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Cytarabine (Liposomal)

Pronunciation

(sye TARE a been lye po SO mal)

Index Terms

  • Cytarabine Lipid Complex
  • Cytarabine Liposome
  • DepoFoam-Encapsulated Cytarabine
  • DTC 101
  • Liposomal Cytarabine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intrathecal:

DepoCyt: 50 mg/5 mL (5 mL) [contains cholesterol, dioleoylphosphatidylcholine (dopc), dipalmitoylphosphatidylglycerol (dppg), triolein]

Brand Names: U.S.

  • DepoCyt

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)

Pharmacology

Cytarabine liposomal is a sustained-release formulation of the active ingredient cytarabine, an antimetabolite which acts through inhibition of DNA synthesis and is cell cycle-specific for the S phase of cell division. Cytarabine is converted intracellularly to its active metabolite cytarabine-5’-triphosphate (ara-CTP). Ara-CTP also appears to be incorporated into DNA and RNA; however, the primary action is inhibition of DNA polymerase, resulting in decreased DNA synthesis and repair. The liposomal formulation allows for gradual release, resulting in prolonged exposure.

Absorption

Systemic exposure following intrathecal administration is negligible since transfer rate from CSF to plasma is slow

Time to Peak

CSF: Intrathecal: <1 hour

Half-Life Elimination

CSF: 6 to 82 hours

Use: Labeled Indications

Lymphomatous meningitis: Intrathecal treatment of lymphomatous meningitis

Contraindications

Hypersensitivity to cytarabine or any component of the formulation; active meningeal infection

Dosage

Note: Initiate dexamethasone 4 mg twice daily (oral or IV) for 5 days, beginning on the day of cytarabine liposomal administration.

Lymphomatous meningitis: Intrathecal: Adults:

Induction: 50 mg every 14 days for a total of 2 doses (weeks 1 and 3)

Consolidation: 50 mg every 14 days for 3 doses (weeks 5, 7, and 9), followed by an additional dose at week 13

Maintenance: 50 mg every 28 days for 4 doses (weeks 17, 21, 25, and 29)

Dosage reduction for toxicity: If drug-related neurotoxicity develops, reduce dose to 25 mg. If toxicity persists, discontinue treatment.

Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Gloves should be worn during preparation and administration. Allow vial to warm to room temperature. Particles may settle in diluent over time, and may be resuspended with gentle agitation or inversion immediately prior to withdrawing from the vial. Do not agitate aggressively. Withdraw from the vial immediately prior to administration. No further reconstitution or dilution is required. Do not mix with any other medications. Intrathecal medications should not be prepared during the preparation of any other agents (Jacobson, 2009).

Administration

For intrathecal use only. Dose should be removed from vial immediately before administration (must be administered within 4 hours of removal from the vial). An in-line filter should NOT be used. Administer directly into the CSF via an intraventricular reservoir or by direct injection into the lumbar sac. Injection should be made slowly (over 1 to 5 minutes). Patients should lie flat for 1 hour after lumbar puncture. After administration, observe for immediate toxic reactions.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Gloves should be worn during preparation and administration. If contact with skin occurs, immediately wash with soap and water; if contact with mucous membranes occurs, flush thoroughly with water.

Storage

Store intact vial at 2°C to 8°C (36°F to 46°F); protect from freezing. Avoid aggressive agitation. Withdraw from the vial immediately prior to administration; solutions should be used within 4 hours of withdrawal from the vial.

After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only (Jacobson, 2009).

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (11%)

Central nervous system: Chemical arachnoiditis (without dexamethasone premedication: 100%; with dexamethasone premedication: 33% to 42%; grade 4: 19% to 30%; onset: ≤5 days); headache (56%), confusion (33%), fever (32%), fatigue (25%), seizure (20% to 22%), dizziness (18%), lethargy (16%), insomnia (14%), memory impairment (14%), pain (14%)

Endocrine & metabolic: Dehydration (13%)

Gastrointestinal: Nausea (46%), vomiting (44%), constipation (25%), diarrhea (12%), appetite decreased (11%)

Genitourinary: Urinary tract infection (14%)

Hematologic: Anemia (12%), thrombocytopenia (3% to 11%)

Neuromuscular & skeletal: Weakness (40%), back pain (24%), abnormal gait (23%), limb pain (15%), neck pain (14%), arthralgia (11%), neck stiffness (11%)

Ocular: Blurred vision (11%)

1% to 10%:

Cardiovascular: Tachycardia (9%), hypotension (8%), hypertension (6%), syncope (3%), edema (2%)

Central nervous system: Agitation (10%), hypoesthesia (10%), depression (8%), anxiety (7%), sensory neuropathy (3%)

Dermatologic: Pruritus (2%)

Endocrine & metabolic: Hypokalemia (7%), hyponatremia (7%), hyperglycemia (6%)

Gastrointestinal: Abdominal pain (9%), dysphagia (8%), anorexia (5%), hemorrhoids (3%), mucosal inflammation (3%)

Genitourinary: Incontinence (7%), urinary retention (5%)

Hematologic: Neutropenia (10%), contusion (2%)

Neuromuscular & skeletal: Muscle weakness (10%), tremor (9%), peripheral neuropathy (3% to 4%), abnormal reflexes (3%)

Otic: Hypoacusis (6%)

Respiratory: Dyspnea (10%), cough (7%), pneumonia (6%)

Miscellaneous: Diaphoresis (2%)

1% (Limited to important or life-threatening): Anaphylaxis, bladder control impaired, blindness, bowel control impaired, cauda equine syndrome, cranial nerve palsies, CSF protein increased, CSF WBC increased, deafness, encephalopathy, hemiplegia, hydrocephalus, infectious meningitis, intracranial pressure increased, myelopathy, neurologic deficit, numbness, papilledema, somnolence, visual disturbance

ALERT: U.S. Boxed Warning

Chemical arachnoiditis:

Chemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache, and fever was a common adverse event in all clinical studies. If left untreated, chemical arachnoiditis may be fatal. Patients receiving intrathecal cytarabine should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis.

Warnings/Precautions

Concerns related to adverse effects:

• Chemical arachnoiditis: [US Boxed Warning]: Chemical arachnoiditis (nausea, vomiting, headache, fever) occurs commonly; may be fatal if untreated. Dexamethasone should be administered concomitantly with cytarabine (liposomal) to diminish chemical arachnoid symptoms; the incidence and severity of chemical arachnoiditis is reduced with dexamethasone. If chemical arachnoiditis is suspected, exclude other possible inflammatory, infectious, or neoplastic conditions. Toxic effects may be related to a single dose or to cumulative administration and usually occur within 5 days, although may occur at any time during treatment. Monitor continuously for development of neurotoxicity; dose reduction or discontinuation may be necessary. Hydrocephalus has been reported and may be precipitated by chemical arachnoiditis.

• CSF component elevations: Transient elevations in CSF protein and CSF white blood cell counts have been observed following administration.

• Neurotoxicity: May cause neurotoxicity (including myelopathy), which may lead to permanent neurologic deficit (rare). The risk for neurotoxicity is increased when administered with other antineoplastic agents or with cranial/spinal irradiation. CSF flow blockage may lead to increased free cytarabine concentrations in the CSF and increases the risk for neurotoxicity; consider assessing CSF flow prior to administration. Persistent (extreme) somnolence, hemiplegia, visual disturbances (including blindness; may be total and permanent), deafness, cranial nerve palsies have been reported. Signs/symptoms of peripheral neuropathy (eg, pain, numbness, paresthesia, weakness, impaired bowel/bladder control) have also been reported. Combined neurologic features (cauda equina syndrome) have been reported in some cases. If neurotoxicity develops, reduce subsequent doses or discontinue treatment. Headache, nausea, and fever are early signs of neurotoxicity.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Administration: For intrathecal use only.

• Intrathecal safety: Intrathecal medications should not be prepared during the preparation of any other agents. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only. Delivery of intrathecal medications to the patient should only be with other medications intended for administration into the central nervous system (Jacobson, 2009).

Monitoring Parameters

Monitor closely for signs of an immediate reaction; chemical arachnoiditis; neurotoxicity

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects were observed in animal reproductive studies with conventional cytarabine. Conventional cytarabine has been associated with fetal malformations when given as a component of systemic combination chemotherapy during the first trimester. Systemic exposure following intrathecal administration of cytarabine liposomal is negligible; however, women of childbearing potential should avoid becoming pregnant during treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, headache, constipation, diarrhea, abdominal pain, back pain, insomnia, or tremors. Have patient report immediately to prescriber signs of chemical arachnoiditis (a brain irritation; fever, headache, nausea, vomiting, back pain, neck stiffness, or neck pain), signs of infection, illogical thinking, seizures, severe nausea, vomiting, loss of strength and energy, severe dizziness, passing out, memory impairment, bruising, bleeding, signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), or signs of severe neuropathy (vision changes, hearing impairment, burning or numbness feeling in hands or feet, or muscle weakness) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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