ZEPZELCA Powder for concentrate for solution for infusion Ref.[116643] Active ingredients: Lurbinectedin

Myelosupression

ZEPZELCA can cause severe and life-threatening myelosuppression including febrile neutropenia and sepsis.

ZEPZELCA should not be administered to patients with baseline neutrophil counts of less than 1.5 x 10⁹/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 at baseline 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 is associated with infection/sepsis, the use of G-CSF is recommended.

Hepatotoxicity

ALT 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 and periodically during treatment as clinically indicated. Dose modifications may be required (see Table 1 in section 4.2).

Extravasation resulting in tissue necrosis

Extravasation of ZEPZELCA resulting in skin and soft tissue injury, including necrosis requiring debridement, 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 and symptoms of extravasation during the ZEPZELCA infusion.

If extravasation occurs, the infusion should be immediately discontinued, the infusion catheter should be removed, and the patient should be monitored for signs and symptoms of tissue necrosis. The time to onset of necrosis after extravasation may vary. Supportive care should be administered and an appropriate medical specialist should be consulted as needed for management of signs and symptoms of extravasation. Subsequent infusions should be administered at a site that was not affected by extravasation.

Rhabdomyolysis

Rhabdomyolysis has been reported in patients treated with ZEPZELCA (see section 4.8).

Creatine phosphokinase (CPK) should be monitored prior to initiating ZEPZELCA and periodically during treatment as clinically indicated.

If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be promptly established, as indicated. Based on severity, ZEPZELCA treatment should be 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 be increased.

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 high tumour burden. Key precautions include preventing dehydration and managing electrolyte imbalances.

If TLS develops, it should be treated promptly, and the potential need for interruption or discontinuation 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 is recommended in women of childbearing potential prior to starting treatment.

Female patient of childbearing potential should use highly effective contraception during treatment and for 7 months after the last dose.

Male patients with female partners of childbearing potential should use condom during treatment and for 4 months after the last dose. Female partners of childbearing potential should use highly effective contraception 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 of autoimmune disease, or administration of systemic immunosuppressive medicinal products within 1 week prior to enrolment were excluded in the pivotal study in SCLC (see section 5.1). In the absence of data, lurbinectedin in combination with atezolizumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Excipients

This medicinal product contains less than 1 mmol of sodium (23 mg) per vial, that is to say essentially "sodium-free".

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 (AUC_0-∞) and total plasma 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 lurbinectedin administration).

Co-administration of ZEPZELCA with strong or moderate CYP3A inhibitors should be avoided. If co-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 adverse reactions 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, systemic exposure of total lurbinectedin was decreased by approximately 20% (AUC_0-∞) and total plasma clearance was increased by 25% when lurbinectedin was given concomitantly with bosentan (125 mg twice daily during 5 days). Therefore, the magnitude of these changes precludes a clinically relevant effect of co-administration of moderate CYP3A4 inducers (e.g., bosentan, cenobamate, dabrafenib, efavirenz, etravirine, lorlatinib, pexidartinib, phenobarbital, primidone, sotorasib) on lurbinectedin exposure 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 should be avoided. Consider alternative agents with less CYP3A induction (see section 4.4).

Women of childbearing potential / Contraception in males and females

Pregnancy testing is recommended in women of childbearing potential prior to starting treatment with lurbinectedin.

Female patients of childbearing potential should use highly effective contraception during treatment and for 7 months after the last dose.

Male patients with female partners of childbearing potential should use condom during treatment and for 4 months after the last dose. Female partners of childbearing potential should use highly effective contraception for the same period (see sections 4.4 and 5.3).

Pregnancy

There 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 woman requires treatment with lurbinectedin.

Pregnant or non-pregnant women of childbearing potential should be advised of the potential risk to a foetus. 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.

Breastfeeding

It is unknown whether lurbinectedin/metabolites are excreted in human milk.

A risk to the suckling child cannot be excluded.

Lurbinectedin is contraindicated during breastfeeding.

Fertility

Although no specific studies were conducted to assess fertility with lurbinectedin, and no clear signals of 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 the possibility of irreversible infertility due to therapy with lurbinectedin. Genetic counselling is also recommended for patients wishing to have children after therapy.

ZEPZELCA has moderate influence on the ability to drive and use machines. Patients experiencing fatigue, dizziness, vertigo and nausea should be advised not to drive and use machines until symptoms abate (see section 4.8).

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 ¾ 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. The most 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% of patients receiving ZEPZELCA with atezolizumab, in most cases due to pneumonia and other lung infections.

Treatment with ZEPZELCA was permanently discontinued due to adverse reactions in 5.8% of patients who were receiving ZEPZELCA in combination with atezolizumab. The most frequent adverse reaction requiring permanent discontinuation of ZEPZELCA was neutropenia (1.7%).

Adverse reactions leading to interruption of ZEPZELCA in patients who received ZEPZELCA with atezolizumab occurred in 28.9% of patients; the most common adverse reactions leading to interruption 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 with atezolizumab occurred in 16.1% of patients. The most frequent adverse reactions requiring dose reductions 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 reactions

Adverse reactions reported in IMforte clinical study are listed by MedDRA System Organ Class and by frequency in Table 3.

The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 242 patients exposed to lurbinectedin in combination with atezolizumab during a median treatment duration of 4.4 months in the clinical study IMforte (see section 5.1 for information on the main characteristics 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 be estimated from available data)". Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3. Adverse reactions experienced by patients treated with ZEPZELCA in combination with atezolizumab:

^a including, Urinary tract infection, Cystitis
^b including Skin infection, Cellulitis
^c 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, Pain
in extremity
^g including Asthenia, Fatigue.
h including Oedema, Oedema peripheral
ⁱ in few cases tissue necrosis was reported
^j including Alanine aminotransferase increased, Aspartate aminotransferase increased, Transaminases increased

Description of selected adverse reaction

Neutropenia

In IMforte, 25.2% of patients experienced neutropenia (all grades), 12.4% experienced Grade ¾ neutropenia, and 1.7% experienced febrile neutropenia and 0.4% sepsis. The median time to first onset of 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.

Hepatotoxicity

In IMforte, ALT increase was reported in 6.6% of patients (2.5% ≥Grade 3), while AST increase was reported in 7.0% of patients (1.2% ≥Grade 3). The median time to first onset of ALT increase (all grade) was 7 (range: 3-22) days. The median duration was 17 (range: 7-21) days. ALT increase led to dose 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.

Rhabdomyolysis

Cases of rhabdomyolysis have been reported with post-marketing use of ZEPZELCA. No fatal cases have been reported.

Extravasation

Cases of extravasation with local irritation have been uncommonly reported with post-marketing use of ZEPZELCA. In a few cases, tissue necrosis requiring debridement was reported.

Tumour lysis syndrome

Cases of tumour lysis syndrome have been reported with post-marketing use of ZEPZELCA.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.