommended dosage, geometric means (%CV) of plasma Cmax and AUC0-inf, were 107 ug/L (79%) and 551 ugoh/L (94%), respectively. No accumulation of lurbinectedin in plasma is observed upon repeated administrations every weeks. DistributionThe volume of distribution of lurbinectedin at steady state is 504 (39%). Plasma protein binding is approximately 99%, to both albumin and -1-acid glycoprotein.EliminationThe terminal half-life of lurbinectedin is 51 hours. Total plasma clearance of lurbinectedin is 11 L/h (50%).MetabolismLurbinectedin is metabolized by CYP3A4, in vitro.ExcretionAfter single dose of radiolabeled lurbinectedin administration, 89% of the radioactivity was recovered in feces (< 0.2% unchanged) and 6% in urine (1% unchanged). Specific PopulationsNo clinically significant differences in the pharmacokinetics of lurbinectedin were identified based on age (18-85 years), sex, body weight (39-154 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min) or mild hepatic impairment (total bilirubin <= ULN and AST ULN, or total bilirubin between 1.0 1.5 ULN and any AST). The effects of severe renal impairment (CLcr 30 mL/min) and moderate or severe hepatic impairment (total bilirubin 1.5 ULN and any AST) on the pharmacokinetics of lurbinectedin have not been studied. Drug Interactions StudiesDedicated clinical drug-drug interaction studies with CYP3A modulators have not been conducted with lurbinectedin. In vitro StudiesCytochrome P450 (CYP) Enzymes: Lurbinectedin is metabolized by CYP3A4. Lurbinectedin is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Lurbinectedin is not an inducer of CYP1A2 or CYP3A4. Transporter Systems: Lurbinectedin is substrate of MDR1, but is not substrate of OATB1P1, OATP1B3, OCT1, or MATE1. Lurbinectedin inhibits MDR1, OATP1B1, OATP1B3, and OCT1 but not BCRP, BSEP, MATE1, OAT1, OAT3, or OCT2.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).MyelosuppressionAdvise patients to immediately contact their healthcare provider for fever, other signs of infection, unusual bruising, bleeding, tiredness or pallor [see Warnings and Precautions (5.1)].HepatotoxicityAdvise patients to contact their healthcare provider immediately for signs and symptoms suggestive of hepatotoxicity [see Warnings and Precautions (5.2)].Embryo-Fetal ToxicityoAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].oAdvise females of reproductive potential to use effective contraception during treatment with ZEPZELCA and for months after the final dose [see Use in Specific Populations (8.3)].oAdvise males with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for months after the final dose [see Use in Specific Populations (8.3)].LactationAdvise women not to breastfeed during treatment with ZEPZELCA and for at least weeks after the final dose [see Use in Specific Populations (8.2)].Drug InteractionsAdvise patients to inform their healthcare providers of all concomitant medications, herbal and dietary supplements. Advise patients to avoid grapefruit products during treatment with ZEPZELCA [see Drug Interactions (7.1)].Distributed by:Jazz Pharmaceuticals, Inc.Palo Alto, CA 94304 Under license from Pharma Mar, S.A. Protected by U.S. Patent No. 7,763,615. oAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].. oAdvise females of reproductive potential to use effective contraception during treatment with ZEPZELCA and for months after the final dose [see Use in Specific Populations (8.3)].. oAdvise males with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for months after the final dose [see Use in Specific Populations (8.3)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES PM1183-B-005-14 (Study B-005; NCT02454972) is multicenter, open-label, multi-cohort trial evaluating ZEPZELCA as single agent in patients with advanced or metastatic solid tumors. cohort of patients with small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy received ZEPZELCA 3.2 mg/m2 by intravenous infusion every 21 days (one cycle). Patients received median of cycles of ZEPZELCA (range to 24 cycles). The trial excluded patients with central nervous system (CNS) involvement, grade >=3 dyspnea, daily intermittent oxygen requirement, hepatitis or cirrhosis, and immunocompromised patients. Tumor assessments were conducted every weeks for the first 18 weeks and every weeks thereafter. The major efficacy outcome measure was confirmed investigator-assessed overall response rate (ORR). Additional efficacy outcome measures included duration of response (DoR), and an Independent Review Committee (IRC) assessed ORR using Response Evaluation Criteria in Solid Tumors (RECIST v1.1).A total of 105 patients with SCLC who progressed on or after platinum-based chemotherapy were enrolled. The median age was 60 years (range: 40 to 83) with 65% of patients 65 years and 35% of patients >= 65 years, and 60% were male. The majority (75%) of the patients were White, 1% were Asian, 1% were Black and 23% were not reported. Baseline ECOG performance status was or in 92% of patients, and 92% were former/current smokers. All patients received at least one line of platinum-based chemotherapy (range 1-2 lines), and prior radiotherapy had been administered to 71% of patients. Eight patients (8%) had prior immunotherapy in addition to platinum-based chemotherapy. Sixty patients (57%) had platinum-sensitive SCLC, defined as recurrence or progression >= 90 days after the last dose of platinum-containing therapy (chemotherapy free interval [CTFI] >= 90 days). The remaining 45 patients had platinum-resistant SCLC, defined as recurrence or progression 90 days after the last dose of platinum-containing therapy (CTFI 90 days).Table summarizes investigator-assessed and independent review committee assessed key efficacy measures in all patients and in platinum-resistant and platinum-sensitive subgroups.Table 5: Efficacy Results in SCLC Cohort of Study B-005Investigator Assessed Responsea ZEPZELCAAll Patients(n=105)ZEPZELCACTFI <90 days(n=45)ZEPZELCACTFI >=90 days(n=60)Overall Response Rate (95% CI)35% (26%, 45%)22% (11%, 37%)45% (32%, 58%) Complete response0%0%0% Partial response35%22%45%Duration of Response Median in months (95% CI)5.3 (4.1, 6.4)4.7 (2.6, 5.6)6.2 (3.5, 7.3) with >=6 monthsb 35%10%44%Independent Review Committee Assessed Responsea All Patients(n=105)CTFI <90 days(n=45)CTFI >=90 days(n=60)Overall Response Rate (95% CI)30% (22%, 40%)13% (5%, 27%)43% (31%, 57%) Complete response0%0%0% Partial response30%13%43%Duration of Response Median in months (95% CI)5.1 (4.9, 6.4)4.8 (2.4, 5.3)5.3 (4.9, 7.0) with >=6 monthsb 25%0%31% CI: confidence interval, CTFI: chemotherapy free intervalaConfirmed overall response rate.bBased on observed duration of response.. CI: confidence interval, CTFI: chemotherapy free interval. aConfirmed overall response rate.. bBased on observed duration of response.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oRecommended dosage: 3.2 mg/m2 every 21 days. (2.1)oAdminister ZEPZELCA as an intravenous infusion over 60 minutes. (2.1)oConsider premedication with corticosteroids and serotonin antagonists. (2.3). oRecommended dosage: 3.2 mg/m2 every 21 days. (2.1). oAdminister ZEPZELCA as an intravenous infusion over 60 minutes. (2.1). oConsider premedication with corticosteroids and serotonin antagonists. (2.3). 2.1 Recommended Dosage 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.. 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 are unable to tolerate mg/m2 or require dose delay greater than two weeks.Table 1: Dose Reduction for ZEPZELCA for Adverse ReactionsDose ReductionTotal DoseFirstSecond2.6 mg/m2 every 21 days2 mg/m2 every 21 daysDosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.Table 2: Dosage Modifications for ZEPZELCA for Adverse ReactionsAdverse ReactionSeveritya Dosage ModificationNeutropeniab [see Warnings and Precautions (5.1)]Grade 4orAny grade febrile neutropeniaoWithhold ZEPZELCA until Grade <= 1oResume ZEPZELCA at reduced doseThrombocytopenia[see Warnings and Precautions (5.1)]Grade with bleedingorGrade 4oWithhold ZEPZELCA until platelet >= 100,000/mm3 oResume ZEPZELCA at reduced doseHepatotoxicity[see Warnings and Precautions (5.2)] and other adverse reactionsGrade 2oWithhold ZEPZELCA until Grade <= 1oResume ZEPZELCA at same doseGrade >= 3oWithhold ZEPZELCA until Grade <= 1oResume ZEPZELCA at reduced doseaNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0bPatients with isolated Grade neutropenia (neutrophil count less than 500 cells/mm3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.. oWithhold ZEPZELCA until Grade <= 1. oResume ZEPZELCA at reduced dose. oWithhold ZEPZELCA until platelet >= 100,000/mm3 oResume ZEPZELCA at reduced dose. oWithhold ZEPZELCA until Grade <= 1. oResume ZEPZELCA at same dose. oWithhold ZEPZELCA until Grade <= 1. oResume ZEPZELCA at reduced dose. aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. bPatients with isolated Grade neutropenia (neutrophil count less than 500 cells/mm3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.. 2.3 Premedication Consider administering the following pre-infusion medications for antiemetic prophylaxis [see Adverse Reactions (6.1) ]:oCorticosteroids (dexamethasone mg intravenously or equivalent)oSerotonin antagonists (ondansetron mg intravenously or equivalent). oCorticosteroids (dexamethasone mg intravenously or equivalent). oSerotonin antagonists (ondansetron mg intravenously or equivalent). 2.4 Preparation, Administration and Storage ZEPZELCA is hazardous drug. Follow applicable special handling and disposal procedures1.Preparation and AdministrationoInject mL of Sterile Water for Injection USP into the vial, yielding solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution. oVisually inspect the solution for particulate matter and discoloration. The reconstituted solution is clear, colorless or slightly yellowish solution, essentially free of visible particles.oCalculate the required volume of reconstituted solution as follows: oFor administration through 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).oFor administration through 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).oIf 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. oIn-line Nylon membrane filters should not be used 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.oCompatibility with other IV administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials: oPolyolefin containers (polyethylene, polypropylene and mixtures). oPVC (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene). oImplantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters. oCompatibility with other administration materials has not been investigated.oIn the absence of compatibility studies with other medicinal products do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.oParenteral 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.Storage of Infusion SolutionoIf 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.. oInject mL of Sterile Water for Injection USP into the vial, yielding solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution. oVisually inspect the solution for particulate matter and discoloration. The reconstituted solution is clear, colorless or slightly yellowish solution, essentially free of visible particles.. oCalculate the required volume of reconstituted solution as follows:. oFor administration through 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).. oFor administration through 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).. oIf 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. oIn-line Nylon membrane filters should not be used 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.. oIn-line Nylon membrane filters should not be used 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.. oCompatibility with other IV administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials: oPolyolefin containers (polyethylene, polypropylene and mixtures). oPVC (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene). oImplantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters. oPolyolefin containers (polyethylene, polypropylene and mixtures). oPVC (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene). oImplantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters. oCompatibility with other administration materials has not been investigated.. oIn the absence of compatibility studies with other medicinal products do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.. oParenteral 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.. oIf 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.. volume calculation.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Following the approved recommended dosage, geometric means (%CV) of plasma Cmax and AUC0-inf, were 107 ug/L (79%) and 551 ugoh/L (94%), respectively. No accumulation of lurbinectedin in plasma is observed upon repeated administrations every weeks. DistributionThe volume of distribution of lurbinectedin at steady state is 504 (39%). Plasma protein binding is approximately 99%, to both albumin and -1-acid glycoprotein.EliminationThe terminal half-life of lurbinectedin is 51 hours. Total plasma clearance of lurbinectedin is 11 L/h (50%).MetabolismLurbinectedin is metabolized by CYP3A4, in vitro.ExcretionAfter single dose of radiolabeled lurbinectedin administration, 89% of the radioactivity was recovered in feces (< 0.2% unchanged) and 6% in urine (1% unchanged). Specific PopulationsNo clinically significant differences in the pharmacokinetics of lurbinectedin were identified based on age (18-85 years), sex, body weight (39-154 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min) or mild hepatic impairment (total bilirubin <= ULN and AST ULN, or total bilirubin between 1.0 1.5 ULN and any AST). The effects of severe renal impairment (CLcr 30 mL/min) and moderate or severe hepatic impairment (total bilirubin 1.5 ULN and any AST) on the pharmacokinetics of lurbinectedin have not been studied. Drug Interactions StudiesDedicated clinical drug-drug interaction studies with CYP3A modulators have not been conducted with lurbinectedin. In vitro StudiesCytochrome P450 (CYP) Enzymes: Lurbinectedin is metabolized by CYP3A4. Lurbinectedin is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Lurbinectedin is not an inducer of CYP1A2 or CYP3A4. Transporter Systems: Lurbinectedin is substrate of MDR1, but is not substrate of OATB1P1, OATP1B3, OCT1, or MATE1. Lurbinectedin inhibits MDR1, OATP1B1, OATP1B3, and OCT1 but not BCRP, BSEP, MATE1, OAT1, OAT3, or OCT2.

SPL MEDGUIDE SECTION.

Patient Information PATIENT INFORMATIONZEPZELCA(R) [zep zel kah](lurbinectedin)for injectionWhat is ZEPZELCAoZEPZELCA is used to treat adults with kind of lung cancer called small cell lung cancer (SCLC). ZEPZELCA may be used when your lung cancer:ohas spread to other parts of the body (metastatic), andoyou have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working.It is not known if ZEPZELCA is safe and effective in children.Before receiving ZEPZELCA, tell your healthcare provider about all of your medical conditions, including if you:ohave liver or kidney problems.oare pregnant or plan to become pregnant. ZEPZELCA can harm your unborn baby. Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with ZEPZELCA.oYou should use effective birth control (contraception) during treatment with and for months after your final dose of ZEPZELCA.oTell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ZEPZELCA. Males with female partners who are able to become pregnant should use effective birth control during treatment with and for months after your final dose of ZEPZELCA.oare breastfeeding or plan to breastfeed. It is not known if ZEPZELCA passes into your breastmilk. Do not breastfeed during treatment with ZEPZELCA and for weeks after your final dose of ZEPZELCA. Talk to your healthcare provider about the best way to feed your baby during treatment with ZEPZELCA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain other medicines may affect how ZEPZELCA works. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How will receive ZEPZELCAoZEPZELCA is given by an intravenous (IV) infusion into vein over 60 minutes. oZEPZELCA is usually given every 21 days. oBefore each treatment with ZEPZELCA, you may receive medicines to help prevent nausea and vomiting or make it less severe. oYour healthcare provider will decide how long you will continue treatment with ZEPZELCA. oYour healthcare provider may do certain tests during your treatment with ZEPZELCA to check you for side effects, and to see how well you respond to the treatment. What should avoid while using ZEPZELCAoAvoid eating or drinking grapefruit, or products that contain grapefruit juice during treatment with ZEPZELCA.What are the possible side effects of ZEPZELCAoZEPZELCA can cause serious side effects, including:oLow blood cell counts. Low blood counts including low neutrophil counts (neutropenia) and low platelet counts (thrombocytopenia) are common with ZEPZELCA, and can also be severe. Some people with low white blood cell counts may get fever, or an infection throughout the body (sepsis), that can cause death. Your healthcare provider should do blood tests before you receive each treatment with ZEPZELCA to check your blood cell counts. Tell your healthcare provider right away if you develop:ofever or any other signs of infectionounusual bruising or bleedingotirednessopale colored skinoLiver problems. Increased liver function tests are common with ZEPZELCA, and can also be severe. Your healthcare provider should do blood tests to check your liver function before you start and during treatment with ZEPZELCA. Tell your healthcare provider right away if you develop symptoms of liver problems including:oloss of appetiteonausea or vomitingopain on the right side of your stomach-area (abdomen) Your healthcare provider may temporarily stop treatment, lower your dose, or permanently stop ZEPZELCA if you develop low blood cell counts or liver problems during treatment with ZEPZELCA.The most common side effects of ZEPZELCA include:otirednessolow white and red blood cell countsoincreased kidney function blood test (creatinine)oincreased liver function blood testsoincreased blood sugar (glucose)onauseaodecreased appetiteomuscle and joint (musculoskeletal) painolow level of albumin in the bloodoconstipationotrouble breathingolow levels of sodium and magnesium in the bloodovomitingocoughodiarrheaThese are not all of the possible side effects of ZEPZELCA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ZEPZELCA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ZEPZELCA that is written for health professionals.What are the ingredients in ZEPZELCAActive ingredient: lurbinectedin Inactive ingredients: sucrose, lactic acid and sodium hydroxide. Distributed by: Jazz Pharmaceuticals, Inc.Palo Alto, CA 94304Under license from Pharma Mar, S.A.ZEPZELCA is registered trademark of Pharma Mar, S.A. For more information, go to www.ZEPZELCA.com or call 1-800-520-5568.This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 10/2021. oZEPZELCA is used to treat adults with kind of lung cancer called small cell lung cancer (SCLC). ZEPZELCA may be used when your lung cancer:ohas spread to other parts of the body (metastatic), andoyou have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working.. ohas spread to other parts of the body (metastatic), and. oyou have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working.. ohave liver or kidney problems.. oare pregnant or plan to become pregnant. ZEPZELCA can harm your unborn baby. Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with ZEPZELCA.oYou should use effective birth control (contraception) during treatment with and for months after your final dose of ZEPZELCA.oTell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ZEPZELCA.. oYour healthcare provider should do pregnancy test before you start treatment with ZEPZELCA.. oYou should use effective birth control (contraception) during treatment with and for months after your final dose of ZEPZELCA.. oTell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ZEPZELCA.. Males with female partners who are able to become pregnant should use effective birth control during treatment with and for months after your final dose of ZEPZELCA.. oare breastfeeding or plan to breastfeed. It is not known if ZEPZELCA passes into your breastmilk. Do not breastfeed during treatment with ZEPZELCA and for weeks after your final dose of ZEPZELCA. Talk to your healthcare provider about the best way to feed your baby during treatment with ZEPZELCA.. oZEPZELCA is given by an intravenous (IV) infusion into vein over 60 minutes. oZEPZELCA is usually given every 21 days. oBefore each treatment with ZEPZELCA, you may receive medicines to help prevent nausea and vomiting or make it less severe. oYour healthcare provider will decide how long you will continue treatment with ZEPZELCA. oYour healthcare provider may do certain tests during your treatment with ZEPZELCA to check you for side effects, and to see how well you respond to the treatment. oAvoid eating or drinking grapefruit, or products that contain grapefruit juice during treatment with ZEPZELCA.. oZEPZELCA can cause serious side effects, including:. oLow blood cell counts. Low blood counts including low neutrophil counts (neutropenia) and low platelet counts (thrombocytopenia) are common with ZEPZELCA, and can also be severe. Some people with low white blood cell counts may get fever, or an infection throughout the body (sepsis), that can cause death. Your healthcare provider should do blood tests before you receive each treatment with ZEPZELCA to check your blood cell counts.. Tell your healthcare provider right away if you develop:ofever or any other signs of infectionounusual bruising or bleedingotirednessopale colored skin. ofever or any other signs of infection. ounusual bruising or bleeding. otiredness. opale colored skin. oLiver problems. Increased liver function tests are common with ZEPZELCA, and can also be severe. Your healthcare provider should do blood tests to check your liver function before you start and during treatment with ZEPZELCA. Tell your healthcare provider right away if you develop symptoms of liver problems including:oloss of appetiteonausea or vomitingopain on the right side of your stomach-area (abdomen). oloss of appetite. onausea or vomiting. opain on the right side of your stomach-area (abdomen). Your healthcare provider may temporarily stop treatment, lower your dose, or permanently stop ZEPZELCA if you develop low blood cell counts or liver problems during treatment with ZEPZELCA.. otiredness. olow white and red blood cell counts. oincreased kidney function blood test (creatinine). oincreased liver function blood tests. oincreased blood sugar (glucose). onausea. odecreased appetite. omuscle and joint (musculoskeletal) pain. olow level of albumin in the blood. oconstipation. otrouble breathing. olow levels of sodium and magnesium in the blood. ovomiting. ocough. odiarrhea.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy Risk SummaryBased on animal data and its mechanism of action [see Clinical Pharmacology (12.1)], ZEPZELCA can cause fetal harm when administered to pregnant woman. There are no available data to inform the risk of ZEPZELCA use in pregnant women. Intravenous administration of single lurbinectedin dose (approximately 0.2 times the 3.2 mg/m2 clinical dose) to pregnant rats during the period of organogenesis caused embryolethality (see Data). Advise pregnant women of the potential risk to fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.DataAnimal DataIn reproductive toxicity study, administration of single lurbinectedin dose of 0.6 mg/m2 (approximately 0.2 times of the human dose of 3.2 mg/m2) to pregnant rats on Gestation Day 10 resulted in 100% post-implantation loss.. 8.2 Lactation Risk SummaryThere are no data on the presence of lurbinectedin in human milk or its effects on the breastfed child 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 weeks after the final dose.. 8.3 Females and Males of Reproductive Potential ZEPZELCA can cause embryolethality at doses lower than the human dose of 3.2 mg/m2 [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating ZEPZELCA.ContraceptionFemalesAdvise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for months after the final dose.MalesAdvise males with female sexual partner of reproductive potential to use effective contraception during treatment with ZEPZELCA and for months after the final dose.. 8.4 Pediatric Use The safety and effectiveness of ZEPZELCA in pediatric patients have not been established.. 8.5 Geriatric Use Of the 105 patients with SCLC administered ZEPZELCA in clinical studies, 37 (35%) patients were 65 years of age and older, while (9%) patients were 75 years of age and older. No overall difference in effectiveness was observed between patients aged 65 and older and younger patients.There was higher incidence of serious adverse reactions in patients >= 65 years of age than in patients 65 years of age (49% vs. 26%, respectively). The serious adverse reactions most frequently reported in patients >= 65 years of age were related to myelosuppression and consisted of febrile neutropenia (11%), neutropenia (11%), thrombocytopenia (8%), and anemia (8%) [see Adverse Reactions (6.1) ].. 8.6 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 of ZEPZELCA is recommended for patients with mild hepatic impairment (total bilirubin <= ULN and AST ULN, or total bilirubin 1.0-1.5 ULN and any AST) [see Clinical Pharmacology (12.3) ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oMyelosuppression: Monitor blood counts prior to each administration. Initiate treatment with ZEPZELCA only if baseline neutrophil count is >=1,500 cells/mm3 and platelet count is >=100,000/mm3. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity. 2.2 5.1 oHepatotoxicity: 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. (2.2, 5.2)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to fetus and to use an effective method of contraception. (5.3). oMyelosuppression: Monitor blood counts prior to each administration. Initiate treatment with ZEPZELCA only if baseline neutrophil count is >=1,500 cells/mm3 and platelet count is >=100,000/mm3. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity. 2.2 5.1 . oHepatotoxicity: 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. (2.2, 5.2). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to fetus and to use an effective method of contraception. (5.3). 5.1 Myelosuppression ZEPZELCA can cause myelosuppression. In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA [see Adverse Reactions (6.1) ], Grade or neutropenia occurred in 41% of patients, with median time to onset of 15 days and median duration of 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 or thrombocytopenia occurred in 10%, with median time to onset of 10 days and median duration of days. Grade or anemia occurred in 17% of patients.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 [see Dosage and Administration (2.2)]. 5.2 Hepatotoxicity ZEPZELCA can cause hepatotoxicity.In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA [see Adverse Reactions (6.1) ], Grade elevations of ALT and AST were observed in 6% and 3% of patients, respectively, and Grade 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 days (range: to 49), with median duration of days.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 [see Dosage and Administration (2.2)]. 5.3 Embryo-Fetal Toxicity Based on animal data and its mechanism of action ZEPZELCA can cause fetal harm when administered to pregnant woman. Intravenous administration of single dose of lurbinectedin (approximately 0.2 times the 3.2 mg/m2 clinical dose) to pregnant animals during the period of organogenesis caused 100% embryolethality in rats. Advise pregnant women of the potential risk to fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for months after the final dose [see Use in Specific Populations (8.1, 8.3)].

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert PATIENT INFORMATIONZEPZELCA(R) (zep zel kah)(lurbinectedin)for injectionWhat is ZEPZELCAoZEPZELCA is used to treat adults with kind of lung cancer called small cell lung cancer (SCLC). ZEPZELCA may be used when your lung cancer:ohas spread to other parts of the body (metastatic), andoyou have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working.It is not known if ZEPZELCA is safe and effective in children.Before receiving ZEPZELCA, tell your healthcare provider about all of your medical conditions, including if you:ohave liver or kidney problems.oare pregnant or plan to become pregnant. ZEPZELCA can harm your unborn baby.Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with ZEPZELCA.oYou should use effective birth control (contraception) during treatment with and for months after your last dose of ZEPZELCA.oTell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ZEPZELCA. Males with female partners who are able to become pregnant should use effective birth control during treatment with and for months after your last dose of ZEPZELCA.oare breastfeeding or plan to breastfeed. It is not known if ZEPZELCA passes into your breastmilk. Do not breastfeed during treatment with ZEPZELCA and for weeks after your last dose of ZEPZELCA. Talk to your healthcare provider about the best way to feed your baby during treatment with ZEPZELCA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain other medicines may affect how ZEPZELCA works. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How will receive ZEPZELCAoZEPZELCA is given by an intravenous (IV) infusion into vein over 60 minutes. oZEPZELCA is usually given every 21 days. oBefore each treatment with ZEPZELCA, you may receive medicines to help prevent nausea and vomiting or make it less severe. oYour healthcare provider will decide how long you will continue treatment with ZEPZELCA. oYour healthcare provider may do certain tests during your treatment with ZEPZELCA to check you for side effects, and to see how well you respond to the treatment. What should avoid while using ZEPZELCAoAvoid eating or drinking grapefruit, Seville oranges, or products that contain grapefruit juice and Seville oranges during treatment with ZEPZELCA.What are the possible side effects of ZEPZELCAZEPZELCA can cause serious side effects, including:oLow blood cell counts. Low blood counts including low neutrophil counts (neutropenia) and low platelet counts (thrombocytopenia) are common with ZEPZELCA, and can also be severe. Some people with low white blood cell counts may get fever, or an infection throughout the body (sepsis), that can cause death. Your healthcare provider should do blood tests before you receive each treatment with ZEPZELCA to check your blood cell counts. Tell your healthcare provider right away if you develop: fever or any other signs of infection unusual bruising or bleeding tiredness pale colored skinoLiver problems. Increased liver function tests are common with ZEPZELCA and can also be severe. Your healthcare provider should do blood tests to check your liver function before you start and during treatment with ZEPZELCA. Tell your healthcare provider right away if you develop symptoms of liver problems including: loss of appetite nausea or vomiting pain on the right side of your stomach-area (abdomen)oLeakage of ZEPZELCA out of your vein during the infusion. If ZEPZELCA leaks into the tissues around your infusion site, it can cause damage and death of tissue cells around the infusion site. You may need to have surgery to remove any dead tissue. Tell your healthcare provider right away if you see any ZEPZELCA leaking out of your vein or around the catheter during your infusion, or if you notice any redness, swelling, itching or discomfort at the infusion site at any time. oSevere muscle problems (rhabdomyolysis). Tell your healthcare provider if you have severe muscle pain or weakness. Your healthcare provider may temporarily stop treatment, lower your dose, or permanently stop ZEPZELCA if you develop serious side effects during treatment with ZEPZELCA.The most common side effects of ZEPZELCA include:otirednessolow white and red blood cell countsoincreased kidney function blood test (creatinine)oincreased liver function blood testsoincreased blood sugar (glucose)onauseaodecreased appetiteomuscle and joint (musculoskeletal) painolow level of albumin in the bloodoconstipationotrouble breathingolow levels of sodium and magnesium in the bloodovomitingocoughodiarrheaThese are not all of the possible side effects of ZEPZELCA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ZEPZELCA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ZEPZELCA that is written for health professionals.What are the ingredients in ZEPZELCAActive ingredient: lurbinectedin Inactive ingredients: sucrose, lactic acid and sodium hydroxide. Distributed by: Jazz Pharmaceuticals, Inc.Palo Alto, CA 94304Under license from Pharma Mar, S.A.ZEPZELCA is registered trademark of Pharma Mar, S.A. For more information, go to www.ZEPZELCA.com or call 1-800-520-5568.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 07/2023. oZEPZELCA is used to treat adults with kind of lung cancer called small cell lung cancer (SCLC). ZEPZELCA may be used when your lung cancer:ohas spread to other parts of the body (metastatic), andoyou have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working.. ohas spread to other parts of the body (metastatic), and. oyou have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working.. ohave liver or kidney problems.. oare pregnant or plan to become pregnant. ZEPZELCA can harm your unborn baby.Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with ZEPZELCA.oYou should use effective birth control (contraception) during treatment with and for months after your last dose of ZEPZELCA.oTell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ZEPZELCA.. oYour healthcare provider should do pregnancy test before you start treatment with ZEPZELCA.. oYou should use effective birth control (contraception) during treatment with and for months after your last dose of ZEPZELCA.. oTell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ZEPZELCA.. Males with female partners who are able to become pregnant should use effective birth control during treatment with and for months after your last dose of ZEPZELCA.. oare breastfeeding or plan to breastfeed. It is not known if ZEPZELCA passes into your breastmilk. Do not breastfeed during treatment with ZEPZELCA and for weeks after your last dose of ZEPZELCA. Talk to your healthcare provider about the best way to feed your baby during treatment with ZEPZELCA.. oZEPZELCA is given by an intravenous (IV) infusion into vein over 60 minutes. oZEPZELCA is usually given every 21 days. oBefore each treatment with ZEPZELCA, you may receive medicines to help prevent nausea and vomiting or make it less severe. oYour healthcare provider will decide how long you will continue treatment with ZEPZELCA. oYour healthcare provider may do certain tests during your treatment with ZEPZELCA to check you for side effects, and to see how well you respond to the treatment. oAvoid eating or drinking grapefruit, Seville oranges, or products that contain grapefruit juice and Seville oranges during treatment with ZEPZELCA.. oLow blood cell counts. Low blood counts including low neutrophil counts (neutropenia) and low platelet counts (thrombocytopenia) are common with ZEPZELCA, and can also be severe. Some people with low white blood cell counts may get fever, or an infection throughout the body (sepsis), that can cause death. Your healthcare provider should do blood tests before you receive each treatment with ZEPZELCA to check your blood cell counts. Tell your healthcare provider right away if you develop: oLiver problems. Increased liver function tests are common with ZEPZELCA and can also be severe. Your healthcare provider should do blood tests to check your liver function before you start and during treatment with ZEPZELCA. Tell your healthcare provider right away if you develop symptoms of liver problems including: oLeakage of ZEPZELCA out of your vein during the infusion. If ZEPZELCA leaks into the tissues around your infusion site, it can cause damage and death of tissue cells around the infusion site. You may need to have surgery to remove any dead tissue. Tell your healthcare provider right away if you see any ZEPZELCA leaking out of your vein or around the catheter during your infusion, or if you notice any redness, swelling, itching or discomfort at the infusion site at any time. oSevere muscle problems (rhabdomyolysis). Tell your healthcare provider if you have severe muscle pain or weakness. otiredness. olow white and red blood cell counts. oincreased kidney function blood test (creatinine). oincreased liver function blood tests. oincreased blood sugar (glucose). onausea. odecreased appetite. omuscle and joint (musculoskeletal) pain. olow level of albumin in the blood. oconstipation. otrouble breathing. olow levels of sodium and magnesium in the blood. ovomiting. ocough. odiarrhea.