The FDA has withdrawn the approval of the NDA for Acrotech’s Marqibo (vincristine sulfate liposome) injection due to the lack of verification of clinical benefit. Acrotech has voluntarily requested that the FDA withdraw approval of this application and has waived its right for a hearing.
Further information may be found at https://www.federalregister.gov/documents/2022/05/02/2022-09235/acrotech-biopharma-llc-withdrawal-of-approval-of-new-drug-application-for-marqibo-vincristine.
Vincristine (liposomal) is for IV use only and is fatal if given by other routes. Death has occurred with intrathecal administration.
Vincristine (liposomal) injection has different dosage recommendations than vincristine injection. Verify drug name and dose prior to preparation and administration to avoid overdosage.
Note: Vincristine liposomal and conventional vincristine are NOT interchangeable. Dosing differs between formulations; verify intended product and dose prior to preparation and administration. The liposomal vincristine dose is based on actual BSA and was not capped in studies (O'Brien 2013; Rodriguez 2009). Assess risk for tumor lysis syndrome prior to treatment. Patients should be initiated on a prophylactic bowel regimen, including a stool softener, dietary fiber, and hydration; additional laxative treatments may be considered.
Acute lymphoblastic leukemia, relapsed, Philadelphia chromosome-negative: IV: 2.25 mg/m2 once every 7 days (O’Brien 2013).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, liposomal vincristine is minimally excreted by the kidney and like the conventional formulation, likely does not require dosage adjustment in renal impairment.
Hepatic impairment prior to treatment initiation:
Mild or moderate impairment (Child-Pugh class A or B): No dose adjustment is recommended. In a study in a limited number of melanoma patients with moderate (Child-Pugh class B) hepatic impairment secondary to liver metastases, Cmax and AUC were comparable to those in patients with normal hepatic function; patients with hepatic impairment received a dose of 1 mg/m2 every 2 weeks versus 2 mg/m2 in subjects with normal hepatic function (Bedikian 2011).
Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment: Reduce dose or interrupt treatment.
Refer to adult dosing.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 : Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full, weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (ASCO [Griggs 2021]). Note: The liposomal vincristine dose is based on actual BSA and was not capped in studies (O'Brien 2013; Rodriguez 2009).
Demyelinating conditions (including Charcot-Marie-Tooth syndrome): Use is contraindicated.
Fatigue, severe: Consider dose delay, reduction, or therapy discontinuation.
Hematologic toxicity: Grade 3 or 4 neutropenia, thrombocytopenia, or anemia: Consider dose reduction or modification, as well as supportive care measures.
Peripheral neuropathy:
Grade 3 (severe symptoms; limiting self-care activities of daily living [ADL]) or persistent grade 2 (moderate symptoms; limiting instrumental ADL) toxicity: Interrupt therapy until recovery to grade 1 or 2, then reduce dose to 2 mg/m2. If grade 3 toxicity persists or if grade 4 toxicity occurs, discontinue liposomal vincristine.
Persistent grade 2 toxicity after first dose reduction to 2 mg/m2: Interrupt therapy for up to 7 days until recovery to grade 1, then reduce dose to 1.825 mg/m2. If neuropathy increases to grade 3 or 4, discontinue liposomal vincristine.
Persistent grade 2 toxicity after second dose reduction to 1.825 mg/m2: Interrupt therapy for up to 7 days until recovery to grade 1, then reduce dose to 1.5 mg/m2. If neuropathy increases to grade 3 or 4, discontinue liposomal vincristine.
Pre-existing neuropathy, severe: Assess treatment benefit versus risk.
Tumor lysis syndrome: Manage as clinically appropriate.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Suspension, Intravenous, as sulfate [preservative free]:
Marqibo: 5 mg/31 mL (1 ea [DSC])
No
For IV administration only. Fatal if given by other routes. Liposomal vincristine should NOT be delivered to the patient at the same time as any medications intended for CNS administration.
IV: Infuse over 1 hour. Do not administer IV push or bolus; do not use with in-line filters. Do not administer with other medications. Infusion must be completed within 12 hours of initiation of preparation.
Extravasation of liposomal vincristine may cause tissue injury, although the extent and incidence are not defined; conventional vincristine is a vesicant. Ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. If extravasation occurs, discontinue liposomal vincristine infusion immediately and institute appropriate extravasation management procedures.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Acute lymphoblastic leukemia (relapsed): Treatment of relapsed Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in adults in second or greater relapse or whose disease has progressed after 2 or more antileukemic therapies.
VinCRIStine liposomal may be confused with vinblastine, vinCRIStine conventional, vinorelbine
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Vincristine liposomal and conventional vincristine are NOT interchangeable. Dosing differs between formulations; verify intended product and dose prior to preparation and administration.
For IV administration only. Fatal if given by other routes; inadvertent intrathecal administration of vinca alkaloids has resulted in death. To prevent fatal inadvertent intrathecal injection, dispense vinca alkaloid doses in an infusion bag and NOT a syringe (ISMP 2020). Liposomal vincristine should NOT be prepared during the preparation of any medications intended for CNS administration. After preparation, keep liposomal vincristine in a location away from the separate storage location recommended for medications intended for CNS administration. Liposomal vincristine should NOT be delivered to the patient at the same time with any medications intended for CNS administration.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Gastrointestinal: Constipation (57%), decreased appetite (33%), diarrhea (37%), nausea (52%)
Hematologic & oncologic: Anemia (34%; grades ≥3: 17%), febrile neutropenia (38%; grades ≥3: 31%), neutropenia (grades ≥3: 18%), thrombocytopenia (grades ≥3: 17%)
Hepatic: Increased serum aspartate aminotransferase (grades ≥3: 6% to 11%)
Nervous system: Fatigue (41%), insomnia (32%), peripheral motor neuropathy (grades ≥3: ≤17%), peripheral neuropathy (39%), peripheral sensory neuropathy (grades ≥3: ≤17%)
Miscellaneous: Fever (43%)
1% to 10%:
Cardiovascular: Hypotension (grades ≥3: 6%), septic shock (grades ≥3: 6%)
Gastrointestinal: Abdominal pain (grades ≥3: 8%), intestinal obstruction (grades ≥3: ≤6%), non-Hirschsprung megacolon (grades ≥3: ≤6%)
Infection: Staphylococcal bacteremia (grades ≥3: 6%)
Nervous system: Mental status changes (grades ≥3: 4%), myasthenia (grades ≥3: 1%), pain (grades ≥3: 8%)
Neuromuscular & skeletal: Asthenia (grades ≥3: 5%)
Respiratory: Pneumonia (grades ≥3: 8%), respiratory distress (grades ≥3: 6%), respiratory failure (grades ≥3: 5%)
Frequency not defined: Hematologic & oncologic: Tumor lysis syndrome
Postmarketing: Ophthalmic: Blepharoptosis (Hatzipantelis 2015; Revannasiddaiah 2011)
Hypersensitivity to vincristine, liposomal vincristine, or any component of the formulation; patients with Charcot-Marie-Tooth syndrome or other demyelinating conditions; administration via the intrathecal route
Concerns related to adverse effects:
• Bone marrow suppression: Neutropenia, thrombocytopenia, and anemia may occur, including grade 3 and greater events.
• Constipation: Constipation, ileus, bowel obstruction, and colonic pseudo-obstruction have occurred with liposomal vincristine. Patients should be initiated on a prophylactic bowel regimen including a stool softener, dietary fiber, and hydration; additional laxative treatments may be considered.
• Extravasation: Extravasation may occur with liposomal vincristine and causes tissue injury. Avoid extravasation of liposomal vincristine (conventional vincristine is a vesicant). Administer through a secure and free-flowing venous access line. Check for proper needle/catheter placement prior to and during infusion. If extravasation occurs, discontinue liposomal vincristine infusion immediately and institute appropriate extravasation management procedures.
• Fatigue: Severe fatigue was noted in clinical trials.
• Hepatotoxicity: Hepatotoxicity (including fatal cases) and increased AST (including grade 3 and higher events) have been reported.
• Neurotoxicity: Neuropathies (sensory and motor) are common and cumulative. Symptoms of neuropathy (peripheral motor and sensory, central, and autonomic) may include paresthesia, hyper-/hypoesthesia, hyporeflexia or areflexia, neuralgia, jaw pain, decreased vibratory sense, cranial neuropathy, ileus, burning sensation, arthralgia, myalgia, muscle spasm, and/or weakness. Neurologic toxicity risk is greater when given to patients with preexisting neuromuscular conditions or when used concomitantly with other neurotoxic agents. Administer liposomal vincristine to patients with preexisting neuropathy only after careful risk-benefit assessment.
• Tumor lysis syndrome: Tumor lysis syndrome may occur as a consequence of therapy.
Dosage form specific issues:
• Liposomal vs conventional formulation dosing: Vincristine liposomal and conventional vincristine are NOT interchangeable. Dosing differs between formulations; verify intended product and dose prior to preparation and administration to avoid overdoses.
Other warnings/precautions:
• For IV use only: [US Boxed Warning]: For IV administration only. Fatal if given by other routes; inadvertent intrathecal administration has resulted in death. To prevent fatal inadvertent intrathecal injection, dispense vinca alkaloid doses in an infusion bag and NOT a syringe (ISMP 2020). Liposomal vincristine should NOT be prepared during the preparation of any medications intended for CNS administration. After preparation, keep liposomal vincristine in a location away from the separate storage location recommended for medications intended for CNS administration. Liposomal vincristine should NOT be delivered to the patient at the same time with any medications intended for CNS administration (ASCO/ONS [Neuss 2016]).
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of VinCRIStine (Liposomal). Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: If coadministration with these narrow therapeutic index/sensitive P-gp substrates is unavoidable, separate erdafitinib administration by at least 6 hours before or after administration of these P-gp substrates. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Fosphenytoin: May decrease the serum concentration of VinCRIStine (Liposomal). VinCRIStine (Liposomal) may decrease the serum concentration of Fosphenytoin. Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Futibatinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
MitoMYcin (Systemic): Antineoplastic Agents (Vinca Alkaloids) may enhance the adverse/toxic effect of MitoMYcin (Systemic). Specifically, the risk of pulmonary toxicity may be increased. Risk C: Monitor therapy
NIFEdipine: May increase the serum concentration of VinCRIStine (Liposomal). Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Pacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
Phenytoin: VinCRIStine (Liposomal) may decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Sotorasib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: Consider avoiding use of sotorasib and narrow therapeutic index/sensitive P-gp substrates. If combined use is unavoidable, monitor for increased toxicities of the substrate and consider a decrease in the substrate dosage. Risk D: Consider therapy modification
Taurursodiol: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Teniposide: May enhance the neurotoxic effect of VinCRIStine (Liposomal). Risk C: Monitor therapy
Verify pregnancy status prior to treatment initiation in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for 6 months after the last vincristine (liposomal) dose. Patients with partners who could become pregnant should use effective contraception during therapy and for 3 months after the last vincristine (liposomal) dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to vincristine (liposomal) may cause fetal harm.
It is not known if liposomal vincristine is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends to discontinue breastfeeding during treatment and for at least 1 week after the last vincristine (liposomal) dose.
CBC with differential and platelets (prior to each dose and as clinically necessary); hepatic function. Monitor sodium (in elderly patients; conventional vincristine may cause or exacerbate hyponatremia or syndrome of inappropriate antidiuretic hormone secretion). Evaluate pregnancy status prior to therapy initiation (in patients who could become pregnant). Monitor for signs/symptoms of peripheral neuropathy or other neurologic toxicities; evaluate neurologic status of patients closely prior to liposomal vincristine administration. Monitor for signs/symptoms of tumor lysis syndrome and symptoms of constipation. Monitor infusion site for extravasation.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
The vincristine liposomal formulation increases the half-life, allowing for enhanced cytotoxic activity in tumor cells. The liposomal formulation of vincristine consists of vincristine encapsulated in sphingosomes, which are composed of sphingomyelin and cholesterol (Bedikian 2006).
Distribution: Vdss: 2.7 L (Bedikian 2006),
Metabolism: Primarily hepatic via CYP3A4.
Half-life elimination: 45 hours (urinary half-life); dependent on rate of vincristine release from sphingosome (Bedikian 2006).
Excretion: Feces (69%); urine (<8%).
Suspension (Marqibo Intravenous)
5 mg/31 mL (per each): $20,636.03
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