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Lurbinectedin

Class: Antineoplastic Agents
Chemical Name: [(1R,2R,3R,11S,12S,14R,26R)-5,12-dihydroxy-6,6'-dimethoxy-7,21,30-trimethyl-27-oxospiro[17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.13,11.02,13.04,9.015,23.016,20]triaconta-4(9),5,7,15,20,22-hexaene-26,1'-2,3,4,9-tetrahydropyrido[3,4-b]indole]-22-yl] acetate
Molecular Formula: C41H44N4O10S
CAS Number: 497871-47-3
Brands: Zepzelca

Medically reviewed by Drugs.com. Last updated on July 27, 2020.

Introduction

Lurbinectedin is an antineoplastic agent.

Uses for Lurbinectedin

Lurbinectedin has the following uses:

Lurbinectedin is an alkylating drug indicated for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.1

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).1

Lurbinectedin Dosage and Administration

General

Lurbinectedin is available in the following dosage form(s) and strength(s):

For injection: 4 mg lyophilized powder in a single-dose vial.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • Recommended dosage: 3.2 mg/m2 every 21 days until disease progression or unacceptable toxicity occurs.1

  • Administer lurbinectedin as an intravenous infusion over 60 minutes.1

  • Consider premedication with corticosteroids and serotonin antagonists.1

  • Initiate treatment with lurbinectedin only if absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000/mm3.1

  • Consult manufacturer’s labeling for recommended dosage modifications for adverse reactions or concomitant use with strong or moderate CYP3A inhibitors and inducers.1

Cautions for Lurbinectedin

Contraindications

None.1

Warnings/Precautions

Myelosuppression

Lurbinectedin can cause myelosuppression. 1

In clinical studies of 554 patients with advanced solid tumors receiving lurbinectedin, 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.1

Administer lurbinectedin only to patients with baseline neutrophil count of at least 1500 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 a neutrophil count less than 500 cells/mm3 or any value less than the lower limit of normal, the use of granulocyte colony-stimulating factors (G-CSF) is recommended. Withhold, reduce the dose, or permanently discontinue lurbinectedin based on severity.1

Hepatotoxicity

Lurbinectedin can cause hepatotoxicity.1

In clinical studies of 554 patients with advanced solid tumors receiving lurbinectedin, 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.1

Monitor liver function tests prior to initiating lurbinectedin, periodically during treatment, and as clinically indicated. Withhold, reduce the dose, or permanently discontinue lurbinectedin based on severity.1

Embryo-fetal Toxicity

Based on animal data and its mechanism of action, lurbinectedin 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 lurbinectedin and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with lurbinectedin and for 4 months after the final dose.1

Specific Populations

Pregnancy

Risk Summary: Based on animal data and its mechanism of action, lurbinectedin can cause fetal harm when administered to a pregnant woman. There are no available data to inform the risk of lurbinectedin 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.1

Advise pregnant women of the potential risk to a fetus.1

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.1

Animal Data: In a reproductive toxicity study, administration of a single lurbinectedin dose of 0.6 mg/m2 (approximately 0.2 times the human dose of 3.2 mg/m2) to pregnant rats on gestation day 10 resulted in 100% post-implantation loss.1

Lactation

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 lurbinectedin in breastfed children, advise women not to breastfeed during treatment with lurbinectedin and for 2 weeks after the final dose.1

Females and Males of Reproductive Potential

Lurbinectedin can cause embryolethality at doses lower than the human dose of 3.2 mg/m2.1

Verify the pregnancy status of females of reproductive potential prior to initiating lurbinectedin.1

Advise female patients of reproductive potential to use effective contraception during treatment with lurbinectedin and for 6 months after the final dose.1

Advise males with a female sexual partner of reproductive potential to use effective contraception during treatment with lurbinectedin and for 4 months after the final dose.1

Pediatric Use

The safety and effectiveness of lurbinectedin in pediatric patients have not been established.1

Geriatric Use

Of the 105 patients with SCLC administered lurbinectedin 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.1

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%).1

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 lurbinectedin is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1–1.5 × ULN and any AST).1

Common Adverse Effects

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.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong or moderate CYP3A inhibitors: Avoid coadministration.1

  • Strong or moderate CYP3A inducers: Avoid coadministration.1

Actions

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. 1

Lurbinectedin inhibited human monocyte activity in vitro and reduced macrophage infiltration in implanted tumors in mice.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Myelosuppression

Advise patients to immediately contact their healthcare provider for fever, other signs of infection, unusual bruising, bleeding, tiredness or pallor.1

Hepatotoxicity

Advise patients to contact their healthcare provider immediately for signs and symptoms suggestive of hepatotoxicity.1

Embryo-Fetal Toxicity

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.1

Advise females of reproductive potential to use effective contraception during treatment with lurbinectedin and for 6 months after the final dose.1

Advise males with female partners of reproductive potential to use effective contraception during treatment with lurbinectedin and for 4 months after the final dose.1

Lactation

Advise women not to breast-feed during treatment with lurbinectedin and for at least 2 weeks after the final dose.1

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 lurbinectedin.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lurbinectedin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion only

4 mg

Zepzelca

Jazz Pharmaceuticals Inc.

AHFS Drug Information. © Copyright 2021, Selected Revisions July 27, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Jazz Pharmaceuticals, Inc.. ZEPZELCA (Lurbinectedin) INTRAVENOUS prescribing information. 2020 Jun http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=632bb50c-3bcb-4c85-9056-fc33410550ae