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

ZEPZELCA therapy should be initiated and supervised by health professionals experienced in the use of anticancer products.

Posology

The recommended dose of lurbinectedin is 3.2 mg/m² every 21 days until disease progression or unacceptable toxicity when it is administered in combination with atezolizumab.

When administering lurbinectedin on the same day, atezolizumab should be administered first (see section 5.1).

For the recommended intravenous or subcutaneous dose of atezolizumab, as well as for recommendations 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 1.5 x 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 patient fulfils all the treatment continuation criteria listed above (see also Table 2 for dose modifications criteria 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 the treatment 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 with lurbinectedin may be continued at its current dose as a single agent. If immune toxicity re-occurs despite 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 reduce the 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:

^* Dose reduction schedule applicable to the 50% reduced dose (i.e., 1.6 mg/m²) used in cases of moderated hepatic impairment 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:

^a 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 as primary 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. If co-administration cannot be avoided, dose of lurbinectedin should be reduced by 50% of the approved dose (see section 4.5). 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).

Special population

Elderly

No dose adjustment is needed in patients aged ≥65 years.

Renal impairment

No dose adjustment is recommended in patients with mild (CrCL 60-89 mL/min) or moderate (CrCL of 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 be administered to these patients (see section 5.2).

Hepatic impairment

Treatment 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 ≤ ULN and 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), the recommended dose of ZEPZELCA is 1.6 mg/m² by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity (see section 5.2). Patients with moderate hepatic impairment should be monitored for increased adverse reactions. 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).

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 is 1.6 mg/m² by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity (see section 5.2). Patients with severe hepatic impairment should be monitored for increased adverse reactions. 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).

Paediatric population

There is no relevant use of ZEPZELCA in the paediatric population in the treatment of SCLC.

Method of administration

ZEPZELCA is for intravenous use only. It must be administered by intravenous infusion over a period of one hour.

Precautions to be taken before handling or administering the medicinal product

ZEPZELCA 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 (see section 4.4) and thrombophlebitis, particularly in patients with limited venous access.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

If an overdose is suspected, monitor the patient closely for myelosuppression and hepatic enzymes and institute 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 is highly bound to plasma proteins (99%), and renal excretion is negligible.

Unopened vial:

ZEPZELCA 2 mg powder for concentrate for solution for infusion

18 months.

ZEPZELCA 4 mg powder for concentrate for solution for infusion

5 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 used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. If reconstitution/dilution has taken place in controlled and validated aseptic conditions the prepared ready to administer product can be stored up to 24 hours at either +2°C to +8°C or +25°C.

Store in a refrigerator (2°C–8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

ZEPZELCA 2 mg powder for concentrate for solution for infusion:

20 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 infusion:

30 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.

Appropriate procedures for proper handling and disposal of cytotoxic medicinal products must be followed. 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 the reconstitution and dilution. Accidental contact with the skin, eyes or mucous membranes must be treated immediately with copious amounts of water. You should not work with this medicine if you are 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 the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution. The reconstituted solution is a clear, colourless or slightly yellowish solution, essentially free of visible particles. Visually inspect the solution for particulate matter and discoloration.
• 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 of reconstituted solution from the vial and add to an infusion container containing at least 100 mL of diluent sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 50 mg/mL (5%) solution for infusion.
• For administration through a peripheral venous line, withdraw the appropriate amount of reconstituted solution from the vial and add to an infusion container containing at least 250 mL of diluent sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 50 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 polyurethane or 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 material should be disposed of in accordance with local requirements.