VinCRIStine Sulfate Liposome Injection

Marqibo (vinCRIStine sulfate LIPOSOME injection) is vincristine encapsulated in sphingomyelin/cholesterol liposomes for intravenous administration.

The active ingredient in Marqibo is vincristine sulfate. Vincristine sulfate is a vinca alkaloid isolated as a 1:1 sulfate salt from the periwinkle plant (Catharanthus roseus). It is a hygroscopic, white to slightly yellowish crystalline powder that is soluble in water. It has a molecular weight of 923.04 (salt form) / 824.98 (base form) and a molecular formula of C46H56N4O10•H2SO4. The chemical name for vincristine sulfate is 22-oxovincaleukoblastine and it has the following chemical structure:

Vincristine is encapsulated in a Sphingomyelin/Cholesterol liposome. The lipid components in the liposome are sphingomyelin and cholesterol at a molar ratio of approximately 60:40 (mol:mol).

After preparation, each vial of Marqibo contains 5 mg vincristine sulfate, 500 mg mannitol, 73.5 mg sphingomyelin, 29.5 mg cholesterol, 36 mg sodium citrate, 38 mg citric acid, 355 mg sodium phosphate, and 225 mg sodium chloride.

Marqibo (vinCRIStine sulfate LIPOSOME injection) appears as a white to off-white, translucent suspension, essentially free of visible foreign matter and aggregates, comprised of sphingomyelin/cholesterol liposomes, with an approximate liposome mean diameter of 100 nm. Greater than 95% of the drug is encapsulated in the liposomes.

The Marqibo Kit component vials for the preparation of Marqibo (vinCRIStine sulfate LIPOSOME injection) include:

• VinCRIStine Sulfate Injection, USP (5 mg/5 mL). Each VinCRIStine Sulfate Injection vial consists of 5 mg/5 mL vincristine sulfate (which is equivalent to 4.5 mg/5 mL vincristine free base) and 500 mg/5 mL mannitol.
• Sphingomyelin/Cholesterol Liposome Injection (103 mg/mL). Each Sphingomyelin/Cholesterol Liposome Injection vial consists of 73.5 mg/mL sphingomyelin, 29.5 mg/mL cholesterol, 33.6 mg/mL citric acid, 35.4 mg/mL sodium citrate, and not more than 0.1% ethanol.
• Sodium Phosphate Injection (355 mg/25 mL). Each Sodium Phosphate Injection vial consists of 355 mg/25 mL dibasic sodium phosphate and 225 mg/25 mL sodium chloride.

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.

Physicians are advised to discuss the following with patients prior to treatment with Marqibo:

Extravasation Tissue Injury

Advise patients to report immediately any burning or local irritation during or after the infusion [see WARNINGS AND PRECAUTIONS].

Ability to Drive or Operate Machinery or Impairment of Mental Ability

Marqibo may cause fatigue and symptoms of peripheral neuropathy. Advise patients not to drive or operate machinery if they experience any of these symptoms [see WARNINGS AND PRECAUTIONS].

Gastrointestinal/Constipation

Patients receiving Marqibo may experience constipation. Advise patients how to avoid constipation by a diet high in bulk fiber, fruits and vegetables, and adequate fluid intake as well as use of a stool softener, such as docusate. Instruct patients to seek medical advice if they experience symptoms of constipation such bowel movement infrequency, abdominal pain, bloating, diarrhea, nausea, or vomiting [see WARNINGS AND PRECAUTIONS].

Pregnancy/Nursing

Advise patients to use effective contraceptive measures to prevent pregnancy during treatment with Marqibo [see WARNINGS AND PRECAUTIONS]. Instruct patients to report pregnancy to their physicians immediately. Advise patients that they should not receive Marqibo while pregnant or breastfeeding. If a patient wishes to re-start breastfeeding after treatment, she should be advised to discuss the appropriate timing with her physician [see Use in Specific Populations].

Concomitant Medications

Advise patients to speak with their physicians about any other medication they are currently taking [see DRUG INTERACTIONS].

Peripheral Neuropathy

Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the feet or hands [see WARNINGS AND PRECAUTIONS].

Other

Instruct patients to notify their physicians if they experience fever, productive cough, or decreased appetite [see WARNINGS AND PRECAUTIONS].

The following adverse reactions are also discussed in other sections of the labeling:

• For intravenous use only [see WARNINGS AND PRECAUTIONS]
• Extravasation tissue injury [see WARNINGS AND PRECAUTIONS]
• Peripheral Neuropathy [see WARNINGS AND PRECAUTIONS]
• Myelosuppression [see WARNINGS AND PRECAUTIONS]
• Tumor lysis syndrome [see WARNINGS AND PRECAUTIONS]
• Constipation and bowel obstruction [see WARNINGS AND PRECAUTIONS]
• Fatigue [see WARNINGS AND PRECAUTIONS]
• Hepatic toxicity [see WARNINGS AND PRECAUTIONS]

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.

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%) Grade a 3 or Greater Adverse Reactions among 83 Patients Receiving the Clinical Dosing Regimen

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).

Read the entire FDA prescribing information for Marqibo (VinCRIStine Sulfate Liposome Injection)

• Chemotherapy
• Complete Blood Count (CBC)
• Hematocrit
• Leukemia