vincristine liposomal (Rx)

>10%

Blood and lymphatic system disorders (56.6%)

Infections (39.8%)

General disorders and administration site condition (37.3%)

Neuropathy (32.5%)

Febrile neutropenia (31.3%)

Respiratory thoracic and mediastinal disorders (20.5%)

Investigations (24.1%)

Gastrointestinal disorders (25.3%)

Neutropenia (18.1%)

Peripheral sensory and motor neuropathy (16.7%)

Anemia (16.9%)

Thrombocytopenia (16.9%)

Pyrexia (14.5%)

Fatigue (12%)

Psychiatric disorders (10.8%)

Cardiac disorders (10.8%)

1-10%

Vascular disorders (9.6%)

Abdominal pain (8.4%)

Musculoskeletal and connective tissue disorders (8.4%)

Pain (8.4%)

Pneumonia (8.4)

Increased aspartate aminotransferase (7.2%)

Renal and urinary disorders (7.2%)

Cardiac arrest (6%)

Septic shock (6%)

Hypotension (6%)

Staphylococcal bacteremia (6%)

Ileus, colonic pseudo-obstruction (6%)

Respiratory distress (6%)

Constipation (4.8%)

Asthenia (4.8%)

Respiratory failure (4.8%)

Mental status changes (3.6%)

Muscular weakness (1.2%)

Black Box Warnings

For IV use only; other routes may result in fatalities

Death has occurred with intrathecal administration

Do not confuse liposomal injection with vincristine injection due to different dosage recommendations; verify drug name and dose prior to administration

Contraindications

Hypersensitivity

Demyelinating conditions including Charcot-Marie-Tooth syndrome

Intrathecal administration (see Black Box Warnings)

Cautions

IV use only (see Black Box Warnings)

Only administer through secure and free-flowing venous access line; discontinue infusion immediately if extravasation is suspected consider local treatment measures

Orthostatic hypotension may occur

Monitor due to risk of myelosuppression; monitor complete blood counts prior to each dose; consider dose modification/ reduction if Grade 3/4 neutropenia, thrombocytopenia, or anemia develops

Tumor lysis syndrome (TLS) may occur in patients with ALL receiving drug; anticipate, monitor for, and manage as appropriate

Ileus, bowel obstruction, and colonic pseudo-obstruction; risk of constipation; institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction, and paralytic ileus; consider adequate dietary fiber intake, hydration, and stool softeners; use additional laxative products as needed

Severe fatigue; dose delay, reduction, or discontinuation may be necessary

Fatal liver toxicity and elevated levels of aspartate aminotransferase; monitor hepatic function tests; reduce or interrupt therapy if necessary

Teratogenic; women of childbearing potential should avoid becoming pregnant while being treated (see Pregnancy & Lactation)

Neurologic toxicity

• Sensory and motor neuropathies common and cumulative
• Monitor patients before and after treatment for symptoms of peripheral motor and sensory, central and autonomic neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, hyporeflexia, areflexia, neuralgia, jaw pain, decreased vibratory sense, cranial neuropathy, ileus, burning sensation, arthralgia, myalgia, muscle spasm, or weakness
• Rsk greater with history of preexisting neuromuscular disorders or concomitant drugs with risk of neurological toxicity

Pregnancy

Based on its mechanism of action and findings from animal studies, there are insufficient data on use in pregnant women to evaluate for a drug-associated risk; drug can cause fetal harm when administered to pregnant women

If drug is used during pregnancy, or if patient becomes pregnant while taking drug, patient should be apprised of potential hazard to fetus

Verify pregnancy status in females of reproductive potential prior to initiating therapy

Contraception

• Females: Advise females of reproductive potential to use effective contraception during treatment and for 6 months after last dose.
• Males: Based on genotoxicity findings with non-liposomal vincristine, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after last dose

Infertility

• Based on findings in humans with non-liposomal vincristine sulfate and in animals administered vincristine sulfate liposome injection, drug may impair fertility
• Gonadal dysfunction has been reported in both male and female post-pubertal patients who received multi-agent chemotherapy, including non-liposomal vincristine sulfate; the degree to which testicular or ovarian functions are affected is age-, dose-, and agent-dependent
• Recovery may occur in some, but not all patients;
• in animals, adverse effects on male reproductive organs were not reversible after a recovery period

Animal data

• In animal reproduction studies, intravenous administration of vincristine sulfate liposome injection to pregnant rats during organogenesis caused adverse developmental outcomes including increased embryo-fetal mortality, alterations to growth, and structural abnormalities; decreased fetal weights, increased numbers of early resorptions and post-implantation losses, and decreased maternal body weights
• Malformations were observed at doses greater than or equal to 0.044 mg/kg/day in animals at systemic exposures approximately 20-40% of those reported in patients at recommended dose

Lactation

There are no data on presence of drug or metabolites in human milk, effects on breastfed child, or on milk production; because many drugs are excreted in human milk and because of potential for serious adverse reactions in nursing infants, advise women not to breastfeed during treatment and for at least 1 week after the last dose; make decision on whether to discontinue nursing or discontinue drug taking into account importance of drug to mother

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Spingomyelin/cholesterol liposome-encapsulated formulation of vincristine; binds to tubulin and alters polymerization equilibrium, resulting in altered microtubule structure and function; prevents chromosome segregation and triggers metaphase arrest and inhibition of mitosis

Absorption

Bioavailability: 100%

Peak plasma concentration: 1,220 ng/mL

AUC: 14,566 hr•ng/mL

Metabolism

Metabolized by CYP3A4 isozymes

Elimination

Total body clearance: 347 mL/hr

IV Preparation

Follow proper procedures for handling and disposal of chemotherapy

Preparation takes 60-90 minutes; preparer must have uninterrupted time due to the extensive monitoring of temperature and time required

Observe aseptic technique strictly due to lack of preservative or bacteriostatic agents; prepare in a biological safety cabinet

Do not use with in-line filters

Do not mix with other drugs

Mixing procedure

• Fill 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; water bath must remain outside of the sterile area
• Place calibrated thermometer in water bath to monitor water temperature and leave it in the water bath until procedure completed; preheat water bath to 63-67°C; maintain this water temperature until completion of the procedure
• Visually inspect each vial in the kit for particulate matter and discoloration prior to preparation, whenever solution and container permit; do not use if precipitate or foreign matter observed
• Remove all the caps on the vials and swab the vials with sterile alcohol pads
• 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 injection
• Withdraw 1 mL of sphingomyelin/cholesterol liposome Injection and inject this into the sodium phosphate injection vial
• Withdraw 5 mL of vincristine sulfate injection (ie, 5 mg) and inject into the sodium phosphate injection vial
• Remove the venting needle and gently invert the sodium phosphate injection vial 5 times to mix; DO NOT SHAKE
• Fit flotation ring around the neck of the sodium phosphate injection vial 10. Confirm that the water bath temperature is at 63-67°C using the calibrated thermometer; remove the sodium phosphate injection vial containing vincristine, sphingomyelin/cholesterol liposome, and sodium phosphate from the biological safety cabinet and place into the water bath for 10 minutes using the calibrated electronic timer
• Monitor the water bath temperature to ensure it is maintained between 63-67°C
• Immediately after placing the mixture vial into the water bath, record the constitution start time and water temperature on the vincristine liposomal overlabel
• At the end of the 10 minutes, confirm that the water temperature is 63-67°C using the calibrated thermometer; remove the vial from the water bath (use tongs to prevent burns) and remove the flotation ring
• Record the final constitution time and the water temperature on the vincristine liposomal overlabel

Labeling

• Dry the exterior of the constituted vial (ie, vincristine liposomal injection) overlabel, and gently invert 5 times to mix; DO NOT SHAKE
• Permit the constituted vial contents to equilibrate for at least 30 minutes to controlled room temperature (15- 30°C, 59-86°F)
• Final vincristine concentration is 5 mg/31 mL (0.16 mg/mL)
• Once vincristine liposomal is prepared, may store at controlled room temperature (15-30°C, 59-86°F) not to exceed 12 hr
• Swab the top of the vial now containing vincristine liposomal with a sterile alcohol pad and return the vial back into the biological safety cabinet
• Calculate the dose based on the patient’s actual body surface area (BSA) and remove the volume corresponding to the dose from an infusion bag containing 100 mL of 5% dextrose injection or 0.9% NaCl injection Inject the vincristine liposomal dose into the infusion bag to result in a final volume of 100 mL
• Complete the information required on the infusion bag label and apply to the infusion bag
• Complete administration of the diluted product within 12 hr of the initiation of vincristine liposomal preparation
• Empty, clean, and dry the water bath after each use
• 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

IV Administration

Infuse IV over 1 hr

Storage

Kit: Store in refrigerator at 2-8°C; do not freeze

Constituted vial (ie, 5 mg/31 mL prepared vial): May store at controlled room temperature 15-30°C (59-86°F) for up to 12 hr in biological safety hood