Dose adjustment in hepatic impairment
Dose adjustment may be needed in liver disease.
Leaflet ZEPZELCA 4mg powder for concentrate for solution for infusion
- Product code:
- W72107001
- Quantity:
- 1
- Indicated for:
- maintenance treatment of extensive-stage small cell lung cancer with atezolizumab, without progression after induction w
- Route of administration:
- infusion
- Substance:
- lurbinectedin (cytotoxic antineoplastic DNA-alkylating transcription inhibitor)
- ATC
- L01XX69 — Antineoplastic and immunomodulating agents | Other antineoplastic agents
Lurbinectedin is an anticancer medicine for extensive-stage small cell lung cancer. In the EU it is used with atezolizumab as maintenance treatment in adults whose disease has not progressed after atezolizumab, carboplatin and etoposide. It acts on tumour-cell DNA and disrupts processes required for cancer-cell multiplication.
It is given in an oncology unit as an intravenous infusion lasting about one hour, usually every three weeks. Anti-sickness medicines are given beforehand, and the regimen includes prevention of low neutrophil counts. Treatment can be delayed or reduced according to blood tests. Blood counts and liver function need monitoring.
Adverse effects include tiredness, nausea, anaemia and low white blood cell or platelet counts. These changes can lead to serious infections and bleeding. Liver injury and other effects of the combined treatment can occur. Report pain, burning or swelling around the infusion immediately because leakage outside the vein can damage tissue.
Fever, chills, breathlessness, unusual bruising or bleeding require urgent contact with the oncology team. Check before starting any new medicine or supplement because interactions matter. Treatment can harm an unborn baby: follow contraception advice and report a possible pregnancy. Breastfeeding is contraindicated during treatment.
It is given in an oncology unit as an intravenous infusion lasting about one hour, usually every three weeks. Anti-sickness medicines are given beforehand, and the regimen includes prevention of low neutrophil counts. Treatment can be delayed or reduced according to blood tests. Blood counts and liver function need monitoring.
Adverse effects include tiredness, nausea, anaemia and low white blood cell or platelet counts. These changes can lead to serious infections and bleeding. Liver injury and other effects of the combined treatment can occur. Report pain, burning or swelling around the infusion immediately because leakage outside the vein can damage tissue.
Fever, chills, breathlessness, unusual bruising or bleeding require urgent contact with the oncology team. Check before starting any new medicine or supplement because interactions matter. Treatment can harm an unborn baby: follow contraception advice and report a possible pregnancy. Breastfeeding is contraindicated during treatment.
General data about ZEPZELCA 4mg
- Substance:
- lurbinectedin
- Date of latest medicines list:
- 01-09-2026
- Product code:
- W72107001
- Concentration:
- 4mg
- Pharmaceutical form:
- powder for concentrate for solution for infusion
- Quantity:
- 1
- Product type:
- Original
- Prescription status:
- P-RF — Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Concentrations available for lurbinectedin
- 2mg
- 4mg
Official documents
- Added to database:
- 01/06/2026
Precautions:
General warning
Read the package leaflet before use.
Cytotoxic / special handling
Handle with special care.
Contraception required
Effective contraception is required during treatment.
Contraindicated during breastfeeding
Do not use this medicine while breastfeeding.
Avoid grapefruit
Avoid grapefruit and grapefruit juice.
Hepatotoxicity
This medicine may affect the liver.
Immunosuppression / infection risk
This medicine may increase the risk of infections.
Major drug interactions
This medicine may have important interactions with other medicines.
Myelosuppression / agranulocytosis
This medicine may lower blood cell counts.
Myopathy / rhabdomyolysis
Seek medical advice if unexplained muscle pain occurs.
Additional monitoring
This medicine is subject to additional monitoring.
Requires periodic laboratory tests
Periodic laboratory tests may be required during treatment.
Pregnancy warning
Use during pregnancy only on medical advice.
Pediatric warning
Use in children only as recommended in the leaflet or by a doctor.
Teratogenic / fetal risk
This medicine may affect fetal development.
Contents of the package leaflet for the medicine ZEPZELCA 4mg powder for concentrate for solution for infusion
Find in leaflet
Leaflet ZEPZELCA 4mg
1. NAME OF THE MEDICINAL PRODUCT
ZEPZELCA 2 mg powder for concentrate for solution for infusion
ZEPZELCA 4 mg powder for concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
ZEPZELCA 2 mg powder for concentrate for solution for infusion
Each vial of powder contains 2 mg of lurbinectedin.
ZEPZELCA 4 mg powder for concentrate for solution for infusion
Each vial of powder contains 4 mg of lurbinectedin.
One mL of reconstituted solution contains 0.5 mg of lurbinectedin.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion (powder for concentrate).
White to off-white powder
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
ZEPZELCA, in combination with atezolizumab, is indicated for the maintenance treatment of adultpatients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has not progressed afterfirst-line induction therapy with atezolizumab, carboplatin and etoposide.
4.2 Posology and method of administration
ZEPZELCA therapy should be initiated and supervised by health professionals experienced in the useof anticancer products.
PosologyThe recommended dose of lurbinectedin is 3.2 mg/m2 every 21 days until disease progression orunacceptable toxicity when it is administered in combination with atezolizumab.
When administering lurbinectedin on the same day, atezolizumab should be administered first (seesection 5.1).
For the recommended intravenous or subcutaneous dose of atezolizumab, as well as forrecommendations regarding dose modification due to toxicity, refer to their prescribing information.
Treatment with ZEPZELCA should be initiated only if absolute neutrophil count (ANC) is at least 1.5x 109/L and platelet count is at least 100 x 109/L.
Treatment continuation and treatment delays
Further treatment cycles (i.e., cycle 2 or subsequent) will be administered every 21 days if the patientfulfils all the treatment continuation criteria listed above (see also Table 2 for dose modificationscriteria for ZEPZELCA adverse reactions).
If a patient does not meet the requirements for treatment continuation on Day 1 of any cycle after
Cycle 1, treatment will be withheld until appropriate recovery, for a maximum of 21 days after thetreatment due date. If there is no recovery after a 21-days delay, treatment must be stopped.
In case atezolizumab is discontinued due to an immune-related severe adverse reaction, treatment withlurbinectedin may be continued at its current dose as a single agent. If immune toxicity re-occursdespite discontinuation of atezolizumab, treatment with lurbinectedin should also be discontinued.
Pre-infusion medicinal products
The following pre-infusion medicinal products should be administered for antiemetic prophylaxis:
* Corticosteroids (intravenous dexamethasone 8 mg or equivalent)
* Serotonin antagonists (intravenous ondansetron 8 mg or equivalent)
Post-infusion medicinal products
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is recommended to reducethe risk of severe neutropenia/febrile neutropenia.
If needed, post-medication can include administration of extended antiemetic treatment for 2 days:
* Corticosteroids (oral dexamethasone 4 mg or equivalent), or
* Serotonin antagonists (oral ondansetron 8 mg or equivalent) or
* Metoclopramide (intravenous or oral 10 mg or equivalent every 8 hours)
Dose adjustment for adverse reactions
The recommended dose reductions for adverse reactions are listed in Table 1.
Table 1: Dose reduction for ZEPZELCA for adverse reactions
Recommended 1st Dose reduction 2nd Dose reduction 3rd Dose reductionstarting dose3.2 mg/m2 2.6 mg/m2 2.0 mg/m2 Stop1.6 mg/m2* 1.3 mg/m2 1.0 mg/m2 Stop
*Dose reduction schedule applicable to the 50% reduced dose (i.e., 1.6 mg/m2) used in cases of moderated hepaticimpairment or co-administration with strong or moderate CYP3A inhibitors.
The recommended dose modifications for adverse reactions are presented in Table 2.
Table 2: Dose modifications criteria for ZEPZELCA for adverse reactions
Adverse reaction Severitya Dose modification
Neutropeniab Grade 4 * Withhold ZEPZELCA until Grade ≤ 1 and(see section 4.4) OR resolution of any associatedany grade febrile fever/infection/sepsis,neutropenia AND
OR * Resume ZEPZELCA at a reduced dosebassociated withinfection/sepsis atany grade
Thrombocytopenia Grade 3 with * Withhold ZEPZELCA until platelet ≥ 100 x(see section 4.4) bleeding 109/L,
OR AND
Grade 4 * Resume ZEPZELCA at reduced dose
Hepatotoxicity Grade 2 * Withhold ZEPZELCA until Grade ≤ 1 (for(see section 4.4) AST and ALT until ≤ 3 ULN),and other adverse reactions AND
* Resume ZEPZELCA at same dose
Grade ≥ 3 * Withhold ZEPZELCA until Grade ≤ 1 (for
AST and ALT until ≤ 3 ULN).
AND
* Resume ZEPZELCA at reduced dose
Rhabdomyolysis Grade 2 * Withhold ZEPZELCA until Grade ≤ 1,
AND
* Resume ZEPZELCA at same dose
Grade ≥ 3 * Permanently discontinue ZEPZELCA
Non-haematological Grade 2 * Withhold ZEPZELCA until Grade ≤ 1, ANDtoxicity * Resume ZEPZELCA at same dose
Grade ≥ 3 * Withhold ZEPZELCA until Grade ≤ 1,
AND
* Resume ZEPZELCA at reduced dose
Tumour Lysis Syndrome Grade 2 * Withhold ZEPZELCA until Grade ≤ 1,
AND
* Resume ZEPZELCA at same dose
Grade ≥ 3 * Permanently discontinue ZEPZELCA
Any adverse reaction that - * Reduce the dose of ZEPZELCA orrequires frequent or discontinueprolonged (>2 weeks) dosedelaysa National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.b Patients with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3) and who had not received G-CSF asprimary prophylaxis, may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.
Dose adjustment for co-administration with strong or moderate CYP3A inhibitors
Co-administration of lurbinectedin with strong or moderate CYP3A inhibitors should be avoided. Ifco-administration cannot be avoided, dose of lurbinectedin should be reduced by 50% of the approveddose (see section 4.5). In case of adverse reactions with the reduced initial dose, up to two subsequentdose reductions by 20% each are allowed (see Table 1 in section 4.2).
Special population
ElderlyNo dose adjustment is needed in patients aged ≥65 years.
Renal impairmentNo dose adjustment is recommended in patients with mild (CrCL 60-89 mL/min) or moderate (CrCLof 30-59 mL/min) renal impairment.
Lurbinectedin has not been evaluated in a sufficient number of patients with severe renal impairment(CrCL < 30 mL/min) or end-stage renal disease to estimate the risk; therefore, it should not beadministered to these patients (see section 5.2).
Hepatic impairmentTreatment with lurbinectedin is not recommended in patients with elevated AST or ALT (AST or ALT> 3 × ULN), due to limited clinical experience.
No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULNand AST > ULN, or total bilirubin 1 to ≤ 1.5 × ULN and any AST).
In patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN and any AST), therecommended dose of ZEPZELCA is 1.6 mg/m2 by intravenous infusion over 60 minutes every 21 daysuntil disease progression or unacceptable toxicity (see section 5.2). Patients with moderate hepaticimpairment should be monitored for increased adverse reactions. In case of adverse reactions with thereduced initial dose, up to two subsequent dose reductions by 20% each are allowed (see Table 1 insection 4.2).
Administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × ULN)should be avoided. If administration of ZEPZELCA cannot be avoided, the recommended dose is1.6 mg/m2 by intravenous infusion over 60 minutes every 21 days until disease progression orunacceptable toxicity (see section 5.2). Patients with severe hepatic impairment should be monitored forincreased adverse reactions. In case of adverse reactions with the reduced initial dose, up to twosubsequent dose reductions by 20% each are allowed (see Table 1 in section 4.2).
Paediatric populationThere is no relevant use of ZEPZELCA in the paediatric population in the treatment of SCLC.
Method of administrationZEPZELCA is for intravenous use only. It must be administered by intravenous infusion over a periodof one hour.
Precautions to be taken before handling or administering the medicinal productZEPZELCA is to be reconstituted and then further diluted prior to administration.
The use of a central venous catheter should be considered to reduce the risk of extravasation (seesection 4.4) and thrombophlebitis, particularly in patients with limited venous access.
For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Breastfeeding (see section 4.6).
4.4 Special warnings and precautions for use
Myelosupression
ZEPZELCA can cause severe and life-threatening myelosuppression including febrile neutropenia andsepsis.
ZEPZELCA should not be administered to patients with baseline neutrophil counts of less than 1.5 x109/L and platelet counts of less than 100 x 109/L.
Full blood counts including differential white blood cells and platelet count should be monitored atbaseline and prior to each cycle. Dose modifications may be required (see Table 2 in section 4.2).
In case of neutrophil counts of less than 500/mm3 or any value less than lower limit of normal that isassociated with infection/sepsis, the use of G-CSF is recommended.
HepatotoxicityALT and AST increases have been reported with ZEPZELCA (see section 4.8).
Liver tests, including ALT, AST and bilirubin should be monitored prior to initiating ZEPZELCA andperiodically during treatment as clinically indicated. Dose modifications may be required (see Table 1in section 4.2).
Extravasation resulting in tissue necrosis
Extravasation of ZEPZELCA resulting in skin and soft tissue injury, including necrosis requiringdebridement, may occur (see section 4.8).
The use of a central venous catheter should be considered to reduce the risk of extravasation,particularly in patients with limited venous access. Patients should be monitored for signs andsymptoms of extravasation during the ZEPZELCA infusion.
If extravasation occurs, the infusion should be immediately discontinued, the infusion catheter shouldbe removed, and the patient should be monitored for signs and symptoms of tissue necrosis. The timeto onset of necrosis after extravasation may vary. Supportive care should be administered and anappropriate medical specialist should be consulted as needed for management of signs and symptomsof extravasation. Subsequent infusions should be administered at a site that was not affected byextravasation.
RhabdomyolysisRhabdomyolysis has been reported in patients treated with ZEPZELCA (see section 4.8).
Creatine phosphokinase (CPK) should be monitored prior to initiating ZEPZELCA and periodicallyduring treatment as clinically indicated.
If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation anddialysis should be promptly established, as indicated. Based on severity, ZEPZELCA treatment shouldbe withhold or the dose should be reduced [see Table 2 in section 4.2].
Caution should be taken if medicinal products with known association with rhabdomyolysis (e.g.,statins), are administered concomitantly with lurbinectedin, since the risk of rhabdomyolysis may beincreased.
Tumour lysis syndrome (TLS)Tumour lysis syndrome (TLS), which may be fatal, has been reported with ZEPZELCA therapy.
Healthcare professionals are advised to closely monitor patients for TLS, especially those with a hightumour burden. Key precautions include preventing dehydration and managing electrolyte imbalances.
If TLS develops, it should be treated promptly, and the potential need for interruption ordiscontinuation of treatment should be considered (see section 4.2).
Co-administration with strong CYP3A inducers
Co-administration of strong CYP3A inducers should be avoided (see section 4.5).
Embryo-foetal toxicity
Lurbinectedin can cause fetal harm when administered to a pregnant woman. Pregnancy testing isrecommended in women of childbearing potential prior to starting treatment.
Female patient of childbearing potential should use highly effective contraception during treatmentand for 7 months after the last dose.
Male patients with female partners of childbearing potential should use condom during treatment andfor 4 months after the last dose. Female partners of childbearing potential should use highly effectivecontraception for the same period (see section 4.6 and 5.3).
Disease-specific precautions - SCLC
Patients with ECOG performance status ≥ 2; central nervous system (CNS) metastases, a history ofautoimmune disease, or administration of systemic immunosuppressive medicinal products within 1week prior to enrolment were excluded in the pivotal study in SCLC (see section 5.1). In the absenceof data, lurbinectedin in combination with atezolizumab should be used with caution in thesepopulations after careful consideration of the potential benefit/risk on an individual basis.
ExcipientsThis medicinal product contains less than 1 mmol of sodium (23 mg) per vial, that is to say essentially“sodium-free”.
4.5 Interaction with other medicinal products and other forms of interaction
Effect of strong or moderate CYP3A inhibitors on lurbinectedin
In a dedicated drug-drug interaction study (n=8) with itraconazole, a strong CYP3A4 inhibitor,systemic exposure of total lurbinectedin was increased by approximately 2.7-fold (AUC0-∞) and totalplasma clearance was reduced by 63%, when lurbinectedin was given concomitantly with itraconazole(total daily dose of 200 mg during 12 days, 4 days before up to 8 days after the lurbinectedinadministration).
Co-administration of ZEPZELCA with strong or moderate CYP3A inhibitors should be avoided. Ifco-administration with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole,voriconazole, clarithromycin, telithromycin, lopinavir, ritonavir, saquinavir, nelfinavir, atazanavir,indinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., aprepitant, ciprofloxacin,erythromycin, cyclosporine, fluconazole, diltiazem, verapamil) cannot be avoided, the dose of
ZEPZELCA should be reduced by 50% of the approved dose (see section 4.2). In case of adversereactions with the reduced initial dose, up to two subsequent dose reductions by 20% each are allowed(see Table 1 in section 4.2).
Effect of strong CYP3A inducers on lurbinectedin
In a dedicated drug-drug interaction study (n=8) with bosentan, a moderate CYP3A4 inducer, systemicexposure of total lurbinectedin was decreased by approximately 20% (AUC0-∞) and total plasmaclearance was increased by 25% when lurbinectedin was given concomitantly with bosentan (125 mgtwice daily during 5 days). Therefore, the magnitude of these changes precludes a clinically relevanteffect of co-administration of moderate CYP3A4 inducers (e.g., bosentan, cenobamate, dabrafenib,efavirenz, etravirine, lorlatinib, pexidartinib, phenobarbital, primidone, sotorasib) on lurbinectedinexposure and no dose adjustment is required.
Co-administration of strong CYP3A inducers (e.g., carbamazepine, phenobarbital, phenytoin,rifampicin, rifabutin, rifapentine, St. John’s Wort (Hypericum perforatum)) with ZEPZELCA shouldbe avoided. Consider alternative agents with less CYP3A induction (see section 4.4).
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Pregnancy testing is recommended in women of childbearing potential prior to starting treatment withlurbinectedin.
Female patients of childbearing potential should use highly effective contraception during treatmentand for 7 months after the last dose.
Male patients with female partners of childbearing potential should use condom during treatment andfor 4 months after the last dose. Female partners of childbearing potential should use highly effectivecontraception for the same period (see sections 4.4 and 5.3).
PregnancyThere are no or limited amount of data from the use of lurbinectedin in pregnant women.
Studies in animals have shown severe embryo-foetal development toxicity (see section 5.3).
Lurbinectedin should not be used during pregnancy unless the clinical condition of the womanrequires treatment with lurbinectedin.
Pregnant or non-pregnant women of childbearing potential should be advised of the potential risk to afoetus. If ZEPZELCA is used during pregnancy, or if a patient becomes pregnant while receiving
ZEPZELCA, the patient should be apprised of the potential risk to the foetus.
BreastfeedingIt is unknown whether lurbinectedin/metabolites are excreted in human milk.
A risk to the suckling child cannot be excluded.
Lurbinectedin is contraindicated during breastfeeding.
FertilityAlthough no specific studies were conducted to assess fertility with lurbinectedin, and no clear signalsof toxicity of reproductive organs were observed in toxicity studies, due to the nature of the compound(cytotoxic and mutagenic) it is likely to affect the reproductive capacity.
Advice on conservation of ovules or sperm should be sought prior to treatment because of thepossibility of irreversible infertility due to therapy with lurbinectedin. Genetic counselling is alsorecommended for patients wishing to have children after therapy.
4.7 Effects on ability to drive and use machines
ZEPZELCA has moderate influence on the ability to drive and use machines. Patients experiencingfatigue, dizziness, vertigo and nausea should be advised not to drive and use machines until symptomsabate (see section 4.8)
4.8 Undesirable effects
Summary of the safety profile
The most common adverse reactions were nausea (37.6%), fatigue* (34.3%), anaemia (33.9%),thrombocytopenia (27.7%), and neutropenia (25.2%).
The most frequent grade 3/4 adverse reactions were neutropenia (12.4%), thrombocytopenia (11.2%),anaemia (9.5%) and fatigue* (5.0%).
Serious adverse reactions occurred in 34.3% of patients receiving ZEPZELCA with atezolizumab. Themost frequent serious adverse reactions were thrombocytopenia (2.9%), pneumonia (3.7%),respiratory tract infection (2.5%) and dyspnoea (2.1%). Fatal adverse reactions occurred in 5% ofpatients receiving ZEPZELCA with atezolizumab, in most cases due to pneumonia and other lunginfections.
Treatment with ZEPZELCA was permanently discontinued due to adverse reactions in 5.8% ofpatients who were receiving ZEPZELCA in combination with atezolizumab. The most frequentadverse reaction requiring permanent discontinuation of ZEPZELCA was neutropenia (1.7%).
Adverse reactions leading to interruption of ZEPZELCA in patients who received ZEPZELCA withatezolizumab occurred in 28.9% of patients; the most common adverse reactions leading tointerruption were neutropenia (5.4%), anaemia (5.0%), fatigue* (4.6%) and thrombocytopenia (3.3%).
Dose reductions of ZEPZELCA due to an adverse reaction in patients who received ZEPZELCA withatezolizumab occurred in 16.1% of patients. The most frequent adverse reactions requiring dosereductions in patients who received ZEPZELCA with atezolizumab included thrombocytopenia(4.1%), fatigue* (3.3%), nausea (2.1%) and vomiting (2.1%).
* For Preferred Terms merged see footnote in Table 3.
Tabulated list of adverse reactionsAdverse reactions reported in IMforte clinical study are listed by MedDRA System Organ Class and byfrequency in Table 3.
The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 242patients exposed to lurbinectedin in combination with atezolizumab during a median treatmentduration of 4.4 months in the clinical study IMforte (see section 5.1 for information on the maincharacteristics of participants in this clinical study). Additional adverse reactions were reported post-marketing.
Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥1/1 000 to < 1/100); rare (≥ 1/10 000 to <1/1 000); very rare (< 1/10 000); “not known (cannot beestimated from available data)”. Within each frequency grouping, adverse reactions are presented inthe order of decreasing seriousness.
Table 3. Adverse reactions experienced by patients treated with ZEPZELCA in combinationwith atezolizumab
Frequency category Adverse reaction by system organ Any grade Grade ≥3(any grade) class (%) (%)
Infections and infestationsCommon Pneumonia 5.4 3.3
Frequency category Adverse reaction by system organ Any grade Grade ≥3(any grade) class (%) (%)
Urinary tract infectiona 5.4 0.4
Infection 3.3 1.2
Skin infectionb 2.1 0.4
Uncommon Sepsis 0.4 0.4
Blood and lymphatic system disordersVery common Anaemia 33.9 9.5
Thrombocytopenia 27.7 11.2
Neutropenia 25.2 12.4
Leukopenia 12.4 2.9
Common Lymphopenia 5.4 2.1
Febrile neutropenia 1.7 1.7
Uncommon Pancytopenia 0.4 0.4
Endocrine disordersCommon Hypothyroidism 7.9 0
Metabolism and nutrition disordersVery common Decreased appetite 18.2 0.8
Common Hypomagnesaemia 5.4 0.4
Hypocalcaemia 4.5 0.8
Very rare Tumour Lysis Syndromec frequency -not known
Nervous system disordersCommon Neuropathy peripherald 8.3 0.8
Headache 6.6 0
Dysgeusia 2.9 0
Vascular disordersCommon Phlebitis 7.0 0
Thrombophlebitis 4.5 0.4
Respiratory, thoracic and mediastinal disordersVery common Dyspnoea 10.7 2.5
Common Cough 9.9 0
Pneumonitis 4.5 0.8
Productive cough 4.1 0
Gastrointestinal disordersVery common Nausea 37.6 2.9
Diarrhoea 15.7 0.4
Vomiting 14.9 0.8
Constipation 12.8 0
Common Abdominal paine 9.9 0.4
Dyspesia 4.5 0
Stomatitis 2.5 0
Skin and subcutaneous tissue disordersCommon Pruritus 7.9 0.4
Rash 5.8 0
Musculoskeletal and connective tissue disordersVery common Musculoskeletal painf 15.7 0.8
Common Arthralgia 8.3 1.2
Rare Rhabdomyolysisc frequency -not known
General disorders and administration site conditionsVery common Fatigueg 34.3 5.0
Common Oedemah 6.2 0.4
Frequency category Adverse reaction by system organ Any grade Grade ≥3(any grade) class (%) (%)
Pyrexia 5.4 0
Peripheral swelling 4.5 0.4
Extravasationi 3.3 0
Mucosal inflammation 2.5 0
InvestigationsCommon Transaminases increasedj 9.1 2.9
Blood creatinine increased 5.4 0
Gamma-glutamyltransferase increased 3.3 0.8
Blood creatine phosphokinase 2.1 0.4increased
Weight decreased 3.3 0a including, Urinary tract infection, Cystitisb including Skin infection, Cellulitisc frequency not known (cannot be estimated from available data), reported in port-marketing setting(information related to grade not available).d including Hypoesthesia, Neuropathy peripheral, Paraesthesia, Peripheral sensory neuropathy.e including Abdominal discomfort, Abdominal distension, Abdominal pain, Abdominal pain upper.f including Back pain, Musculoskeletal chest pain, Musculoskeletal pain, Myalgia, Neck pain, Painin extremityg including Asthenia, Fatigue.h including Oedema, Oedema peripherali in few cases tissue necrosis was reportedj including Alanine aminotransferase increased, Aspartate aminotransferase increased,
Transaminases increased
Description of selected adverse reaction
NeutropeniaIn IMforte, 25.2% of patients experienced neutropenia (all grades), 12.4% experienced Grade 3/4neutropenia, and 1.7% experienced febrile neutropenia and 0.4% sepsis. The median time to first onsetof neutropenia* (all grade) was 10 (range: 7-29) days. The median duration was 11 (range: 1-196)days. Neutropenia* led to dose reduction or interruption in 1.7% or 5.4% of patients, respectively.
Treatment was permanently discontinued in 1.7% of patients.
HepatotoxicityIn IMforte, ALT increase was reported in 6.6% of patients (2.5% ≥Grade 3), while AST increase wasreported in 7.0% of patients (1.2% ≥Grade 3). The median time to first onset of ALT increase (allgrade) was 7 (range: 3-22) days. The median duration was 17 (range: 7-21) days. ALT increase led todose reduction or interruption in 0.4% of patients each, respectively. The median time to first onset of
AST increased (all grade) was 4 (range: 3-8) days. The median duration was 9 (range: 6-21) days.
AST increased led to dose reduction in 0.8% of patients.
RhabdomyolysisCases of rhabdomyolysis have been reported with post-marketing use of ZEPZELCA. No fatal caseshave been reported.
ExtravasationCases of extravasation with local irritation have been uncommonly reported with post-marketing useof ZEPZELCA. In a few cases, tissue necrosis requiring debridement was reported.
Tumour lysis syndromeCases of tumour lysis syndrome have been reported with post-marketing use of ZEPZELCA.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
If an overdose is suspected, monitor the patient closely for myelosuppression and hepatic enzymes andinstitute supportive-care measures as appropriate.
There is no known antidote for overdose with lurbinectedin.
Haemodialysis is not expected to enhance the elimination of lurbinectedin because lurbinectedin ishighly bound to plasma proteins (99%), and renal excretion is negligible.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX69
Mechanism of actionLurbinectedin inhibits the oncogenic transcription process through (i) its binding to CG-rich sequencesof DNA, located within promoters of protein-coding genes; (ii) the eviction of oncogenic transcriptionfactors from their binding sites; and (iii) the stalling of elongating RNA polymerase II and its specificdegradation by the ubiquitin/proteasome machinery with all these processes leading to subsequent cellcycle arrest and tumour cell apoptosis.
Lurbinectedin suppresses the expression of inflammatory and motility-related genes at non-toxicnanomolar concentrations in vitro, while also inhibiting cell migration and adhesion. At higherconcentrations, it induces apoptosis in monocytes and macrophages through caspase-8 activation. Invivo (murine models), antitumour dosing (0.18-0.20 mg/kg) restricts tumour growth, reduces specificimmune cell populations, and decreases tumour vascularity.
Pharmacodynamic effectsCardiac Electrophysiology
The potential for QTc prolongation with lurbinectedin was evaluated in 39 patients with advancedcancer. Large effects (>10 ms) on the QTc interval were not detected with lurbinectedin dosed at3.2 mg/m² every 21 days.
Clinical efficacy and safetyExtensive-stage small cell lung cancer
The efficacy of maintenance treatment with ZEPZELCA in combination with atezolizumab wasinvestigated in 483 patients with first-line ES-SCLC in IMforte, a randomised, multicentre, open-labelstudy. Participants were eligible for randomisation if they have achieved CR, PR, or SD by RECISTv1.1 based on radiographic assessment within 28 days prior to randomisation after completion of 4cycles of induction treatment with atezolizumab, carboplatin and etoposide and if they had an ECOGperformance status of 0 or 1. Eligible patients were randomised 1:1 to receive maintenance treatmentwith either lurbinectedin with atezolizumab or atezolizumab alone. Unless contraindicated, primaryprophylaxis with G-CSF was given for patients assigned to the lurbinectedin with atezolizumab arm.
The study excluded patients with CNS metastases, a history of autoimmune disease, or administrationof systemic immunosuppressive medicines within 1 week prior to enrolment. Randomisation wasstratified by ECOG performance status (0 vs. 1), lactate dehydrogenase (LDH) (≤ ULN vs. > ULN),presence of liver metastases at enrolment (yes vs. no), and prior receipt of prophylactic cranialirradiation (yes vs. no).
Patients were randomised to one of the following two treatment arms:
* ZEPZELCA 3.2 mg/m2 intravenous with atezolizumab 1200 mg intravenous once every 3 weeksuntil disease progression or unacceptable toxicity, or
* Atezolizumab 1200 mg intravenous once every 3 weeks until disease progression or unacceptabletoxicity.
Primary efficacy endpoints were overall survival (OS) and Independent Review Facility (IRF)-assessed progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumours(RECIST) v1.1 in the randomised population. (see Table 5).
A total of 483 patients were randomised: 242 to the ZEPZELCA with atezolizumab arm and 241 to theatezolizumab arm. The median age was 66 years (range 35 to 85 years, being 13% ≥75 years). Themajority of patients were White (81.6%); 12.8% were Asian, 6.6% were Hispanic and <1% were
Black or African American. Most patients were male (62.5%) and 97.5% were current or previoussmokers. Baseline ECOG performance status was 0 (42.9%) or 1 (57.1%).
Efficacy results are presented in Table 5 and Figures 1 and 2.
Table 4: Efficacy results from IMfortelurbinectedin with atezolizumabatezolizumab N=241
N=242
Overall Survival1
Deaths (%) 113 (46.7%) 136 (56.4%)
Median, months 13.2 10.6(95% CI) (11.9, 16.4) (9.5, 12.2)
Hazard ratio2 (95% CI) 0.73 (0.57, 0.95)p-value3, 6 0.0174
Progression-Free Survival1, 4, 5
Number of events (%) 174 (71.9%) 202 (83.8%)
Median, months 5.4 2.1(95% CI) (4.2, 5.8) (1.6, 2.7)
Hazard ratio2 (95% CI) 0.54 (0.43, 0.67)p-value3, 7 <0.0001
Cut-off: 29 July 20241Measured from the time of randomisation2Stratified by ECOG performance status, LDH level, presence of liver metastases and prior receipt of prophylactic cranialirradiation3Based on the stratified log-rank test4As determined by IRF5per RECIST v1.16Compared to the allocated alpha of 0.0313 (two-sided) for this interim OS analysis.7Compared to the allocated alpha of 0.001 (two- sided) for this final PFS analysis.
CI=confidence interval
Figure 1: Kaplan-Meier plot of overall survival in IMforte
Figure 2: Kaplan-Meier plot of IRF-assessed progression free survival in IMforte
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with
ZEPZELCA in all subsets of the paediatric population in the treatment of SCLC (see section 4.2 forinformation on paediatric use).
5.2 Pharmacokinetic properties
After a 3.2 mg/m2 lurbinectedin dose administered as a 1-hour intravenous infusion, geometric meansof total plasma Cmax and AUC∞, were 107 μg/L and 551 μg*h/L, respectively. No accumulation oflurbinectedin in plasma is observed upon repeated administrations every 21 days.
DistributionTypical volume of distribution of lurbinectedin at steady state is 504 L. Binding to plasma proteins isapproximately 99%, to both albumin and α-1-acid glycoprotein, with a calculated blood-to-plasmapartitioning ratio of 0.68.
BiotransformationIn vitro studies
In vitro studies with human liver microsomes and supersomes indicate that CYP3A4 is the main CYPenzyme responsible for the hepatic metabolism of lurbinectedin.
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. The potential of lurbinectedin to induce CYP2B6 is unknown.
Transporter Systems: Lurbinectedin is a substrate of MDR1 (P-gp), but is not a substrate of
OATB1P1, OATP1B3, OCT1, or MATE1. In vitro, lurbinectedin showed inhibitory potential towards
MDR1, OATP1B1, OATP1B3, and OCT1 however, these findings are not considered clinicallyrelevant. Lurbinectedin is not an inhibitor of BCRP, BSEP, MATE1, OAT1, OAT3, or OCT2.
EliminationThe terminal half-life of lurbinectedin is 51 hours. Total plasma clearance of lurbinectedin is 11 L/h.
The major route of lurbinectedin-related radioactivity excretion was via faeces (89% of dose), withonly traces amounts of unchanged lurbinectedin detected in faeces (<0.2% of dose). Excretion in urinewas the minor route (6% of dose), mainly as unchanged compound (1% of dose) and one metabolite(up to 1% of dose).
Linearity/non-linearityLurbinectedin pharmacokinetics is linear at the dose range of 0.02-6.9 mg/m2.
Special populationsPopulation pharmacokinetics analyses showed that weight (range: 39-154 kg), age (range: 18-85years), and gender do not have a clinically meaningful influence on the systemic exposure oflurbinectedin.
Hepatic impairmentA dedicated study was conducted to evaluate the influence of varying degrees of hepatic impairment(HI) on lurbinectedin in patients with advanced solid tumours. Patients were classified according tothe National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification ashaving normal hepatic function or mild (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1to ≤ 1.5 × ULN and AST = any), moderate (total bilirubin > 1.5 to ≤ 3 × ULN and AST = any), orsevere (total bilirubin > 3 × ULN) HI. Patients with normal hepatic function and mild HI receivedlurbinectedin at 3.2 mg/m2 and patients with moderate and severe HI received lurbinectedin at1.6 mg/m2. No statistically significant differences were observed on total lurbinectedinpharmacokinetics among cohorts. A statistically significant higher dose-normalised M1 AUCmetabolite/parent ratio (MPR) was observed in patients with severe HI (ratio: 5.95, 90% CI: 2.54-13.98) and moderate HI (ratio: 8.65, 90% CI: 3.94-19.01) compared to patients with mild HI. Nostatistically significant differences were observed in M4 MPR according to HI groups.
Based on population pharmacokinetic analysis, no apparent pharmacokinetic difference was observedin 125 patients with mild who received lurbinectedin 3.2 mg/m² every 21 days as compared to 625patients with normal hepatic function.
Renal impairmentNo dedicated studies of lurbinectedin have been conducted in patients with renal impairment. Basedon population pharmacokinetic analyses, no apparent pharmacokinetic difference was observed in165 patients with mild renal impairment (CrCL of 60-89 mL/min), 73 patients with moderate renalimpairment (CrCL of 30-59 mL/min), and one patient with severe renal impairment (CrCL of26 mL/min) who received lurbinectedin 3.2 mg/m² every 21 days as compared to 166 patients withnormal renal function. The pharmacokinetic characteristics of lurbinectedin in patients with CrCL< 30 mL/min or patients on dialysis are unknown.
5.3 Preclinical safety data
Toxicology
The primary target for toxicity identified in nonclinical species (rat, dog and NHP) was characterisedby severe, reversible and non-cumulative atrophy of bone marrow, which was associated with dose-related leukopenia, as well as thrombocytopenia and anaemia. In addition, lurbinectedin-treatedanimals experienced liver abnormalities (multiple dark areas or swollen liver, increased liver functionmarkers, bile duct damage with necrosis and/or oedema, and hepatocellular degeneration/apoptosisand periportal hepatocytic hypertrophy). Additional findings were located in the gastro-intestinal tract(mucosal atrophy), kidneys (cortical tubular degeneration and vacuolation), heart (focal, slight tomoderate myocardial degeneration and/or necrosis) and injection site (perivascular/vascularinflammatory reactions). A full recovery, after cessation of dosing, was noted for the majority of thesealterations.
GenotoxicityPositive genotoxicity results were obtained in vitro in mammalian cell lines showing dose relatedtoxicity at all concentrations tested (range from 48 to 0.188 ng/mL). Positive genotoxicity findings areexpected for lurbinectedin as a DNA-interacting antineoplastic agent (see section 4.6).
Carcinogenic potential
Carcinogenicity testing of lurbinectedin has not been performed.
Reproduction and development
Lurbinectedin induced maternal toxicity at the single dose MTD level of 0.6 mg/m2 administered on
Day 10 post-coitum and severe embryo-toxicity, leading to 100% embryo lethality (see section 4.4 and4.6).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sucrose
Lactic acid
Sodium hydroxide (for pH-adjustment)
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.
This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.
6.3 Shelf life
Unopened vial
ZEPZELCA 2 mg powder for concentrate for solution for infusion18 months
ZEPZELCA 4 mg powder for concentrate for solution for infusion5 years
Reconstituted and diluted solution
Chemical and physical in-use stability has been demonstrated for 24 hours at either 2 to 8°C or 25 °C.
From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken placein controlled and validated aseptic conditions. If reconstitution/dilution has taken place in controlledand validated aseptic conditions the prepared ready to administer product can be stored up to 24 hoursat either +2°C to +8°C or +25 °C.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
ZEPZELCA 2 mg powder for concentrate for solution for infusion20 mL vial (clear type 1 glass) with a stopper (butyl rubber) and white coloured overseal (aluminium),containing 2 mg lurbinectedin.
Pack size of 1 vial.
ZEPZELCA 4 mg powder for concentrate for solution for infusion30 mL vial (clear type 1 glass) with a stopper (butyl rubber) and blue coloured overseal (aluminium),containing 4 mg lurbinectedin.
Pack size of 1 vial.
6.6 Special precautions for disposal and other handling
Appropriate procedures for proper handling and disposal of cytotoxic medicinal products must befollowed. You should have received training on the correct techniques to reconstitute and dilute
ZEPZELCA and you should wear protective clothing including mask, goggles and gloves during thereconstitution and dilution. Accidental contact with the skin, eyes or mucous membranes must betreated immediately with copious amounts of water. You should not work with this medicine if youare pregnant.
Prepare the solution for infusion using aseptic technique as follows:
* Inject 8 mL (for 4 mg strength) or 4 mL (for 2 mg strength) of water for injections into thevial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until completedissolution. The reconstituted solution is a clear, colourless or slightly yellowish solution,essentially free of visible particles. Visually inspect the solution for particulate matter anddiscoloration.
* Calculate the required volume of reconstituted solution as follows:
Volume (mL) = Body Surface Area (m2) x Individual Dose (mg/m2)0.5 mg/mL
* For administration through a central venous line, withdraw the appropriate amount ofreconstituted solution from the vial and add to an infusion container containing at least100 mL of diluent sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose50 mg/mL (5%) solution for infusion.
* For administration through a peripheral venous line, withdraw the appropriate amount ofreconstituted solution from the vial and add to an infusion container containing at least250 mL of diluent sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose50 mg/mL (5%) solution for infusion.
The following materials are compatible with ZEPZELCA diluted solution:
* Polyolefin containers (polyethylene, polypropylene and mixtures).
* PVC (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene,polypropylene and polybutadiene).
* Polyether sulfone in-line filters with pore sizes of 0.22 micron.
* Implantable venous access systems with titanium and plastic resin ports and with polyurethaneor silicone intravenous catheters.
ZEPZELCA can be administered with or without an in-line filter.
Infusion lines containing nylon membrane filters should not be used when the reconstituted
ZEPZELCA solution is diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion.
Lurbinectedin is a cytotoxic medicinal product. Any unused medicinal product or waste materialshould be disposed of in accordance with local requirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu