LURBINECTEDIN Drug Interactions: What You Need to Know

INTERACTIONS Effect of Other Drugs on ZEPZELCA : Avoid coadministration with strong or a moderate CYP3A inhibitors and strong CYP3A inducers. ( 7.1 )

7.1 Effect of Other Drugs on ZEPZELCA Strong and Moderate CYP3A Inhibitors Coadministration of ZEPZELCA with a strong or a moderate CYP3A inhibitor increases lurbinectedin systemic exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>, which may increase the incidence and severity of adverse reactions to ZEPZELCA. Avoid grapefruit and Seville oranges during ZEPZELCA treatment, as these contain strong or moderate inhibitors of CYP3A. Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration cannot be avoided, reduce the dose of ZEPZELCA <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Strong CYP3A Inducers Avoid coadministration of ZEPZELCA with strong CYP3A inducers. Coadministration of ZEPZELCA with a strong CYP3A inducer may decrease lurbinectedin systemic exposure, which may decrease the efficacy of ZEPZELCA <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

None. None. ( 4 )

AND PRECAUTIONS

• Myelosuppression : Monitor blood counts prior to each administration. Initiate treatment with ZEPZELCA only if baseline neutrophil count is ≥ 1,500 cells/mm 3 and platelet count is ≥ 100,000/mm 3 . For neutrophil count less than 500 cells/mm 3 or any value less than lower limit of normal, administer G-CSF. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity. ( 5.1 )
• Hepatotoxicity : Monitor liver function tests prior to initiating ZEPZELCA, periodically during treatment and as clinically indicated. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity. ( 5.2 )
• Extravasation Resulting in Tissue Necrosis : Consider use of a central venous catheter to reduce the risk of extravasation. 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. ( 5.3 )
• Rhabdomyolysis : Monitor creatine phosphokinase (CPK) prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity. ( 5.4 )
• Embryo-Fetal Toxicity : Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use an effective method of contraception. ( 5.5 )

5.1 Myelosuppression ZEPZELCA can cause severe and fatal myelosuppression including febrile neutropenia and sepsis, thrombocytopenia and anemia. Administer ZEPZELCA only to patients with baseline neutrophil count of at least 1,500 cells/mm 3 and platelet count of at least 100,000/mm 3 . 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] . Monitor blood counts including neutrophils, red blood cells and platelets prior to each ZEPZELCA administration. For neutrophil count less than 500 cells/mm 3 or any value less than lower limit of normal, administer G-CSF. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . ZEPZELCA with Intravenous Atezolizumab In the IMforte study <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , primary prophylaxis of G-CSF was administered to 84% of patients. Based on laboratory values, decreased neutrophils occurred in 36%, including 18% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. The median time to onset of Grade 3 and 4 decreased neutrophil cells was 31 days and a median duration of 10 days. Febrile neutropenia occurred in 1.7%. Sepsis occurred in 1%. There were 7 fatal infections: pneumonia (n=3), sepsis (n=3), and febrile neutropenia (n=1). Based on laboratory values, decreased platelets occurred in 54%, including 15% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. The median time to onset of Grade 3 and 4 decreased platelet cells was 31 days and a median duration of 12 days. Based on laboratory values, decreased hemoglobin occurred in 51%, including 13% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. The median time to onset of Grade 3 and 4 decreased hemoglobin was 64 days and a median duration of 8 days. ZEPZELCA as a Single-Agent In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA as a single agent <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , 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.

5.2 Hepatotoxicity ZEPZELCA can cause hepatotoxicity which may be severe. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>. ZEPZELCA with Intravenous Atezolizumab In the IMforte study <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , based on laboratory values, increased alanine aminotransferase (ALT) occurred in 25%, including 3% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. Increased aspartate aminotransferase (AST) occurred in 24% including 3% Grade 3 or Grade 4. The median time to onset of Grade ≥ 3 elevation in transaminases was 52 days (range: 6 to 337). ZEPZELCA as a Single-Agent In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA as a single agent <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , 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.

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 )]</span> , 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.

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . ZEPZELCA with Intravenous Atezolizumab In the IMforte study <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 )]</span> , among 235 patients who had a creatine phosphokinase laboratory evaluation, increased creatine phosphokinase occurred in 9% who received ZEPZELCA in combination with atezolizumab.

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/m 2 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 last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3 )]</span> .