(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 myelosuppression. in clinical studies of 554 patients with advanced solid tumors receiving zepzelca [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. 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 . monitor blood counts including neutrophil count and platelet count prior to each administration. for neutrophil count less than 500 cells/mm 3 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 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. 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) ]. 5.3 extravasation resulting in tissue necrosis extravasation of zepzelca resulting in skin and soft tissue injury, including necrosis requiring debridement, can occur. 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. 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) ] . 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 6 months after the final dose. advise male patients with female partners of reproductive potential to use effective contraception during treatment with zepzelca and for 4 months after the final dose [see use in specific populations (8.1 , 8.3 )] .

if patients are unable to tolerate 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 adverse reaction severity a dosage modification neutropenia b [see warnings and precautions (5.1) ] grade 4 or any grade febrile neutropenia • withhold zepzelca until grade ≤ 1 • 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 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 a national cancer institute common terminology criteria for adverse events (nci ctcae) version 4.0 b patients with isolated grade 4 neutropenia (neutrophil count less than 500 cells/mm 3 ) 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) ] : • corticosteroids (dexamethasone 8 mg intravenously or equivalent) • serotonin antagonists (ondansetron 8 mg intravenously or equivalent) 2.4 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, essentially 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 • 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 polyolefin containers (polyethylene, polypropylene and mixtures). o polyvinyl chloride (pvc) (non-dehp-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene). o 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. volume calculation

e because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the pooled safety population described in the warnings and precautions reflect exposure to 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. 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 6 months or longer and 5% were exposed for greater than one year. small cell lung cancer (sclc) the safety of zepzelca was evaluated in a cohort of 105 patients with previously treated sclc in study b-005 [see clinical studies (14) ] . patients received zepzelca 3.2 mg/m 2 intravenously every 21 days. 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. 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 3 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-005 adverse reaction zepzelca (n=105) all grades a,b (%) grades 3-4 (%) general disorders fatigue 77 12 pyrexia 13 0 chest pain 10 0 gastrointestinal disorders nausea 37 0 constipation 31 0 vomiting 22 0 diarrhea 20 4 abdominal pain c 11 1 musculoskeletal and connective tissue disorders musculoskeletal pain d 33 4 metabolism and nutrition disorders decreased appetite 33 1 respiratory, thoracic and mediastinal disorders dyspnea 31 6 cough e 20 0 infections and infestations respiratory tract infection f 18 5 pneumonia g 10 7 nervous system disorders peripheral neuropathy h 11 1 headache 10 1 a graded per nci ctcae 4.0. b no grade 5 adverse reactions were reported. c includes abdominal pain, abdominal pain upper and abdominal discomfort. d includes musculoskeletal pain, back pain, arthralgia, pain in extremity, musculoskeletal chest pain, neck pain, bone pain and myalgia. e includes cough and productive cough. f includes upper respiratory tract infection, viral upper respiratory tract infection, respiratory tract infection and bronchitis. g includes pneumonia and lung infection. h includes 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 4 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-005 laboratory abnormality zepzelca a (n=105) all grades b (%) grades 3-4 (%) hematology decreased leukocytes 79 29 decreased lymphocytes 79 43 decreased hemoglobin 74 10 decreased neutrophils 71 46 decreased platelets 37 7 chemistry increased creatinine 69 0 increased alanine aminotransferase 66 4 increased glucose 52 5 decreased albumin 32 1 decreased sodium 31 7 increased aspartate aminotransferase 26 2 decreased magnesium 22 0 a the denominator used to calculate the rate varied from 95 to 105 based on the number of patients with a baseline value and at least one post-treatment value. b graded 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 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.

oductive toxicity study, administration of a single lurbinectedin dose of 0.6 mg/m 2 (approximately 0.2 times of the human dose of 3.2 mg/m 2 ) to pregnant rats on gestation day 10 resulted in 100% post-implantation loss. 8.2 lactation risk summary there 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 2 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/m 2 [see use in specific populations (8.1) ] . pregnancy testing verify the pregnancy status of females of reproductive potential prior to initiating zepzelca. contraception females advise female patients of reproductive potential to use effective contraception during treatment with zepzelca and for 6 months after the final dose. males advise males with a female sexual partner of reproductive potential to use effective contraception during treatment with zepzelca and for 4 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 (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 a 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) ] .

.6 mg/m 2 (approximately 0.2 times of the human dose of 3.2 mg/m 2 ) to pregnant rats on gestation day 10 resulted in 100% post-implantation loss.

e recommended dose of 3.2 mg/m 2 . 12.3 pharmacokinetics following the approved recommended dosage, geometric means (%cv) of plasma c max and auc 0-inf , were 107 µg/l (79%) and 551 µg•h/l (94%), respectively. no accumulation of lurbinectedin in plasma is observed upon repeated administrations every 3 weeks. distribution the volume of distribution of lurbinectedin at steady state is 504 l (39%). plasma protein binding is approximately 99%, to both albumin and α-1-acid glycoprotein. elimination the terminal half-life of lurbinectedin is 51 hours. total plasma clearance of lurbinectedin is 11 l/h (50%). metabolism lurbinectedin is metabolized by cyp3a4, in vitro. excretion after a single dose of radiolabeled lurbinectedin administration, 89% of the radioactivity was recovered in feces (< 0.2% unchanged) and 6% in urine (1% unchanged). specific populations no 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 studies dedicated clinical drug-drug interaction studies with cyp3a modulators have not been conducted with lurbinectedin. in vitro studies cytochrome 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 a substrate of mdr1, but is not a substrate of oatb1p1, oatp1b3, oct1, or mate1. lurbinectedin inhibits mdr1, oatp1b1, oatp1b3, and oct1 but not bcrp, bsep, mate1, oat1, oat3, or oct2.

ld 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 studies dedicated clinical drug-drug interaction studies with cyp3a modulators have not been conducted with lurbinectedin. in vitro studies cytochrome 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 a substrate of mdr1, but is not a substrate of oatb1p1, oatp1b3, oct1, or mate1. lurbinectedin inhibits mdr1, oatp1b1, oatp1b3, and oct1 but not bcrp, bsep, mate1, oat1, oat3, or oct2.

r 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 0 or 1 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 5 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-005 investigator assessed response a zepzelca all patients (n=105) zepzelca ctfi <90 days (n=45) zepzelca ctfi ≥90 days (n=60) overall response rate (95% ci) 35% (26%, 45%) 22% (11%, 37%) 45% (32%, 58%) complete response 0% 0% 0% partial response 35% 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 months b 35% 10% 44% independent review committee assessed response a 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 response 0% 0% 0% partial response 30% 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 months b 25% 0% 31% ci: confidence interval, ctfi: chemotherapy free interval

e potential risk to a fetus. advise females to inform their healthcare provider of a known or suspected pregnancy [see warnings and precautions (5.5) and use in specific populations (8.1) ] . • advise females of reproductive potential to use effective contraception during treatment with zepzelca and for 6 months after the final dose [see use in specific populations (8.3) ] . • advise males with female partners of reproductive potential to use effective contraception during treatment with zepzelca and for 4 months after the final dose [see use in specific populations (8.3) ] . lactation advise women not to breastfeed during treatment with zepzelca and for at least 2 weeks after the final dose [see use in specific populations (8.2) ] . drug interactions advise 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