ZEPZELCA Powder for solution for injection Ref.[50657] Active ingredients:

5.1 Myelosuppression

ZEPZELCA can cause myelosuppression.

In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA [see Adverse Reactions (6.1)], Grade 3 or 4 neutropenia occurred in 41% of patients, with a median time to onset of 15 days and a median duration of 7 days. Febrile neutropenia occurred in 7% of patients. Sepsis occurred in 2% of patients and was fatal in 1% (all cases occurred in patients with solid tumors other than SCLC). Grade 3 or 4 thrombocytopenia occurred in 10%, with a median time to onset of 10 days and a median duration of 7 days. Grade 3 or 4 anemia occurred in 17% of patients.

Administer ZEPZELCA only to patients with baseline neutrophil count of at least 1,500 cells/mm³ and platelet count of at least 100,000/mm³. Monitor blood counts including neutrophil count and platelet count prior to each administration. For neutrophil count less than 500 cells/mm³ or any value less than lower limit of normal, the use of G-CSF is recommended. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity [see Dosage and Administration (2.2)].

5.2 Hepatotoxicity

ZEPZELCA can cause hepatotoxicity.

In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA [see Adverse Reactions (6.1)], Grade 3 elevations of ALT and AST were observed in 6% and 3% of patients, respectively, and Grade 4 elevations of ALT and AST were observed in 0.4% and 0.5% of patients, respectively. The median time to onset of Grade ≥3 elevation in transaminases was 8 days (range: 3 to 49), with a median duration of 7 days.

Monitor liver function tests prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity [see Dosage and Administration (2.2)].

5.3 Extravasation Resulting in Tissue Necrosis

Extravasation of ZEPZELCA resulting in skin and soft tissue injury, including necrosis requiring debridement, can occur. 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.

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.

5.4 Rhabdomyolysis

Rhabdomyolysis has been reported in patients treated with ZEPZELCA. Monitor creatine phosphokinase (CPK) prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold or reduce the dose based on severity [see Dosage and Administration (2.2)].

5.5 Embryo-Fetal Toxicity

Based on animal data and its mechanism of action ZEPZELCA can cause fetal harm when administered to a pregnant woman. Intravenous administration of a single dose of lurbinectedin (approximately 0.2 times the 3.2 mg/m² clinical dose) to pregnant animals during the period of organogenesis caused 100% embryolethality in rats. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Myelosuppression [see Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.2)]
• Extravasation Resulting in Tissue Necrosis [see Warning and Precautions (5.3)]
• Rhabdomyolysis [see Warnings and Precautions (5.4)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to ZEPZELCA as a single agent at a dose of 3.2 mg/m² intravenously every 21 days in 554 patients with advanced solid tumors. Among 554 patients who received ZEPZELCA, including 105 patients with small cell lung cancer (SCLC) in PM1183-B-005-14 (Study B-005), 24% were exposed for 6 months or longer and 5% were exposed for greater than one year.

Small Cell Lung Cancer (SCLC)

The safety of ZEPZELCA was evaluated in a cohort of 105 patients with previously treated SCLC in Study B-005 [see Clinical Studies (14)]. Patients received ZEPZELCA 3.2 mg/m² intravenously every 21 days. All patients in this study received a pre-specified anti-emetic regimen consisting of a corticosteroid and serotonin antagonist. Patients could receive G-CSF for secondary prophylaxis (i.e., after patients had an initial decrease in WBC), but not primary prophylaxis. Among patients who received ZEPZELCA, 29% were exposed for 6 months or longer and 6% were exposed for greater than one year.

Serious adverse reactions occurred in 34% of patients who received ZEPZELCA. Serious adverse reactions in ≥3% of patients included pneumonia, febrile neutropenia, neutropenia, respiratory tract infection, anemia, dyspnea, and thrombocytopenia.

Permanent discontinuation due to an adverse reaction occurred in two patients (1.9%) who received ZEPZELCA. Adverse reactions resulting in permanent discontinuation in ≥1% of patients who received ZEPZELCA, which included peripheral neuropathy and myelosuppression.

Dosage interruptions due to an adverse reaction occurred in 30.5% of patients who received ZEPZELCA. Adverse reactions requiring dosage interruption in ≥3% of patients who received ZEPZELCA included neutropenia, and hypoalbuminemia.

Dose reductions due to an adverse reaction occurred in 25% of patients who received ZEPZELCA. Adverse reactions requiring dosage reductions in ≥3% of patients who received ZEPZELCA included neutropenia, febrile neutropenia and fatigue.

The most common adverse reactions, including laboratory abnormalities, (≥20%) were leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea.

Table 3 summarizes the adverse reactions in the SCLC cohort of Study B-005.

Table 3. Adverse Reactions (≥10%) in Patients with SCLC Who Received ZEPZELCA in Study B-005:

^a Graded per NCI CTCAE 4.0.
^b No grade 5 adverse reactions were reported.
^c Includes abdominal pain, abdominal pain upper and abdominal discomfort.
^d Includes musculoskeletal pain, back pain, arthralgia, pain in extremity, musculoskeletal chest pain, neck pain, bone pain and myalgia.
^e Includes cough and productive cough.
^f Includes upper respiratory tract infection, viral upper respiratory tract infection, respiratory tract infection and bronchitis.
^g Includes pneumonia and lung infection.
^h Includes neuropathy peripheral, neuralgia, paresthesia, peripheral sensory neuropathy, hypoesthesia, and hyperesthesia.

Clinically relevant adverse reactions in <10% of patients who received ZEPZELCA include dysgeusia, febrile neutropenia and pneumonitis.

Table 4 summarizes the laboratory abnormalities in Study B-005.

Table 4. Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients with SCLC Who Received ZEPZELCA in Study B-005:

^a The denominator used to calculate the rate varied from 95 to 105 based on the number of patients with a baseline value and at least one post-treatment value.
^b Graded per NCI CTCAE 4.0.

The following adverse reactions have been identified during post-approval use of ZEPZELCA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General disorders and administration site conditions: Extravasation including tissue necrosis requiring debridement.

Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.

Metabolism and nutrition disorders: Tumor lysis syndrome.

7.1 Effect of Other Drugs on ZEPZELCA

Strong and Moderate CYP3A Inhibitors

Coadministration with a strong or a moderate CYP3A inhibitor increases lurbinectedin systemic exposure [see Clinical Pharmacology (12.3)] which may increase the incidence and severity of adverse reactions to ZEPZELCA. Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If the coadministration of ZEPZELCA with a moderate CYP3A inhibitor cannot be avoided, consider dose reduction of ZEPZELCA, if clinically indicated [see Dosage and Administration (2.2)].

Strong and Moderate CYP3A Inducers

Coadministration with a strong CYP3A inducer decreases lurbinectedin systemic exposure [see Clinical Pharmacology (12.3)] which may reduce ZEPZELCA efficacy. Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inducers.

Risk Summary

Based on animal data and its mechanism of action [see Clinical Pharmacology (12.1)], ZEPZELCA can cause fetal harm when administered to a pregnant woman. There are no available data to inform the risk of ZEPZELCA use in pregnant women. Intravenous administration of a single lurbinectedin dose (approximately 0.2 times the 3.2 mg/m² clinical dose) to pregnant rats during the period of organogenesis caused embryolethality (see Data).

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In a reproductive toxicity study, administration of a single lurbinectedin dose of 0.6 mg/m² (approximately 0.2 times of the human dose of 3.2 mg/m²) to pregnant rats on Gestation Day 10 resulted in 100% post-implantation loss.

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 final dose.

ZEPZELCA can cause embryolethality at doses lower than the human dose of 3.2 mg/m² [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating ZEPZELCA.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 6 months after the final dose.

Males

Advise males with a female sexual partner of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the final dose.

The safety and effectiveness of ZEPZELCA in pediatric patients have not been established.

Of the 105 patients with SCLC administered ZEPZELCA in clinical studies, 37 (35%) patients were 65 years of age and older, while 9 (9%) patients were 75 years of age and older. No overall difference in effectiveness was observed between patients aged 65 and older and younger patients.

There was a higher incidence of serious adverse reactions in patients ≥65 years of age than in patients <65 years of age (49% vs. 26%, respectively). The serious adverse reactions most frequently reported in patients ≥65 years of age were related to myelosuppression and consisted of febrile neutropenia (11%), neutropenia (11%), thrombocytopenia (8%), and anemia (8%) [see Adverse Reactions (6.1)].

The effect of moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) on the pharmacokinetics of lurbinectedin has not been studied. No dose adjustment of ZEPZELCA is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1.0‑1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)].