Licensing authority

FDA (Food and Drug Administration, USA)

Indication(s)

1 INDICATIONS AND USAGE Marqibo is a vinca alkaloid indicated for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. This indication is based on overall response rate. Clinical benefit such as improvement in overall survival has not been verified (1.1). 1.1 Adult ALL in Second or Greater Relapse Marqibo® is indicated for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. This indication is based on overall response rate. Clinical benefit such as improvement in overall survival has not been verified.

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Advisory information

contraindications
4 CONTRAINDICATIONS Marqibo is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome. Marqibo is contraindicated in patients with hypersensitivity to vincristine sulfate or any of the other components of Marqibo (vinCRIStine sulfate LIPOSOME injection). Marqibo is contraindicated for intrathecal administration. •Marqibo is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome (4) •Marqibo is contraindicated in patients with hypersensitivity to vincristine sulfate or any of the other components of Marqibo (vinCRIStine sulfate LIPOSOME injection) (4) •Marqibo is contraindicated for intrathecal administration (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the labeling: •For intravenous use only [see Warnings and Precautions (5.1) ] •Extravasation tissue injury [see Warnings and Precautions (5.2) ] •Peripheral Neuropathy [see Warnings and Precautions (5.3) ] •Myelosuppression [see Warnings and Precautions (5.4) ] •Tumor lysis syndrome [see Warnings and Precautions (5.5) ] •Constipation and bowel obstruction [see Warnings and Precautions (5.6) ] •Fatigue [see Warnings and Precautions (5.7) ] •Hepatic toxicity [see Warnings and Precautions (5.8) ] Most commonly reported adverse reactions (incidence ≥ 30%) in clinical studies include constipation, nausea, pyrexia, fatigue, peripheral neuropathy, febrile neutropenia, diarrhea, anemia, decreased appetite, and insomnia (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Talon Therapeutics at 1-888 292 9617 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Safety Experience 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 clinical practice. Integrated Summary of Safety in Relapsed and/or Refractory Ph- Adult Acute Lymphoblastic Leukemia Marqibo, at a dose of 2.25 mg/m2 weekly, was studied in a total of 83 patients in two trials: study 1 and study 2. Adverse reactions were observed in 100% of patients. The most common adverse reactions (>30%) were constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%). Adverse reactions of Grade 3 or greater were reported in 96% of patients. Adverse reactions of Grade 3 or greater and occurring in ≥ 5% of patients are summarized in Table 2. Table 2 Most Commonly Reported (> 5%) GradeNational Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. 3 or Greater Adverse Reactions among 83 Patients Receiving the Clinical Dosing Regimen Adverse Reactions Grade ≥ 3 Study 1 and 2 (N=83) n (%) Blood and Lymphatic System Disorders 47 (56.6) Febrile Neutropenia 26 (31.3) Neutropenia 15 (18.1) Anemia 14 (16.9) Thrombocytopenia 14 (16.9) Infections 33 (39.8) Pneumonia 7 (8.4) Septic Shock 5 (6.0) Staphylococcal Bacteremia 5 (6.0) Neuropathy Including neuropathy-associated adverse reactions. 27 (32.5) Peripheral Sensory and Motor Neuropathy 14 (16.7) Constipation 4 (4.8) Ileus, Colonic Pseudo-Obstruction 5 (6.0) Asthenia 4 (4.8) Muscular Weakness 1 (1.2) Respiratory Thoracic and Mediastinal Disorders 17 (20.5) Respiratory Distress 5 (6.0) Respiratory Failure 4 (4.8) General Disorders and Administration Site Condition 31 (37.3) Pyrexia 12 (14.5) Fatigue 10 (12.0) Pain 7 (8.4) Gastrointestinal Disorders 21 (25.3) Abdominal Pain 7 (8.4) Investigations 20 (24.1) Aspartate Aminotransferase Increased 6 (7.2) Vascular Disorders 8 (9.6) Hypotension 5 (6.0) Psychiatric Disorders 9 (10.8) Mental Status Changes 3 (3.6) Cardiac Disorders 9 (10.8) Cardiac Arrest 5 (6.0) Renal and Urinary Disorders 6 (7.2) Musculoskeletal and Connective Tissue Disorders 7 (8.4) A total of 75.9% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%). Dose reduction, delay, or omission occurred in 53% of patients during the treatment. Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most common adverse reactions that caused treatment discontinuation were peripheral neuropathy (10%), leukemia-related (7%), and tumor lysis syndrome (2%). Adverse reactions related to neuropathy and leading to treatment discontinuation were decreased vibratory sense, facial palsy, hyporeflexia, constipation, asthenia, fatigue, and musculoskeletal pain, each reported in at least 1 patient. Deaths occurred in 23% of patients in study 1. The non-leukemia related causes of deaths were brain infarct (1), intracerebral hemorrhage (2), liver failure (1), multi system organ failure (2), pneumonia and septic shock (3), respiratory failure (4), pulmonary hemorrhage (1), and sudden cardiac death (1).

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION For Intravenous Use Only. Fatal if Given by Other Routes. Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage. Intravenous use only. Do not administer by any other route (2) Administer Marqibo at a dose of 2.25 mg/m2 intravenously over 1 hour once every 7 days (2.1). 2.1 Recommended Dosage The recommended dose of Marqibo is 2.25 mg/m2 intravenously over 1 hour once every 7 days. Marqibo is liposome-encapsulated vincristine. 2.2 Dose modifications: Peripheral Neuropathy Marqibo is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome [see Contraindications (4) ]. Patients with preexisting severe neuropathy should be treated with Marqibo only after careful risk-benefit assessment [see Warnings and Precautions (5.3) ]. For dose or schedule modifications guidelines for patients who experience peripheral neuropathy, see Table 1. Table 1 Recommended Dose Modifications for Marqibo-related Peripheral Neuropathy Severity of Peripheral Neuropathy Signs and Symptoms Grading based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Modification of Dose and Regimen If the patient develops Grade 3 (severe symptoms; limiting self-care activities of daily living [ADL]Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.) or persistent Grade 2 (moderate symptoms; limiting instrumental ADLInstrumental ADL: refers to preparing meals, shopping for groceries and clothes, using telephone, managing money, etc.) peripheral neuropathy: Interrupt Marqibo. If the peripheral neuropathy remains at Grade 3 or 4, discontinue Marqibo. If the peripheral neuropathy recovers to Grade 1 or 2, reduce the Marqibo dose to 2 mg/m2. If the patient has persistent Grade 2 peripheral neuropathy after the first dose reduction to 2 mg/m2: Interrupt Marqibo for up to 7 days. If the peripheral neuropathy increases to Grade 3 or 4, discontinue Marqibo. If peripheral neuropathy recovers to Grade 1, reduce the Marqibo dose to 1.825 mg/m2. If the patient has persistent Grade 2 peripheral neuropathy after the second dose reduction to 1.825 mg/m2: Interrupt Marqibo for up to 7 days. If the peripheral neuropathy increases to Grade 3 or 4, discontinue Marqibo. If the toxicity recovers to Grade 1, reduce the Marqibo dose to 1.5 mg/m2. 2.3 Preparation and Handling 2.3.1 Items Required by the Pharmacy to Prepare Marqibo •Marqibo Kit • Water bath The manufacturer will provide the water bath, calibrated thermometer, and calibrated electronic timer to the medical facility at the initial order of Marqibo and will replace them every 2 years. or block heater The manufacturer will provide the block heater to the medical facility at the initial order of Marqibo. The block heater will be replaced every 5 years. • Calibrated thermometer1 (0°C to 100°C) • Calibrated electronic timer1 •Sterile venting needle or other suitable device equipped with a sterile 0.2 micron filter •1 mL or 3 mL sterile syringe with needle, and •5 mL sterile syringe with needle. • Tongs The manufacturer will provide tongs to the medical facility at the initial order of Marqibo. 2.3.2 Preparation Instructions for Marqibo (vinCRIStine sulfate LIPOSOME injection), 5 mg/31 mL (0.16 mg/mL) Procedures for handling and disposal of anticancer drugs should be followed [see References (15) ]. Call [1 888 292 9617] if you have questions about the preparation of Marqibo. Marqibo takes approximately 60 to 90 minutes to prepare. The preparer should have dedicated uninterrupted time to prepare Marqibo due to the extensive monitoring of temperature and time required for the preparation. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Marqibo. The preparation steps of Marqibo that involve mixing the Sodium Phosphate Injection, Sphingomyelin/Cholesterol Liposome Injection, and VinCRIStine Sulfate Injection must be done in a biological safety cabinet or by established pharmacy safety procedures for the preparation of sterile injectable formulations and hazardous drugs. However, the preparation steps that involve placement of the vial in the water bath must be done outside of the sterile area. Do not use with in-line filters. Do not mix with other drugs. Water bath process: 1.Fill a water bath with water to a level of at least 8 cm (3.2 inches) measured from the bottom and maintain this minimum water level throughout the procedure. The water bath must remain outside of the sterile area. 2.Place a calibrated thermometer in the water bath to monitor water temperature and leave it in the water bath until the procedure has been completed. 3.Preheat water bath to 63°C to 67°C. Maintain this water temperature until completion of the procedure using the calibrated thermometer. 4.Visually inspect each vial in the Marqibo Kit for particulate matter and discoloration prior to preparation, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. 5.Remove all the caps on the vials and swab the vials with sterile alcohol pads. 6.Vent the Sodium Phosphate Injection vial with a sterile venting needle equipped with a sterile 0.2 micron filter or other suitable venting device in the biological safety cabinet. Always position venting needle point well above liquid level before adding Sphingomyelin/Cholesterol Liposome Injection and VinCRIStine Sulfate Injection. 7.Withdraw 1 mL of Sphingomyelin/Cholesterol Liposome Injection. 8.Inject 1 mL of Sphingomyelin/Cholesterol Liposome Injection into the Sodium Phosphate Injection vial. 9.Withdraw 5 mL of VinCRIStine Sulfate Injection. 10.Inject 5 mL of VinCRIStine Sulfate Injection into the Sodium Phosphate Injection vial. 11.Remove the venting needle and gently invert the Sodium Phosphate Injection vial 5 times to mix. DO NOT SHAKE. 12.Fit Flotation Ring around the neck of the Sodium Phosphate Injection vial. 13.Confirm that the water bath temperature is at 63°C to 67°C using the calibrated thermometer. Remove the Sodium Phosphate Injection vial containing VinCRIStine Sulfate Injection, Sphingomyelin/Cholesterol Liposome Injection, and Sodium Phosphate Injection from the biological safety cabinet and place into the water bath for 10 minutes using the calibrated electronic timer. Monitor the temperature to ensure the temperature is maintained at 63°C to 67°C. 14.IMMEDIATELY after placing the Sodium Phosphate Injection vial into the water bath, record the constitution start time and water temperature on the Marqibo Overlabel. 15. At the end of the 10 minutes using the water bath , confirm that the water temperature is 63°C to 67°C using the calibrated thermometer. Remove the vial from the water bath (use tongs to prevent burns) and remove the Flotation Ring. 16.Record the final constitution time and the water temperature on the Marqibo Overlabel. 17.Dry the exterior of the Sodium Phosphate Injection vial with a clean paper towel, affix Marqibo (vinCRIStine sulfate LIPOSOME injection) Overlabel, and gently invert 5 times to mix. DO NOT SHAKE. 18.Permit the constituted vial contents to equilibrate for at least 30 minutes to controlled room temperature (15°C to 30°C, 59°F to 86°F). 19.Marqibo (vinCRIStine sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate. ONCE PREPARED, STORE AT CONTROLLED ROOM TEMPERATURE (15°C to 30°C, 59°F to 86°F) FOR NO MORE THAN 12 HOURS. 20.Swab the top of the vial now containing Marqibo with a sterile alcohol pad and return the vial back into the biological safety cabinet. 21.Calculate the patient's Marqibo dose based on the patient's actual body surface area (BSA) and remove the volume corresponding to the patient's Marqibo dose from an infusion bag containing 100 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. 22.Inject the dose of Marqibo into the infusion bag to result in a final volume of 100 mL. 23.Complete the information required on the Infusion Bag Label and apply to the infusion bag. 24.Finish administration of the diluted product within 12 hours of the initiation of Marqibo preparation. 25.Empty, clean, and dry the water bath after each use. 26.Deviations in temperature, time, and preparation procedures may fail to ensure proper encapsulation of vincristine sulfate into the liposomes. In the event that the preparation deviates from the instructions in the above steps, the components of the kit should be discarded and a new kit should be used to prepare the dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. Block heater process: Note: Do NOT use water with the block heater preparation process. Note: The flotation ring included with the Marqibo kit is not required for the block heater application. 1. Arrange the three heater blocks in the block heater such that the block holding the constitution vial is centered between the two other blank heater blocks. (See the illustration below.) 2. Place a calibrated thermometer in the block opening adjacent to the vial well to monitor the temperature. Leave the thermometer in the block opening until the procedure has been completed. 3. Turn on the block heater and set the controller to 75°C. Verify the block temperature by checking that the thermometer inserted in the block reads 75 ±2°C. Equilibrate the heating block at 75 ±2°C for 15 minutes. Maintain this block temperature until completion of the procedure using the calibrated thermometer. 4. Visually inspect each vial in the Marqibo Kit for particulate matter and discoloration prior to preparation, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. 5. Remove all the caps on the vials and swab the vials with sterile alcohol pads. 6. Vent the Sodium Phosphate Injection vial with a sterile venting needle equipped with a sterile 0.2 micron filter or other suitable venting device in the biological safety cabinet. Always position venting needle point well above liquid level before adding Sphingomyelin/Cholesterol Liposome Injection and VinCRIStine Sulfate Injection. 7. Withdraw 1 mL of Sphingomyelin/Cholesterol Liposome Injection. 8. Inject 1 mL of Sphingomyelin/Cholesterol Liposome Injection into the Sodium Phosphate Injection vial. 9. Withdraw 5 mL of VinCRIStine Sulfate Injection. 10. Inject 5 mL of VinCRIStine Sulfate Injection into the Sodium Phosphate Injection vial. 11. Remove the venting needle and gently invert the Sodium Phosphate Injection vial 5 times to mix. DO NOT SHAKE. 12. Confirm that the block heater temperature is at 73°C to 77°C using the calibrated thermometer. Remove the Sodium Phosphate Injection vial containing VinCRIStine Sulfate Injection, Sphingomyelin/Cholesterol Liposome Injection, and Sodium Phosphate Injection from the biological safety cabinet and place into the block heater for 18 minutes using the calibrated electronic timer. Monitor the temperature to ensure the temperature is maintained at 73°C to 77°C. 13. IMMEDIATELY after placing the Sodium Phosphate Injection vial into the block heater, record the constitution start time and block heater temperature on the Marqibo Overlabel. Use only the calibrated thermometer inserted in the block to monitor temperature. 14. At the end of the 18 minutes using the block heater , confirm that the block heater temperature is 73°C to 77°C using the calibrated thermometer. Remove the vial from the block heater (use tongs to prevent burns). 15. Record the final constitution time and the block heater temperature on the Marqibo Overlabel. 16. Affix Marqibo (vinCRIStine sulfate LIPOSOME injection) Overlabel, and gently invert 5 times to mix. DO NOT SHAKE. 17. Permit the constituted vial contents to equilibrate for at least 30 minutes to controlled room temperature (15°C to 30°C, 59°F to 86°F). 18. Marqibo (vinCRIStine sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate. ONCE PREPARED, STORE AT CONTROLLED ROOM TEMPERATURE (15°C to 30°C, 59°F to 86°F) FOR NO MORE THAN 12 HOURS. 19. Swab the top of the vial now containing Marqibo with a sterile alcohol pad and return the vial back into the biological safety cabinet. 20. Calculate the patient’s Marqibo dose based on the patient’s actual body surface area (BSA) and remove the volume corresponding to the patient’s Marqibo dose from an infusion bag containing 100 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. 21. Inject the dose of Marqibo into the infusion bag to result in a final volume of 100 mL. 22. Complete the information required on the Infusion Bag Label and apply to the infusion bag. 23. Finish administration of the diluted product within 12 hours of the initiation of Marqibo preparation. 24. Deviations in temperature, time, and preparation procedures may fail to ensure proper encapsulation of vincristine sulfate into the liposomes. In the event that the preparation deviates from the instructions in the above steps, the components of the kit should be discarded and a new kit should be used to prepare the dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. Marqibo Block Heater.jpg
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pediatric Use: The safety and effectiveness of Marqibo in pediatric patients has not been established (8.4) 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9) ] Based on its mechanism of action and findings from animal studies, Marqibo can cause fetal harm when administered to pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. In an embryofetal developmental study, pregnant rats were administered vincristine sulfate liposome injection intravenously during the period of organogenesis at vincristine sulfate doses of 0.022 to 0.09 mg/kg/day. Drug-related adverse effects included fetal malformations (skeletal and visceral), decreases in fetal weights, increased numbers of early resorptions and post-implantation losses, and decreased maternal body weights Malformations were observed at doses ≥ 0.044 mg/kg/day in animals at systemic exposures approximately 20-40% of those reported in patients at the recommended dose. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of Marqibo in pediatric patients have not been established. 8.5 Geriatric Use Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment The influence of renal impairment on the safety, efficacy, and pharmacokinetics of Marqibo has not been evaluated. 8.7 Hepatic Impairment Non-liposomal vincristine sulfate is excreted primarily by the liver. The influence of severe hepatic impairment on the safety and efficacy of Marqibo has not been evaluated. The pharmacokinetics of Marqibo was evaluated in patients with moderate hepatic dysfunction (Child-Pugh B) secondary to melanoma liver metastases. The dose-adjusted maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of Marqibo in patients with moderate hepatic impairment was comparable to the Cmax and AUC of patients with ALL who had otherwise normal hepatic function.
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with Marqibo. Marqibo is expected to interact with drugs known to interact with non-liposomal vincristine sulfate. Simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non-liposomal vincristine sulfate have been reported to reduce blood levels of phenytoin and to increase seizure activity. Marqibo is expected to interact with drugs known to interact with non-liposomal vincristine sulfate (7). 7.1 CYP3A Interactions Vincristine sulfate, the active agent in Marqibo, is a substrate for cytochrome P450 3A isozymes (CYP3A); therefore, the concomitant use of strong CYP3A inhibitors should be avoided (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). Similarly, the concomitant use of strong CYP3A inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's Wort). 7.2 P-glycoprotein Interactions Vincristine sulfate, the active agent in Marqibo, is also a substrate for P-glycoprotein (P-gp). The effect of concomitant use of potent P-gp inhibitors or inducers has not been investigated; it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of Marqibo. Therefore the concomitant use of potent P-gp inhibitors or inducers should be avoided.

More information

Category Value
Authorisation number NDA202497
Orphan designation
Product NDC 20536-322
Date Last Revised 30-11-2016
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Talon Therapeutics, Inc.
Warnings WARNING • For Intravenous Use Only – Fatal if Given by Other Routes [see Warnings and Precautions (5.1) ]. • Death has occurred with intrathecal administration. • Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vinCRIStine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage. WARNING See full prescribing information for complete boxed warning. • For Intravenous Use Only – Fatal if Given by Other Routes (5.1) • Death has occurred with intrathecal use • Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vinCRIStine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage.