5 WARNINGS AND PRECAUTIONS

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)].

7 DRUG INTERACTIONS

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.

Strong CYP3A Inhibitors

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

Moderate CYP3A Inhibitors

Avoid coadministration of ZEPZELCA with moderate CYP3A inhibitors. If coadministration cannot be avoided, consider dose reduction of ZEPZELCA if clinically indicated [see Dosage and Administration (2.2)].

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)].

13 NONCLINICAL TOXICOLOGY

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.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myelosuppression

Advise 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)].

Hepatotoxicity

Advise patients to contact their healthcare provider immediately for signs and symptoms suggestive of hepatotoxicity [see Warnings and Precautions (5.2)].

Extravasation Resulting in Tissue Necrosis

Advise patients to contact their healthcare provider immediately for signs and symptoms of extravasation. The time to onset of necrosis after extravasation may vary [see Warnings and Precautions (5.3)].

Rhabdomyolysis

Advise patients to contact their healthcare provider immediately for signs and symptoms of rhabdomyolysis [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity

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Advise pregnant women and females of reproductive potential of the 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 last 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 last 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 last 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 and Seville oranges 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