Zepzelca (Lurbinectedin)

Indications of Usage, Extensive-Stage Small Cell Lung Cancer (

Dosage and Administration, Recommended Dosage (

Dosage and Administration, Dosage Modifications for Use with Strong and Moderate CYP3A Inhibitors (

2 DOSAGE AND ADMINISTRATION

• •
  Recommended Dosage
  : 3.2 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
• •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement.
• •Administer ZEPZELCA as an intravenous infusion over 60 minutes.
• •To reduce the risk of nausea, administer corticosteroids and serotonin agonists prior to Cycle 1 and consider use for subsequent cycles.
• •To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information].
• •
  Moderate Hepatic Impairment
  : Recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
• •
  Severe Hepatic Impairment
  : Avoid use of ZEPZELCA. If use cannot be avoided, the recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.

2.1 Recommended Dosage

The recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

[see Dosage and Administration (2.4)].

Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm³and platelet count is at least 100,000/mm³.

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

When administering ZEPZELCA on the same day as atezolizumab or atezolizumab and hyaluronidase-tqjs, administer the chosen atezolizumab drug first. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information.

If discontinuation of atezolizumab or atezolizumab and hyaluronidase-tqjs is required due to an immune-related severe adverse event, treatment with ZEPZELCA may be continued at the same dose as a single agent. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA.

2.2 Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions are listed in Table 1.

Permanently discontinue ZEPZELCA in patients who require a dose interruption of greater than two weeks and in patients who are unable to tolerate 2 mg/m²every 21 days.

Table 1: Dose Reduction for ZEPZELCA for Adverse Reactions

Dose Reduction	Total Dose
First Second	2.6 mg/m2every 21 days 2 mg/m2every 21 days

Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

Withhold ZEPZELCA until absolute neutrophil count (ANC) is ≥ 1500/mm³

Resume ZEPZELCA at a reduced doseWithhold ZEPZELCA until platelet ≥ 100,000/mm³

Resume ZEPZELCA at reduced doseWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at reduced dose or permanently discontinueWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at same dosePermanently discontinue ZEPZELCA.Withhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at reduced dose or permanently discontinue

Table 2: Dosage Modifications for ZEPZELCA for Adverse Reactions

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
bPatients who have not received primary prophylaxis of G-CSF with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.
Adverse Reaction	Severitya	Dosage Modification
Neutropeniab [see Warnings and Precautions (5.1)]	Grade 4 or Any grade febrile neutropenia
Thrombocytopenia [see Warnings and Precautions (5.1)]	Grade 3 with bleeding or Grade 4
Hepatotoxicity [see Warnings and Precautions (5.2)]	Grade 2
	Grade ≥ 3
Rhabdomyolysis [see Warnings and Precautions (5.4)]	Grade 2
	Grade ≥ 3
Other Adverse Reactions [see Adverse Reactions (6.1), Postmarketing (6.2)]	Grade 2
	Grade ≥ 3

2.3 Dosage Modifications for use with Strong and Moderate CYP3A Inhibitors

Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration of ZEPZELCA with a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ZEPZELCA by 50%

[see Drug Interactions (7.1)and Clinical Pharmacology (12.3)]

. After discontinuation of a strong or moderate CYP3A inhibitor for 5 half-lives of the inhibitor, increase the ZEPZELCA dose to the dose used before starting the inhibitor

.

2.4 Dosage Modifications for Patients with Severe and Moderate Hepatic Impairment

Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × Upper Limit of Normal (ULN)). If administration of ZEPZELCA cannot be avoided, the recommended dosage is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]

.

In patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN and any AST), the recommended dosage of ZEPZELCA is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

.

2.5 Recommended Prophylactic Medications

ZEPZELCA as a Single-Agent

Consider administering the following pre-infusion medications for antiemetic prophylaxis

[see Adverse Reactions (6.1)]

:

• •Corticosteroids (dexamethasone 8 mg intravenously or equivalent)
• •Serotonin antagonists (ondansetron 8 mg intravenously or equivalent)

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

• •
  To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information]
  .
• •
  To reduce the risk of nausea, administer the following pre-infusion medications for antiemetic prophylaxis prior to Cycle 1 and consider administering for subsequent cycles

  [see Adverse Reactions (6.1)]
  :
• ⸰    Corticosteroids (dexamethasone 8 mg or equivalent intravenously)
• ⸰    Serotonin antagonists (ondansetron 8 mg or equivalent intravenously)

2.6 Preparation, Administration and Storage

ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures¹.

Preparation

• •Inject 8 mL of Sterile Water for Injection USP into the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution.
• •Visually inspect the solution for particulate matter and discoloration. The reconstituted solution is a clear, colorless or slightly yellowish solution, free of visible particles.
• •Calculate the required volume of reconstituted solution as follows:
  
  
• •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
• •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).

Administration

• •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement
  [see Warnings and Precautions (5.3)]
  .
• •Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
• •ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.
  • oDo not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.

• •Compatibility with other intravenous administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials:
  • oContainers: Polyolefin containers (polyethylene, polypropylene and mixtures).
  • oInfusion sets: Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene).
  • oImplantable venous access systems: Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.
• •Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase

-

tqjs

• •
  Administer either atezolizumab or atezolizumab and hyaluronidase-tqjs first, then administer ZEPZELCA. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information
  .

Storage of Infusion Solution

• •If not used immediately after reconstitution or dilution, the ZEPZELCA solution can be stored prior to administration for up to 24 hours following reconstitution, including infusion time, at either room temperature/ ambient light or under refrigeration at 2ºC to 8ºC (36ºF to 46ºF) conditions.

Dosage and Administration, Dosage Modifications for Patients with Severe and Moderate Hepatic Impairment (

2 DOSAGE AND ADMINISTRATION

• •
  Recommended Dosage
  : 3.2 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
• •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement.
• •Administer ZEPZELCA as an intravenous infusion over 60 minutes.
• •To reduce the risk of nausea, administer corticosteroids and serotonin agonists prior to Cycle 1 and consider use for subsequent cycles.
• •To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information].
• •
  Moderate Hepatic Impairment
  : Recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
• •
  Severe Hepatic Impairment
  : Avoid use of ZEPZELCA. If use cannot be avoided, the recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.

2.1 Recommended Dosage

The recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

[see Dosage and Administration (2.4)].

Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm³and platelet count is at least 100,000/mm³.

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

When administering ZEPZELCA on the same day as atezolizumab or atezolizumab and hyaluronidase-tqjs, administer the chosen atezolizumab drug first. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information.

If discontinuation of atezolizumab or atezolizumab and hyaluronidase-tqjs is required due to an immune-related severe adverse event, treatment with ZEPZELCA may be continued at the same dose as a single agent. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA.

2.2 Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions are listed in Table 1.

Permanently discontinue ZEPZELCA in patients who require a dose interruption of greater than two weeks and in patients who are unable to tolerate 2 mg/m²every 21 days.

Table 1: Dose Reduction for ZEPZELCA for Adverse Reactions

Dose Reduction	Total Dose
First Second	2.6 mg/m2every 21 days 2 mg/m2every 21 days

Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

Withhold ZEPZELCA until absolute neutrophil count (ANC) is ≥ 1500/mm³

Resume ZEPZELCA at a reduced doseWithhold ZEPZELCA until platelet ≥ 100,000/mm³

Resume ZEPZELCA at reduced doseWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at reduced dose or permanently discontinueWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at same dosePermanently discontinue ZEPZELCA.Withhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at reduced dose or permanently discontinue

Table 2: Dosage Modifications for ZEPZELCA for Adverse Reactions

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
bPatients who have not received primary prophylaxis of G-CSF with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.
Adverse Reaction	Severitya	Dosage Modification
Neutropeniab [see Warnings and Precautions (5.1)]	Grade 4 or Any grade febrile neutropenia
Thrombocytopenia [see Warnings and Precautions (5.1)]	Grade 3 with bleeding or Grade 4
Hepatotoxicity [see Warnings and Precautions (5.2)]	Grade 2
	Grade ≥ 3
Rhabdomyolysis [see Warnings and Precautions (5.4)]	Grade 2
	Grade ≥ 3
Other Adverse Reactions [see Adverse Reactions (6.1), Postmarketing (6.2)]	Grade 2
	Grade ≥ 3

2.3 Dosage Modifications for use with Strong and Moderate CYP3A Inhibitors

Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration of ZEPZELCA with a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ZEPZELCA by 50%

[see Drug Interactions (7.1)and Clinical Pharmacology (12.3)]

. After discontinuation of a strong or moderate CYP3A inhibitor for 5 half-lives of the inhibitor, increase the ZEPZELCA dose to the dose used before starting the inhibitor

.

2.4 Dosage Modifications for Patients with Severe and Moderate Hepatic Impairment

Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × Upper Limit of Normal (ULN)). If administration of ZEPZELCA cannot be avoided, the recommended dosage is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]

.

In patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN and any AST), the recommended dosage of ZEPZELCA is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

.

2.5 Recommended Prophylactic Medications

ZEPZELCA as a Single-Agent

Consider administering the following pre-infusion medications for antiemetic prophylaxis

[see Adverse Reactions (6.1)]

:

• •Corticosteroids (dexamethasone 8 mg intravenously or equivalent)
• •Serotonin antagonists (ondansetron 8 mg intravenously or equivalent)

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

• •
  To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information]
  .
• •
  To reduce the risk of nausea, administer the following pre-infusion medications for antiemetic prophylaxis prior to Cycle 1 and consider administering for subsequent cycles

  [see Adverse Reactions (6.1)]
  :
• ⸰    Corticosteroids (dexamethasone 8 mg or equivalent intravenously)
• ⸰    Serotonin antagonists (ondansetron 8 mg or equivalent intravenously)

2.6 Preparation, Administration and Storage

ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures¹.

Preparation

• •Inject 8 mL of Sterile Water for Injection USP into the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution.
• •Visually inspect the solution for particulate matter and discoloration. The reconstituted solution is a clear, colorless or slightly yellowish solution, free of visible particles.
• •Calculate the required volume of reconstituted solution as follows:
  
  
• •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
• •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).

Administration

• •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement
  [see Warnings and Precautions (5.3)]
  .
• •Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
• •ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.
  • oDo not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.

• •Compatibility with other intravenous administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials:
  • oContainers: Polyolefin containers (polyethylene, polypropylene and mixtures).
  • oInfusion sets: Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene).
  • oImplantable venous access systems: Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.
• •Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase

-

tqjs

• •
  Administer either atezolizumab or atezolizumab and hyaluronidase-tqjs first, then administer ZEPZELCA. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information
  .

Storage of Infusion Solution

• •If not used immediately after reconstitution or dilution, the ZEPZELCA solution can be stored prior to administration for up to 24 hours following reconstitution, including infusion time, at either room temperature/ ambient light or under refrigeration at 2ºC to 8ºC (36ºF to 46ºF) conditions.

Dosage and Administration, Premedication (

2 DOSAGE AND ADMINISTRATION

• •
  Recommended Dosage
  : 3.2 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
• •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement.
• •Administer ZEPZELCA as an intravenous infusion over 60 minutes.
• •To reduce the risk of nausea, administer corticosteroids and serotonin agonists prior to Cycle 1 and consider use for subsequent cycles.
• •To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information].
• •
  Moderate Hepatic Impairment
  : Recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
• •
  Severe Hepatic Impairment
  : Avoid use of ZEPZELCA. If use cannot be avoided, the recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.

2.1 Recommended Dosage

The recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

[see Dosage and Administration (2.4)].

Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm³and platelet count is at least 100,000/mm³.

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

When administering ZEPZELCA on the same day as atezolizumab or atezolizumab and hyaluronidase-tqjs, administer the chosen atezolizumab drug first. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information.

If discontinuation of atezolizumab or atezolizumab and hyaluronidase-tqjs is required due to an immune-related severe adverse event, treatment with ZEPZELCA may be continued at the same dose as a single agent. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA.

2.2 Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions are listed in Table 1.

Permanently discontinue ZEPZELCA in patients who require a dose interruption of greater than two weeks and in patients who are unable to tolerate 2 mg/m²every 21 days.

Table 1: Dose Reduction for ZEPZELCA for Adverse Reactions

Dose Reduction	Total Dose
First Second	2.6 mg/m2every 21 days 2 mg/m2every 21 days

Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

Withhold ZEPZELCA until absolute neutrophil count (ANC) is ≥ 1500/mm³

Resume ZEPZELCA at a reduced doseWithhold ZEPZELCA until platelet ≥ 100,000/mm³

Resume ZEPZELCA at reduced doseWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at reduced dose or permanently discontinueWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at same dosePermanently discontinue ZEPZELCA.Withhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

Resume ZEPZELCA at reduced dose or permanently discontinue

Table 2: Dosage Modifications for ZEPZELCA for Adverse Reactions

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
bPatients who have not received primary prophylaxis of G-CSF with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.
Adverse Reaction	Severitya	Dosage Modification
Neutropeniab [see Warnings and Precautions (5.1)]	Grade 4 or Any grade febrile neutropenia
Thrombocytopenia [see Warnings and Precautions (5.1)]	Grade 3 with bleeding or Grade 4
Hepatotoxicity [see Warnings and Precautions (5.2)]	Grade 2
	Grade ≥ 3
Rhabdomyolysis [see Warnings and Precautions (5.4)]	Grade 2
	Grade ≥ 3
Other Adverse Reactions [see Adverse Reactions (6.1), Postmarketing (6.2)]	Grade 2
	Grade ≥ 3

2.3 Dosage Modifications for use with Strong and Moderate CYP3A Inhibitors

Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration of ZEPZELCA with a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ZEPZELCA by 50%

[see Drug Interactions (7.1)and Clinical Pharmacology (12.3)]

. After discontinuation of a strong or moderate CYP3A inhibitor for 5 half-lives of the inhibitor, increase the ZEPZELCA dose to the dose used before starting the inhibitor

.

2.4 Dosage Modifications for Patients with Severe and Moderate Hepatic Impairment

Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × Upper Limit of Normal (ULN)). If administration of ZEPZELCA cannot be avoided, the recommended dosage is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]

.

In patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN and any AST), the recommended dosage of ZEPZELCA is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

.

2.5 Recommended Prophylactic Medications

ZEPZELCA as a Single-Agent

Consider administering the following pre-infusion medications for antiemetic prophylaxis

[see Adverse Reactions (6.1)]

:

• •Corticosteroids (dexamethasone 8 mg intravenously or equivalent)
• •Serotonin antagonists (ondansetron 8 mg intravenously or equivalent)

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

• •
  To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information]
  .
• •
  To reduce the risk of nausea, administer the following pre-infusion medications for antiemetic prophylaxis prior to Cycle 1 and consider administering for subsequent cycles

  [see Adverse Reactions (6.1)]
  :
• ⸰    Corticosteroids (dexamethasone 8 mg or equivalent intravenously)
• ⸰    Serotonin antagonists (ondansetron 8 mg or equivalent intravenously)

2.6 Preparation, Administration and Storage

ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures¹.

Preparation

• •Inject 8 mL of Sterile Water for Injection USP into the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution.
• •Visually inspect the solution for particulate matter and discoloration. The reconstituted solution is a clear, colorless or slightly yellowish solution, free of visible particles.
• •Calculate the required volume of reconstituted solution as follows:
  
  
• •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
• •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).

Administration

• •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement
  [see Warnings and Precautions (5.3)]
  .
• •Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
• •ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.
  • oDo not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.

• •Compatibility with other intravenous administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials:
  • oContainers: Polyolefin containers (polyethylene, polypropylene and mixtures).
  • oInfusion sets: Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene).
  • oImplantable venous access systems: Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.
• •Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.

ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase

-

tqjs

• •
  Administer either atezolizumab or atezolizumab and hyaluronidase-tqjs first, then administer ZEPZELCA. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information
  .

Storage of Infusion Solution

• •If not used immediately after reconstitution or dilution, the ZEPZELCA solution can be stored prior to administration for up to 24 hours following reconstitution, including infusion time, at either room temperature/ ambient light or under refrigeration at 2ºC to 8ºC (36ºF to 46ºF) conditions.

Warnings and Precautions (

ZEPZELCA is an alkylating drug indicated:

• •in combination with atezolizumab or atezolizumab and hyaluronidase-tqj, for the maintenance treatment of adult patients with extensive-stage small cell lung cancer whose disease has not progressed after first-line induction therapy with atezolizumab or atezolizumab and hyaluronidase-tqjs, carboplatin and etoposide. (
  1.1 Extensive-Stage Small Cell Lung Cancer

  ZEPZELCA, in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, is indicated for the maintenance treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has not progressed after first-line induction therapy with atezolizumab or atezolizumab and hyaluronidase-tqjs, carboplatin and etoposide.
  )
• •For the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. (
  1.2 Metastatic Small Cell Lung Cancer

  ZEPZELCA is indicated for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

  This indication is approved under accelerated approval based on overall response rate and duration of response

  [see Clinical Studies (14)]

  . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  )
•  This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). (
  1.2 Metastatic Small Cell Lung Cancer

  ZEPZELCA is indicated for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

  This indication is approved under accelerated approval based on overall response rate and duration of response

  [see Clinical Studies (14)]

  . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  )

• •
  Recommended Dosage
  : 3.2 mg/m² administered intravenously every 21 days until disease progression or unacceptable toxicity.
• •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement. (
  5.3 Extravasation Resulting in Tissue Necrosis

  Extravasation of ZEPZELCA can cause skin and soft tissue injury, including necrosis requiring debridement. Consider use of a central venous catheter to reduce the risk of extravasation, particularly in patients with limited venous access. Monitor patients for signs and symptoms of extravasation during the ZEPZELCA infusion. If extravasation occurs, immediately discontinue the infusion, remove the infusion catheter, and monitor for signs and symptoms of tissue necrosis. The time to onset of necrosis after extravasation may vary.

  ZEPZELCA with Intravenous Atezolizumab

  In the IMforte study

  [see Adverse Reactions (6.1)]

  , extravasation resulting in skin necrosis occurred in one patient who received ZEPZELCA in combination with atezolizumab.

  Administer supportive care and consult with an appropriate medical specialist as needed for signs and symptoms of extravasation. Administer subsequent infusions at a site that was not affected by extravasation.
  )
• •Administer ZEPZELCA as an intravenous infusion over 60 minutes.
• •To reduce the risk of nausea, administer corticosteroids and serotonin agonists prior to Cycle 1 and consider use for subsequent cycles. (
  2 DOSAGE AND ADMINISTRATION

  • •
    Recommended Dosage
    : 3.2 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
  • •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement.
  • •Administer ZEPZELCA as an intravenous infusion over 60 minutes.
  • •To reduce the risk of nausea, administer corticosteroids and serotonin agonists prior to Cycle 1 and consider use for subsequent cycles.
  • •To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information].
  • •
    Moderate Hepatic Impairment
    : Recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
  • •
    Severe Hepatic Impairment
    : Avoid use of ZEPZELCA. If use cannot be avoided, the recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.

  2.1 Recommended Dosage

  The recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

  [see Dosage and Administration (2.4)].

  Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm³and platelet count is at least 100,000/mm³.

  ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

  When administering ZEPZELCA on the same day as atezolizumab or atezolizumab and hyaluronidase-tqjs, administer the chosen atezolizumab drug first. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information.

  If discontinuation of atezolizumab or atezolizumab and hyaluronidase-tqjs is required due to an immune-related severe adverse event, treatment with ZEPZELCA may be continued at the same dose as a single agent. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA.

  2.2 Dosage Modifications for Adverse Reactions

  The recommended dose reductions for adverse reactions are listed in Table 1.

  Permanently discontinue ZEPZELCA in patients who require a dose interruption of greater than two weeks and in patients who are unable to tolerate 2 mg/m²every 21 days.

  Table 1: Dose Reduction for ZEPZELCA for Adverse Reactions

  Dose Reduction	Total Dose
  First Second	2.6 mg/m2every 21 days 2 mg/m2every 21 days

  Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

  Withhold ZEPZELCA until absolute neutrophil count (ANC) is ≥ 1500/mm³

  Resume ZEPZELCA at a reduced doseWithhold ZEPZELCA until platelet ≥ 100,000/mm³

  Resume ZEPZELCA at reduced doseWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at reduced dose or permanently discontinueWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at same dosePermanently discontinue ZEPZELCA.Withhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at reduced dose or permanently discontinue

  Table 2: Dosage Modifications for ZEPZELCA for Adverse Reactions

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
  bPatients who have not received primary prophylaxis of G-CSF with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.
  Adverse Reaction	Severitya	Dosage Modification
  Neutropeniab [see Warnings and Precautions (5.1)]	Grade 4 or Any grade febrile neutropenia
  Thrombocytopenia [see Warnings and Precautions (5.1)]	Grade 3 with bleeding or Grade 4
  Hepatotoxicity [see Warnings and Precautions (5.2)]	Grade 2
  	Grade ≥ 3
  Rhabdomyolysis [see Warnings and Precautions (5.4)]	Grade 2
  	Grade ≥ 3
  Other Adverse Reactions [see Adverse Reactions (6.1), Postmarketing (6.2)]	Grade 2
  	Grade ≥ 3

  2.3 Dosage Modifications for use with Strong and Moderate CYP3A Inhibitors

  Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration of ZEPZELCA with a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ZEPZELCA by 50%

  [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)]

  . After discontinuation of a strong or moderate CYP3A inhibitor for 5 half-lives of the inhibitor, increase the ZEPZELCA dose to the dose used before starting the inhibitor

  .

  2.4 Dosage Modifications for Patients with Severe and Moderate Hepatic Impairment

  Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × Upper Limit of Normal (ULN)). If administration of ZEPZELCA cannot be avoided, the recommended dosage is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

  [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]

  .

  In patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN and any AST), the recommended dosage of ZEPZELCA is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

  .

  2.5 Recommended Prophylactic Medications

  ZEPZELCA as a Single-Agent

  Consider administering the following pre-infusion medications for antiemetic prophylaxis

  [see Adverse Reactions (6.1)]

  :

  • •Corticosteroids (dexamethasone 8 mg intravenously or equivalent)
  • •Serotonin antagonists (ondansetron 8 mg intravenously or equivalent)

  ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

  • •
    To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information]
    .
  • •
    To reduce the risk of nausea, administer the following pre-infusion medications for antiemetic prophylaxis prior to Cycle 1 and consider administering for subsequent cycles

    [see Adverse Reactions (6.1)]
    :
  • ⸰    Corticosteroids (dexamethasone 8 mg or equivalent intravenously)
  • ⸰    Serotonin antagonists (ondansetron 8 mg or equivalent intravenously)

  2.6 Preparation, Administration and Storage

  ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures¹.

  Preparation

  • •Inject 8 mL of Sterile Water for Injection USP into the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution.
  • •Visually inspect the solution for particulate matter and discoloration. The reconstituted solution is a clear, colorless or slightly yellowish solution, free of visible particles.
  • •Calculate the required volume of reconstituted solution as follows:
    
    
  • •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
  • •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).

  Administration

  • •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement
    [see Warnings and Precautions (5.3)]
    .
  • •Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
  • •ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.
    • oDo not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.

  • •Compatibility with other intravenous administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials:
    • oContainers: Polyolefin containers (polyethylene, polypropylene and mixtures).
    • oInfusion sets: Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene).
    • oImplantable venous access systems: Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.
  • •Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.

  ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase

  -

  tqjs

  • •
    Administer either atezolizumab or atezolizumab and hyaluronidase-tqjs first, then administer ZEPZELCA. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information
    .

  Storage of Infusion Solution

  • •If not used immediately after reconstitution or dilution, the ZEPZELCA solution can be stored prior to administration for up to 24 hours following reconstitution, including infusion time, at either room temperature/ ambient light or under refrigeration at 2ºC to 8ºC (36ºF to 46ºF) conditions.

  

  )
• •To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information].
• •
  Moderate Hepatic Impairment
  : Recommended dosage is 1.6 mg/m² administered intravenously every 21 days until disease progression or unacceptable toxicity. (
  2 DOSAGE AND ADMINISTRATION

  • •
    Recommended Dosage
    : 3.2 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
  • •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement.
  • •Administer ZEPZELCA as an intravenous infusion over 60 minutes.
  • •To reduce the risk of nausea, administer corticosteroids and serotonin agonists prior to Cycle 1 and consider use for subsequent cycles.
  • •To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information].
  • •
    Moderate Hepatic Impairment
    : Recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
  • •
    Severe Hepatic Impairment
    : Avoid use of ZEPZELCA. If use cannot be avoided, the recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.

  2.1 Recommended Dosage

  The recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

  [see Dosage and Administration (2.4)].

  Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm³and platelet count is at least 100,000/mm³.

  ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

  When administering ZEPZELCA on the same day as atezolizumab or atezolizumab and hyaluronidase-tqjs, administer the chosen atezolizumab drug first. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information.

  If discontinuation of atezolizumab or atezolizumab and hyaluronidase-tqjs is required due to an immune-related severe adverse event, treatment with ZEPZELCA may be continued at the same dose as a single agent. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA.

  2.2 Dosage Modifications for Adverse Reactions

  The recommended dose reductions for adverse reactions are listed in Table 1.

  Permanently discontinue ZEPZELCA in patients who require a dose interruption of greater than two weeks and in patients who are unable to tolerate 2 mg/m²every 21 days.

  Table 1: Dose Reduction for ZEPZELCA for Adverse Reactions

  Dose Reduction	Total Dose
  First Second	2.6 mg/m2every 21 days 2 mg/m2every 21 days

  Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

  Withhold ZEPZELCA until absolute neutrophil count (ANC) is ≥ 1500/mm³

  Resume ZEPZELCA at a reduced doseWithhold ZEPZELCA until platelet ≥ 100,000/mm³

  Resume ZEPZELCA at reduced doseWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at reduced dose or permanently discontinueWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at same dosePermanently discontinue ZEPZELCA.Withhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at reduced dose or permanently discontinue

  Table 2: Dosage Modifications for ZEPZELCA for Adverse Reactions

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
  bPatients who have not received primary prophylaxis of G-CSF with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.
  Adverse Reaction	Severitya	Dosage Modification
  Neutropeniab [see Warnings and Precautions (5.1)]	Grade 4 or Any grade febrile neutropenia
  Thrombocytopenia [see Warnings and Precautions (5.1)]	Grade 3 with bleeding or Grade 4
  Hepatotoxicity [see Warnings and Precautions (5.2)]	Grade 2
  	Grade ≥ 3
  Rhabdomyolysis [see Warnings and Precautions (5.4)]	Grade 2
  	Grade ≥ 3
  Other Adverse Reactions [see Adverse Reactions (6.1), Postmarketing (6.2)]	Grade 2
  	Grade ≥ 3

  2.3 Dosage Modifications for use with Strong and Moderate CYP3A Inhibitors

  Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration of ZEPZELCA with a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ZEPZELCA by 50%

  [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)]

  . After discontinuation of a strong or moderate CYP3A inhibitor for 5 half-lives of the inhibitor, increase the ZEPZELCA dose to the dose used before starting the inhibitor

  .

  2.4 Dosage Modifications for Patients with Severe and Moderate Hepatic Impairment

  Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × Upper Limit of Normal (ULN)). If administration of ZEPZELCA cannot be avoided, the recommended dosage is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

  [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]

  .

  In patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN and any AST), the recommended dosage of ZEPZELCA is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

  .

  2.5 Recommended Prophylactic Medications

  ZEPZELCA as a Single-Agent

  Consider administering the following pre-infusion medications for antiemetic prophylaxis

  [see Adverse Reactions (6.1)]

  :

  • •Corticosteroids (dexamethasone 8 mg intravenously or equivalent)
  • •Serotonin antagonists (ondansetron 8 mg intravenously or equivalent)

  ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

  • •
    To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information]
    .
  • •
    To reduce the risk of nausea, administer the following pre-infusion medications for antiemetic prophylaxis prior to Cycle 1 and consider administering for subsequent cycles

    [see Adverse Reactions (6.1)]
    :
  • ⸰    Corticosteroids (dexamethasone 8 mg or equivalent intravenously)
  • ⸰    Serotonin antagonists (ondansetron 8 mg or equivalent intravenously)

  2.6 Preparation, Administration and Storage

  ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures¹.

  Preparation

  • •Inject 8 mL of Sterile Water for Injection USP into the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution.
  • •Visually inspect the solution for particulate matter and discoloration. The reconstituted solution is a clear, colorless or slightly yellowish solution, free of visible particles.
  • •Calculate the required volume of reconstituted solution as follows:
    
    
  • •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
  • •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).

  Administration

  • •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement
    [see Warnings and Precautions (5.3)]
    .
  • •Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
  • •ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.
    • oDo not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.

  • •Compatibility with other intravenous administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials:
    • oContainers: Polyolefin containers (polyethylene, polypropylene and mixtures).
    • oInfusion sets: Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene).
    • oImplantable venous access systems: Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.
  • •Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.

  ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase

  -

  tqjs

  • •
    Administer either atezolizumab or atezolizumab and hyaluronidase-tqjs first, then administer ZEPZELCA. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information
    .

  Storage of Infusion Solution

  • •If not used immediately after reconstitution or dilution, the ZEPZELCA solution can be stored prior to administration for up to 24 hours following reconstitution, including infusion time, at either room temperature/ ambient light or under refrigeration at 2ºC to 8ºC (36ºF to 46ºF) conditions.

  

  ,
  8.6 Hepatic Impairment

  Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × ULN). If administration of ZEPZELCA cannot be avoided, reduce the dose

  [see Dosage and Administration (2.4)]

  . Monitor for increased adverse reactions in patients with severe hepatic impairment.

  Reduce the dose of ZEPZELCA in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST)

  [see Dosage and Administration (2.4)]

  . Monitor for increased adverse reactions in patients with moderate hepatic impairment.

  No dose adjustment of ZEPZELCA 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)

  [see Clinical Pharmacology (12.3)]

  .
  )
• •
  Severe Hepatic Impairment
  : Avoid use of ZEPZELCA. If use cannot be avoided, the recommended dosage is 1.6 mg/m² administered intravenously every 21 days until disease progression or unacceptable toxicity. (
  2 DOSAGE AND ADMINISTRATION

  • •
    Recommended Dosage
    : 3.2 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
  • •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement.
  • •Administer ZEPZELCA as an intravenous infusion over 60 minutes.
  • •To reduce the risk of nausea, administer corticosteroids and serotonin agonists prior to Cycle 1 and consider use for subsequent cycles.
  • •To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information].
  • •
    Moderate Hepatic Impairment
    : Recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.
  • •
    Severe Hepatic Impairment
    : Avoid use of ZEPZELCA. If use cannot be avoided, the recommended dosage is 1.6 mg/m²administered intravenously every 21 days until disease progression or unacceptable toxicity.

  2.1 Recommended Dosage

  The recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

  [see Dosage and Administration (2.4)].

  Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm³and platelet count is at least 100,000/mm³.

  ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

  When administering ZEPZELCA on the same day as atezolizumab or atezolizumab and hyaluronidase-tqjs, administer the chosen atezolizumab drug first. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information.

  If discontinuation of atezolizumab or atezolizumab and hyaluronidase-tqjs is required due to an immune-related severe adverse event, treatment with ZEPZELCA may be continued at the same dose as a single agent. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA.

  2.2 Dosage Modifications for Adverse Reactions

  The recommended dose reductions for adverse reactions are listed in Table 1.

  Permanently discontinue ZEPZELCA in patients who require a dose interruption of greater than two weeks and in patients who are unable to tolerate 2 mg/m²every 21 days.

  Table 1: Dose Reduction for ZEPZELCA for Adverse Reactions

  Dose Reduction	Total Dose
  First Second	2.6 mg/m2every 21 days 2 mg/m2every 21 days

  Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

  Withhold ZEPZELCA until absolute neutrophil count (ANC) is ≥ 1500/mm³

  Resume ZEPZELCA at a reduced doseWithhold ZEPZELCA until platelet ≥ 100,000/mm³

  Resume ZEPZELCA at reduced doseWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at reduced dose or permanently discontinueWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at same dosePermanently discontinue ZEPZELCA.Withhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at same doseWithhold ZEPZELCA until Grade ≤ 1

  Resume ZEPZELCA at reduced dose or permanently discontinue

  Table 2: Dosage Modifications for ZEPZELCA for Adverse Reactions

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  •

  aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
  bPatients who have not received primary prophylaxis of G-CSF with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.
  Adverse Reaction	Severitya	Dosage Modification
  Neutropeniab [see Warnings and Precautions (5.1)]	Grade 4 or Any grade febrile neutropenia
  Thrombocytopenia [see Warnings and Precautions (5.1)]	Grade 3 with bleeding or Grade 4
  Hepatotoxicity [see Warnings and Precautions (5.2)]	Grade 2
  	Grade ≥ 3
  Rhabdomyolysis [see Warnings and Precautions (5.4)]	Grade 2
  	Grade ≥ 3
  Other Adverse Reactions [see Adverse Reactions (6.1), Postmarketing (6.2)]	Grade 2
  	Grade ≥ 3

  2.3 Dosage Modifications for use with Strong and Moderate CYP3A Inhibitors

  Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration of ZEPZELCA with a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ZEPZELCA by 50%

  [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)]

  . After discontinuation of a strong or moderate CYP3A inhibitor for 5 half-lives of the inhibitor, increase the ZEPZELCA dose to the dose used before starting the inhibitor

  .

  2.4 Dosage Modifications for Patients with Severe and Moderate Hepatic Impairment

  Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × Upper Limit of Normal (ULN)). If administration of ZEPZELCA cannot be avoided, the recommended dosage is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

  [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]

  .

  In patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN and any AST), the recommended dosage of ZEPZELCA is 1.6 mg/m²by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity

  .

  2.5 Recommended Prophylactic Medications

  ZEPZELCA as a Single-Agent

  Consider administering the following pre-infusion medications for antiemetic prophylaxis

  [see Adverse Reactions (6.1)]

  :

  • •Corticosteroids (dexamethasone 8 mg intravenously or equivalent)
  • •Serotonin antagonists (ondansetron 8 mg intravenously or equivalent)

  ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjs

  • •
    To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information]
    .
  • •
    To reduce the risk of nausea, administer the following pre-infusion medications for antiemetic prophylaxis prior to Cycle 1 and consider administering for subsequent cycles

    [see Adverse Reactions (6.1)]
    :
  • ⸰    Corticosteroids (dexamethasone 8 mg or equivalent intravenously)
  • ⸰    Serotonin antagonists (ondansetron 8 mg or equivalent intravenously)

  2.6 Preparation, Administration and Storage

  ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures¹.

  Preparation

  • •Inject 8 mL of Sterile Water for Injection USP into the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution.
  • •Visually inspect the solution for particulate matter and discoloration. The reconstituted solution is a clear, colorless or slightly yellowish solution, free of visible particles.
  • •Calculate the required volume of reconstituted solution as follows:
    
    
  • •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
  • •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 (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).

  Administration

  • •Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement
    [see Warnings and Precautions (5.3)]
    .
  • •Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
  • •ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.
    • oDo not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.

  • •Compatibility with other intravenous administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials:
    • oContainers: Polyolefin containers (polyethylene, polypropylene and mixtures).
    • oInfusion sets: Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene).
    • oImplantable venous access systems: Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.
  • •Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.

  ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase

  -

  tqjs

  • •
    Administer either atezolizumab or atezolizumab and hyaluronidase-tqjs first, then administer ZEPZELCA. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information
    .

  Storage of Infusion Solution

  • •If not used immediately after reconstitution or dilution, the ZEPZELCA solution can be stored prior to administration for up to 24 hours following reconstitution, including infusion time, at either room temperature/ ambient light or under refrigeration at 2ºC to 8ºC (36ºF to 46ºF) conditions.

  

  ,
  8.6 Hepatic Impairment

  Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × ULN). If administration of ZEPZELCA cannot be avoided, reduce the dose

  [see Dosage and Administration (2.4)]

  . Monitor for increased adverse reactions in patients with severe hepatic impairment.

  Reduce the dose of ZEPZELCA in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST)

  [see Dosage and Administration (2.4)]

  . Monitor for increased adverse reactions in patients with moderate hepatic impairment.

  No dose adjustment of ZEPZELCA 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)

  [see Clinical Pharmacology (12.3)]

  .
  )

For injection: 4 mg of lurbinectedin as a sterile, preservative-free, white to off-white lyophilized powder in a single-dose vial for reconstitution prior to intravenous infusion.

• •
  Lactation
  : Advise not to breastfeed. (
  8.2 Lactation

  Risk Summary

  There are no data on the presence of lurbinectedin in human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from ZEPZELCA in breastfed children, advise women not to breastfeed during treatment with ZEPZELCA and for 2 weeks after the last dose.
  )
• •
  Hepatic Impairment
  : Avoid use of ZEPZELCA in patients with severe hepatic impairment. In patients with moderate hepatic impairment, reduce the dose of ZEPZELCA. (
  8.6 Hepatic Impairment

  Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × ULN). If administration of ZEPZELCA cannot be avoided, reduce the dose

  [see Dosage and Administration (2.4)]

  . Monitor for increased adverse reactions in patients with severe hepatic impairment.

  Reduce the dose of ZEPZELCA in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST)

  [see Dosage and Administration (2.4)]

  . Monitor for increased adverse reactions in patients with moderate hepatic impairment.

  No dose adjustment of ZEPZELCA 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)

  [see Clinical Pharmacology (12.3)]

  .
  )