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 2 mg/m2 or require a dose delay greater than two weeks.

Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

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/m2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity[see 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/m2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.

2.5 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)

2.6 Preparation, Administration and Storage

ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures1.

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 to 8ºC (36ºF to 46ºF) conditions.

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/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 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/m2 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 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)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ZEPZELCA as a single agent at a 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 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/m2 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.

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.

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.

7.1 Effect of Other Drugs on ZEPZELCA

Strong and Moderate CYP3A Inhibitors

Coadministration of ZEPZELCA with a strong or a moderate CYP3A inhibitor increases lurbinectedin systemic exposure [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions to ZEPZELCA.

Avoid grapefruit and Seville oranges during ZEPZELCA treatment, as these contain strong or moderate inhibitors of CYP3A.

Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration cannot be avoided, reduce the dose of ZEPZELCA [see Dosage and Administration (2.3)].

Strong CYP3A Inducers

Avoid coadministration of ZEPZELCA with strong CYP3A inducers. Coadministration of ZEPZELCA with a strong CYP3A inducer may decrease lurbinectedin systemic exposure, which may decrease the efficacy of ZEPZELCA [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary

Based on animal data and its mechanism of action [see Clinical Pharmacology (12.1)], ZEPZELCA can cause fetal harm when administered to a pregnant woman. There are no available data to inform the risk of ZEPZELCA use in pregnant women. Intravenous administration of a single lurbinectedin dose (approximately 0.2 times the 3.2 mg/m2 clinical dose) to pregnant rats during the period of organogenesis caused embryolethality (see Data).

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In a reproductive toxicity study, administration of a 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 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 last 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 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 last 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 last 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

Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × ULN). If administration of ZEPZELCA cannot be avoided, reduce the dose [see Dosage and Administration (2.4)]. Monitor for increased adverse reactions in patients with severe hepatic impairment.

Reduce the dose of ZEPZELCA in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST) [see Dosage and Administration (2.4)]. Monitor for increased adverse reactions in patients with moderate hepatic impairment.

No dose adjustment of ZEPZELCA is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to ≤ 1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)].

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 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.

12.2 Pharmacodynamics

Lurbinectedin exposure-response relationships and the pharmacodynamic time-course for efficacy have not been fully characterized.

Increased incidence of Grade 4 neutropenia and Grade ≥ 3 thrombocytopenia were observed with increased lurbinectedin exposure.

Cardiac Electrophysiology

No large mean increase in QTc (i.e., > 20 ms) was detected at the recommended dose of 3.2 mg/m2.

12.3 Pharmacokinetics

Following the approved recommended dosage, geometric mean (%CV) of plasma Cmax and AUC0-inf, were 107 µg/L (79%) and 551 µg•h/L (94%), respectively. No accumulation of lurbinectedin in plasma is observed upon 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 CYP3A in vitro.

Excretion

After a single dose of radiolabeled lurbinectedin, 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), or mild to moderate renal impairment (CLcr 30 to 89 mL/min). The effects of severe renal impairment (CLcr < 30 mL/min) on the pharmacokinetics of lurbinectedin have not been studied.

Hepatic Impairment

No clinically significant differences in the pharmacokinetics of lurbinectedin were identified for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 × ULN and any AST) compared to that of patients with normal hepatic function.

No clinically significant differences in the pharmacokinetics of lurbinectedin were identified for patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST) who received a lurbinectedin dose of 1.6 mg/m2 compared to that of patients with mild hepatic impairment who received a dose of 3.2 mg/m2.

No clinically significant differences in the pharmacokinetics of lurbinectedin were identified for patients with severe hepatic impairment (total bilirubin > 3 × ULN) who received a lurbinectedin dose of 1.6 mg/m2 compared to that of patients with mild hepatic impairment who received a dose of 3.2 mg/m2.

Drug Interactions Studies

Clinical Studies and Model-Informed Approaches

Effects of CYP3A Inhibitors on Lurbinectedin

Strong CYP3A inhibitors: Coadministration of itraconazole (200 mg once daily) increased the systemic exposure (AUC) of total lurbinectedin by 2.7-fold and unbound lurbinectedin by 2.4‑fold.

Moderate CYP3A inhibitors: Coadministration of verapamil (80 mg every 8 hours) and erythromycin (500 mg every 6 hours) is predicted to increase lurbinectedin AUC by 2.3-fold and 2.1-fold, respectively.

Weak CYP3A inhibitors: Coadministration of fluvoxamine (150 mg every 12 hours) is predicted to increase lurbinectedin AUC by 1.3-fold.

Effects of CYP3A Inducers on Lurbinectedin

Coadministration of bosentan (a moderate CYP3A inducer) decreased systemic exposure (AUC) of total lurbinectedin by 20% and unbound lurbinectedin by 19%. These changes are not considered clinically relevant.

In vitro Studies

Cytochrome P450 (CYP) Enzymes: 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity testing of lurbinectedin has not been performed. Lurbinectedin is genotoxic to mammalian cells in the presence and absence of metabolic activation. Lurbinectedin was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay.

Fertility studies with lurbinectedin were not performed. There were no findings in reproductive organs in general toxicology studies in rats, dogs, or monkeys; however, the highest doses and exposures in these studies were all at levels lower than those at the human dose of 3.2 mg/m2.