Cytarabine (Liposomal)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension, Intrathecal [preservative free]:

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

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

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 and Administration

Dosing: Adult

Note: DepoCyt is no longer available in the US.

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

Lymphomatous meningitis: Intrathecal:

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)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

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

Reconstitution

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

Intrathecal: 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. 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

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. 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

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. 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%), fatigue (25%), abnormal gait (23%), 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%), decreased appetite (11%)

Genitourinary: Urinary tract infection (14%)

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

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

Ophthalmic: Blurred vision (11%)

Miscellaneous: Fever (32%)

1% to 10%:

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

Central nervous system: Agitation (10%), hypoesthesia (10%), myasthenia (10%), depression (8%), anxiety (7%), peripheral neuropathy (3% to 4%), abnormal reflexes (3%), sensorimotor neuropathy (3%)

Dermatologic: Diaphoresis (2%), pruritus (2%)

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

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

Genitourinary: Urinary incontinence (7%), urinary retention (5%)

Hematologic & oncologic: Neutropenia (10%), bruise (2%)

Neuromuscular & skeletal: Tremor (9%)

Otic: Hypoacusis (6%)

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

<1%, postmarketing, and/or case reports: Anaphylaxis, bladder disease (bladder control impaired), blindness, brain disease, cauda equina syndrome, cranial nerve palsy, deafness, drowsiness, fecal incontinence, hemiplegia, hydrocephalus, increased intracranial pressure, leukocytosis (in CSF), meningitis (infectious), myelopathy, nervous system disease (neurologic deficit), numbness, papilledema, visual disturbance

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.

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

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 constipation, diarrhea, abdominal pain, back pain, trouble sleeping, lack of appetite, joint pain, or tremors. Have patient report immediately to prescriber signs of chemical arachnoiditis (fever, headache, nausea, vomiting, back pain, neck stiffness, or neck pain), signs of infection, confusion, change in balance, seizures, severe headache, severe nausea, vomiting, severe loss of strength and energy, severe dizziness, passing out, trouble with memory, bruising, bleeding, signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), swelling of arms or legs, severe fatigue, abnormal movements, shortness of breath, or signs of severe neuropathy (vision changes, trouble hearing, 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 health care 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.