Lurbinectedin (Monograph)

Brand name: Zepzelca
Drug 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

Medically reviewed by Drugs.com on Mar 21, 2024. Written by ASHP.

Introduction

Alkylating antineoplastic agent; a synthetic tetrahydroisoquinoline alkaloid.

Uses for Lurbinectedin

Small Cell Lung Cancer

Treatment of metastatic small cell lung cancer (SCLC) that has progressed during or following therapy with platinum-based chemotherapy. Designated an orphan drug by FDA for treatment of SCLC.

Accelerated approval based on overall response rate and duration of response. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Lurbinectedin Dosage and Administration

General

Pretreatment Screening

Assess blood count at baseline. Initiate treatment only if baseline absolute neutrophil count (ANC) ≥1500/mm³ and platelet count ≥100,000/mm³.
Verify pregnancy status of females of reproductive potential prior to initiation of therapy.
Perform liver function test prior to initiating therapy.

Patient Monitoring

Monitor blood counts including neutrophil count and platelet count prior to each infusion. Initiate treatment only if ANC ≥1500/mm³ and platelet count ≥100,000/mm³. Use of a granulocyte colony-stimulating factor (G-CSF) is recommended for neutrophil count <500/mm³ or below lower limit of normal.
Monitor liver function tests periodically and as clinically indicated.

Premedication and Prophylaxis

Consider antiemetic prophylaxis with a corticosteroid (e.g., dexamethasone phosphate 8 mg IV or equivalent) and a serotonin 5-HT₃ receptor antagonist (e.g., ondansetron 8 mg IV or equivalent) to minimize the risk of nausea and/or vomiting.

Dispensing and Administration Precautions

Follow procedures for proper handling and disposal of antineoplastic agents.

Administration

IV Administration

Administer by IV infusion via central or peripheral venous line. Must reconstitute commercially available lyophilized powder and further dilute prior to administration.

Reconstitution

Reconstitute by adding 8 mL of sterile water for injection to a vial containing 4 mg of lurbinectedin to provide a solution containing 0.5 mg/mL. Shake vial until complete dissolution of the powder.

Reconstituted solution should be clear, colorless or slightly yellowish, and free of visible particulates.

Dilution

For administration through a peripheral venous line: Withdraw appropriate volume of reconstituted solution and add to an infusion container containing at least 250 mL of 0.9% sodium chloride injection or 5% dextrose injection.

For administration through a central venous line: Withdraw appropriate volume of reconstituted solution and add to an infusion container containing at least 100 mL of 0.9% sodium chloride injection or 5% dextrose injection.

Visually inspect diluted solution; do not use if particulate matter is present.

If not used immediately after reconstitution or dilution, the solution can be stored prior to administration for up to 24 hours following reconstitution (including infusion time) at room temperature/ambient light or under refrigeration at 2–8º C.

Rate of Administration

Administer by IV infusion over 60 minutes.

Dosage

Adults

Small Cell Lung Cancer

IV

3.2 mg/m² once every 21 days.

Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Temporary interruption, dosage reduction, and/or permanent discontinuance may be necessary for adverse reactions. If dosage reduction is required, reduce dosage as described in Table 1.

Permanently discontinue lurbinectedin in patients unable to tolerate a dose of 2 mg/m² or who require a dose delay >2 weeks.

Table 1: Recommended Dosage Reduction for Lurbinectedin Toxicity1
Toxicity Occurrence	Dosage Reduction After Recovery from Toxicity
First	2.6 mg/m² every 21 days
Second	2 mg/m² every 21 days
Third	Permanently discontinue therapy

If neutropenia, thrombocytopenia, or hepatotoxicity occurs, modify dosage accordingly (see Table 2).

Table 2. Treatment Modifications for Lurbinectedin Toxicity1
Adverse Reaction	Dosage Modification
Neutropenia	Grade 4 or any grade febrile neutropenia: Withhold therapy; when toxicity improves to grade ≤1, resume at reduced dosage (see Table 1)
	In patients with isolated grade 4 neutropenia (neutrophil count <500/mm³), G-CSF prophylaxis may be administered rather than reducing dosage of lurbinectedin
Thrombocytopenia	Grade 3 with bleeding or grade 4: Withhold therapy; when platelet count improves to ≥100,000/mm³, resume at reduced dosage (see Table 1)
Hepatotoxicity	Grade 2: Withhold therapy; when toxicity improves to grade ≤ 1, resume at same dosage
	Grade 3 or 4: Withhold therapy; when toxicity improves to grade ≤1, resume at reduced dosage (see Table 1)

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN, or total bilirubin 1–1.5 times the ULN with any AST concentration): No dosage adjustment required.

Moderate or severe hepatic impairment (total bilirubin >1.5 times ULN with any AST concentration): No specific dosage recommendations.

Renal Impairment

No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations.

Cautions for Lurbinectedin

Contraindications

None.

Warnings/Precautions

Warnings

Hematologic Effects

Severe myelosuppression, including neutropenia, thrombocytopenia, and anemia may occur.

Monitor blood counts, including neutrophil count and platelet count, prior to each dose of lurbinectedin. Temporary interruption, dosage reduction, or discontinuance of therapy may be necessary based on the findings.

Do not administer to patients with ANC <1500/mm³ or platelet count <100,000/mm³.

Use of a granulocyte colony-stimulating factor (G-CSF) is recommended for neutrophil counts <500/mm³ or below the lower limit of normal.

Hepatotoxicity

Hepatotoxicity may occur.

Perform liver function tests prior to initiation, periodically during therapy, and as clinically indicated. Temporary interruption, dosage reduction, or discontinuance of lurbinectedin may be necessary based on the findings.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings.

Specific Populations

Pregnancy

May cause fetal harm. Advise pregnant patients of the potential risk of fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether lurbinectedin distributes into milk or affects milk production or the nursing infant.

Women should not breast-feed during therapy and for 2 weeks after the last dose of the drug.

Females and Males of Reproductive Potential

Verify pregnancy status in women of reproductive potential prior to initiation of therapy, and advise such women to use effective contraceptive methods while receiving lurbinectedin and for 6 months after the last dose of the drug.

Men with female partners of reproductive potential should use effective contraceptive methods while receiving lurbinectedin and for 4 months after the last dose of the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Although no differences in efficacy were observed between geriatric patients and younger adults in principal efficacy study, the frequency of serious adverse events was higher in geriatric patients.

Hepatic Impairment

Pharmacokinetics not substantially altered by mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN, or total bilirubin 1–1.5 times ULN with any AST concentration); no dosage adjustment necessary.

Not studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 times ULN with any AST concentration).

Renal Impairment

Pharmacokinetics not substantially affected by mild or moderate renal impairment (Cl_cr 30–89 mL/minute).

Not formally studied in patients with severe renal impairment (Cl_cr <30 mL/minute); however, renal elimination of lurbinectedin is minimal.

Common Adverse Effects

Adverse effects reported in ≥20% of patients receiving lurbinectedin include leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased ALT/AST, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, vomiting, cough, decreased magnesium concentrations, and diarrhea.

Drug Interactions

Metabolized by CYP3A4.

Substrate of P-glycoprotein (P-gp; multidrug resistance protein 1 [MDR1]).

Inhibits P-gp, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and organic cation transporter (OCT) 1.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Formal drug interaction studies with drugs affecting CYP3A not conducted to date.

Moderate or potent inhibitors of CYP3A: Possible increased systemic exposure to, and increased toxicity of, lurbinectedin. Avoid concomitant use. If concomitant use of a moderate CYP3A inhibitor cannot be avoided, may consider dosage reduction of lurbinectedin if clinically indicated.

Moderate or potent inducers of CYP3A: Possible decreased systemic exposure to, and reduced efficacy of lurbinectedin. Avoid concomitant use.

Specific Drugs or Food

Drug	Interaction	Comments
Grapefruit or grapefruit juice	Possible increased systemic exposure to, and increased toxicity of, lurbinectedin	Avoid consumption of grapefruit juice or products containing grapefruit during lurbinectedin therapy

Lurbinectedin Pharmacokinetics

Absorption

Bioavailability

Plasma accumulation not observed following repeated administration.

Special Populations

Mild to moderate renal impairment (Cl_cr 30–89 mL/minute): No clinically important pharmacokinetic effects.

Mild hepatic impairment (total bilirubin ≤ULN with AST concentration >ULN, or total bilirubin 1–1.5 times ULN with any AST concentration): No clinically important pharmacokinetic effects.

Age (18–85 years), sex, and body weight (39–154 kg) do not substantially affect pharmacokinetics of lurbinectedin.

Distribution

Plasma Protein Binding

99% bound to plasma proteins (albumin and α₁-acid glycoprotein).

Elimination

Metabolism

Metabolized by CYP3A4.

Elimination Route

Eliminated in feces (89%; <0.2% as unchanged drug) and urine (6%; 1% as unchanged drug).

Half-life

51 hours.

Stability

Storage

Parenteral

Powder for Injection

Unopened vials of lurbinectedin powder for injection: store at 2–8°C.

May store reconstituted or diluted solution at room temperature and ambient light or at 2–8°C for up to 24 hours following reconstitution (including infusion time).

Compatibility

Parenteral

Solution Compatibility

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Actions

Synthetic tetrahydroisoquinoline alkaloid that is structurally similar to trabectedin.

Alkylating antineoplastic agent; forms covalent adducts with guanine residues in the minor groove of DNA, bending the helix towards the major groove.
Affects function of DNA binding proteins, including transcription factors and DNA repair pathways, resulting in double-strand breaks, cell growth arrest, and apoptosis.
Antiproliferative activity demonstrated in vitro and in xenograft models of human cancers.
May have direct effects on tumor microenvironment; inhibits human monocyte activity in vitro, and reduces tumor macrophage infiltration in mouse xenograft models, including a lurbinectedin-resistant cell line.

Advice to Patients

Importance of advising patients to read the manufacturer's patient information.

Risk of myelosuppression. Importance of immediately contacting clinician if fever or other signs of infection, unusual bruising, bleeding, fatigue, or pallor occurs.
Risk of hepatotoxicity. Importance of immediately contacting clinician if possible manifestations of hepatotoxicity (e.g., loss of appetite, nausea or vomiting, right upper quadrant pain) occur.
Risk of fetal harm. Advise patients of potential risk of fetal harm. Necessity of advising women of reproductive potential to use effective contraception during lurbinectedin therapy and for 6 months after the last dose of the drug. Necessity of advising men who are partners of such women to use effective contraception during lurbinectedin therapy and for 4 months after the last dose of the drug. Importance of women informing their clinicians if they become pregnant during therapy or think they may be pregnant.
Importance of advising women to avoid breast-feeding while receiving lurbinectedin and for at least 2 weeks after the last dose of the drug.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of advising patients to avoid consuming products containing grapefruit during lurbinectedin therapy.
Importance of informing patients of other important precautionary information. (See Cautions.)

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 is available through a specialty pharmacy network. Consult the Zepzelca website for additional information ([Web]).