ZEPZELCA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZEPZELCA (ZEPZELCA).
Lurbinectedin is a selective inhibitor of oncogenic transcription. It binds to the minor groove of DNA, inhibiting the activity of RNA polymerase II and promoting its degradation, thereby reducing transcription of certain oncogenes and inducing apoptosis in cancer cells.
| Metabolism | Lurbinectedin is primarily metabolized by CYP3A4. |
| Excretion | Primarily hepatic metabolism, with biliary/fecal excretion as the major route (approximately 60-80% of the administered dose). Renal excretion accounts for <20% of the dose as unchanged drug and metabolites. |
| Half-life | Terminal elimination half-life is approximately 7-9 hours in patients with normal hepatic function, supporting once-daily dosing. |
| Protein binding | Highly bound to human plasma proteins (>99%), primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is approximately 3.5 L/kg, indicating extensive tissue distribution beyond plasma. |
| Bioavailability | Absolute bioavailability after oral administration is approximately 30% (range 20-40%) due to first-pass metabolism. |
| Onset of Action | Oral: Not well-defined; clinical effects observed within 1-2 weeks of continuous dosing based on response and tolerability. |
| Duration of Action | Duration of action is related to exposure; effects persist as long as drug concentrations are maintained above therapeutic threshold. Peak concentrations occur 1-2 hours post-dose, with sustained activity throughout the dosing interval. |
| Molecular Weight | 368.4 |
3.24 mg/m2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity.
| Dosage form | POWDER |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not studied in severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | For moderate hepatic impairment (Child-Pugh B), reduce dose to 2.25 mg/m2. Not recommended in severe hepatic impairment (Child-Pugh C). |
| Pediatric use | Safety and effectiveness in pediatric patients have not been established. |
| Geriatric use | No specific dose adjustments recommended; patients ≥65 years may have increased toxicity, but no dose modifications based on age alone. |
| 1st trimester | Avoid use; based on mechanism of action and animal studies, there is a potential for embryofetal toxicity and teratogenicity. |
| 2nd trimester | Avoid use; no human data available but risk of fetal harm cannot be excluded. |
| 3rd trimester | Avoid use; may cause fetal harm based on animal reproduction studies. |
Clinical note
Comprehensive clinical and safety monograph for ZEPZELCA (ZEPZELCA).
| Placental transfer | Based on molecular weight (368.4 Da) and animal studies, lurbinectedin likely crosses the placenta. |
| Breastfeeding | No data on presence in human milk or effects on breastfed infant; due to potential for serious adverse reactions, advise patients not to breastfeed during treatment and for at least 2 weeks after last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
Concurrent administration with strong CYP3A inhibitors or inducersHistory of severe hypersensitivity to lurbinectedin or any excipients
| Precautions | Myelosuppression: Monitor blood counts, can cause neutropenia, thrombocytopenia, anemia., Hepatotoxicity: Monitor liver function tests, dose modify for elevated liver enzymes., Neutropenic colitis: Monitor for signs/symptoms., Embryo-fetal toxicity: Advise females of reproductive potential to use effective contraception. |
| Food/Dietary | Grapefruit juice and Seville oranges (and their juices) should be avoided as they inhibit CYP3A4 and may increase lurbinectedin exposure. No other specific food restrictions. |
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| Lactation Rating |
| L5 |
| Teratogenic Risk | Based on its mechanism of action (inhibiting transcription by targeting the RNA polymerase I transcription complex) and animal studies, ZEPZELCA (lurbinectedin) is embryotoxic and teratogenic. There are no adequate human data; however, use in pregnancy is contraindicated. First trimester exposure carries highest risk of major congenital malformations and spontaneous abortion. Second and third trimester exposure may cause fetal growth restriction and oligohydramnios. Effective contraception is required during treatment and for 6 months after the last dose. |
| Fetal Monitoring | Women of reproductive potential should have pregnancy testing prior to initiation of ZEPZELCA. During pregnancy, if exposure occurs, monitor fetal growth by ultrasound every 2-4 weeks. Assess amniotic fluid volume. Monitor for signs of myelosuppression (complete blood counts) in the mother. Neonates should be monitored for hematologic toxicity if exposure occurred near delivery. |
| Fertility Effects | ZEPZELCA may impair fertility in both males and females based on animal studies showing testicular degeneration and ovarian atrophy. In humans, the effect on fertility is unknown, but given its mechanism (DNA alkylation), it is likely to cause gonadal toxicity. Patients should be counseled on fertility preservation prior to treatment. |
| Clinical Pearls |
| ZEPZELCA (lurbinectedin) is a selective inhibitor of oncogenic transcription. Premedicate with corticosteroids (e.g., dexamethasone) to reduce incidence and severity of myelosuppression, especially neutropenia. Administer IV over 60 minutes. Monitor for hepatotoxicity; check LFTs before each cycle. Dose reduction required for moderate hepatic impairment (bilirubin >1.5-3x ULN). Avoid concomitant strong CYP3A4 inhibitors (e.g., ketoconazole) as they increase lurbinectedin AUC by 2.4-fold. |
| Patient Advice | Take anti-nausea medications as prescribed before each infusion. · Report any signs of infection (fever, chills) or unusual bleeding/bruising immediately. · Avoid grapefruit juice and Seville oranges during treatment. · Use effective contraception during treatment and for 6 months after the last dose. · Do not breastfeed while taking ZEPZELCA and for 2 weeks after the last dose. |