DepoCyt

Pyrimidine Analogs

Observe and exercise appropriate cautions for preparing, handling, and administering solutions of cytotoxic drugs; glove use is recommended.
If liposomal cytarabine contact with the skin occurs, immediately wash the exposed area with soap and water. If contact with mucous membranes occurs, thoroughly flush the exposed area with water.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit; the suspension is white to off-white.
For intrathecal use only; do not give systemically.
Do not mix liposomal cytarabine with any other medications.

Preparation:
Allow vials to warm to room temperature and gently agitate or invert to resuspend the particles immediately prior to withdrawal from the vial. Drug particles are more dense than the diluent and have a tendency to settle. Avoid vigorous shaking.
No further reconstitution or dilution is required and is not recommended.
If possible, withdraw the drug from the vial immediately before administration. After withdrawal from the vial, use the drug within 4 hours. Discard any unused portion; no preservatives are contained in the single-use vial.
 
Intrathecal injection:
Inject the drug into the cerebral spinal fluid via an intraventricular reservoir or by direct injection into the lumbar sac over 1—5 minutes.
Administer dexamethasone (4 mg PO or IV two times daily) for 5 days beginning on the day of liposomal cytarabine intrathecal injection.
Following lumbar puncture, patients should be instructed to lie flat for at least 1 hour.
Do not use an in-line filter during administration.

arachnoiditis / Early / 19.0-30.0
seizures / Delayed / 20.0-21.0
cranial nerve palsies / Delayed / Incidence not known
hydrocephalus / Delayed / Incidence not known

confusion / Early / 33.0-36.0
neutropenia / Delayed / 10.0-36.0
constipation / Delayed / 24.0-25.0
thrombocytopenia / Delayed / 11.0-24.0
anemia / Delayed / 12.0-18.0
depression / Delayed / 8.0-18.0
dehydration / Delayed / 13.0-18.0
peripheral edema / Delayed / 11.0-18.0
hypotension / Rapid / 8.0-18.0
hypokalemia / Delayed / 7.0-15.0
hypertension / Early / 6.0-15.0
memory impairment / Delayed / 12.0-14.0
peripheral neuropathy / Delayed / 3.0-12.0
hyperglycemia / Delayed / 6.0-12.0
hyponatremia / Delayed / 7.0-12.0
dyspnea / Early / 10.0-12.0
dysphagia / Delayed / 8.0-9.0
urinary incontinence / Early / 7.0-9.0
sinus tachycardia / Rapid / 0-9.0
urinary retention / Early / 0-5.0
hemorrhoids / Delayed / 0-3.0
edema / Delayed / 2.0-3.0

headache / Early / 52.0-56.0
nausea / Early / 33.0-46.0
fever / Early / 32.0-45.0
vomiting / Early / 33.0-44.0
weakness / Early / 10.0-40.0
diarrhea / Early / 12.0-27.0
fatigue / Early / 25.0-27.0
back pain / Delayed / 21.0-24.0
dizziness / Early / 18.0-21.0
insomnia / Early / 14.0-18.0
infection / Delayed / 6.0-18.0
lethargy / Early / 12.0-16.0
tremor / Early / 9.0-15.0
abdominal pain / Early / 9.0-15.0
agitation / Early / 10.0-15.0
hypoesthesia / Delayed / 10.0-12.0
arthralgia / Delayed / 9.0-11.0
cough / Delayed / 7.0-9.0
anxiety / Delayed / 3.0-7.0
anorexia / Delayed / 3.0-5.0
syncope / Early / 0-3.0
hyperhidrosis / Delayed / 2.0-3.0
pruritus / Rapid / 0-2.0
paresthesias / Delayed / Incidence not known
drowsiness / Early / Incidence not known

Chemical arachnoiditis has been reported with intrathecal liposomal cytarabine therapy; this condition may be fatal if untreated. Symptoms of chemical arachnoiditis include nausea, vomiting, headache, and fever. All patients receiving liposomal cytarabine should receive dexamethasone concurrently to mitigate the symptoms of chemical arachnoiditis; both the incidence and severity of chemical arachnoiditis can be reduced by dexamethasone coadministration. If chemical arachnoiditis is suspected, rule out other inflammatory, infectious, or malignant conditions.

DepoCyt

Rx

A cell cycle phase-specific antimetabolite agent that is enapsulated into multivesicular lipid-based particles or liposome
FDA approved for the intrathecal treatment of lymphomatous meningitis
Fatal chemical arachnoiditis has been reported; 5 days of oral or IV dexamethasone is recommended with each intrathecal dose

50 mg intrathecally (intraventricular or lumbar puncture) over 1 to 5 minutes every 14 days on induction and consolidation weeks 1, 3, 5, 7, and 9; give an additional 50 mg intrathecally at week 13. For maintenance therapy, give 50 mg intrathecally every 28 days for 4 doses on weeks 17, 21, 25, and 29. Also give dexamethasone 4 mg PO or IV twice daily for 5 days beginning on the day of each cytarabine dose. If drug-induced neurotoxicity develops, reduce the dose to 25 mg. If the toxicity persists, discontinue treatment. Intrathecal cytarabine liposome was compared with conventional intrathecal cytarabine in patients with lymphomatous meningitis in 2 multicenter, randomized trials. The complete cytological response (CCR), defined as the absence of malignant cells in the cerebrospinal fluid and the absence of neurologic progression, was improved with cytarabine liposome in both studies. In the first study, the CCR rate was 41% in the cytarabine liposome arm (n = 7/17) and 6% in the conventional cytarabine arm (n = 1/16). In the second study, the CCR rate was 33% in the cytarabine liposome arm (n = 4/12) and 17% in the conventional cytarabine arm (n = 2/12).

No dosage recommendations are available; however, it does not appear dosage adjustments are necessary for patients with hepatic impairment.

No dosage recommendations are available; however, it does not appear dosage adjustments are necessary for patients with renal impairment.

There are no drug interactions associated with Cytarabine Liposomal, ARA-C products.

DepoCyt Intrathecal Inj Susp: 1mL, 10mg

50 mg/dose intrathecally.

50 mg/dose intrathecally.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Cytarabine is an S-phase specific cytotoxic agent and has no effect on non-dividing cells or cells in any other phase. The cytotoxicity of cytarabine is also dependent upon the rate of DNA synthesis and the duration of exposure of cells to cytarabine. Therefore, in tissue cultures, cytotoxicity is greatest if cells are exposed to cytarabine for extended periods during maximal DNA synthesis to allow cytarabine to be incorporated into a larger number of cells as they pass through the S-phase. Intracellularly, cytarabine is metabolized by deoxycytidine kinases to form 1-beta-D-arabinofuranosylcytosine-5'-triphosphate (Ara-CTP). Ara-CTP competitively inhibits DNA polymerase-alpha and halts DNA strand elongation and repair, which seems to decrease the phosphorylation of cytarabine to the active metabolite. The most important cytotoxic effect of Ara-CTP is incorporation into DNA. Once incorporated into DNA, the tumor cells are unable to remove Ara-CTP and this results in inhibition of template function and chain elongation. In addition, deoxycytidine levels are reduced within the cell due to the production of Ara-CTP. Both of these processes block further polymerization of DNA and lead to shortened DNA strands. Cytarabine also causes unusual multiple duplications of DNA strands that increase the possibility of recombination, crossover, and gene amplification.
 
Other actions of cytarabine include inhibition of ribonucleotide reductase, formation of Ara-CDP-choline and induction of cellular differentiation. Ara-CDP-choline is an analog of cytidine 5'-diphosphocholine (CDP-choline) and inhibits synthesis of membrane glycoproteins and glycolipids altering membrane structure, stability, antigenicity and function. Cytarabine can promote differentiation of leukemic cells and decrease c-myc expression.

Liposomal cytarabine is administered intrathecally or via intraventricular reservoir; it is not given systemically. Cytarabine is released as the lipid membrane breaks down. The lipid membrane is broken down into triglycerides, phospholipids, and cholesterol, which are cleared through the lymphatics. Once cytarabine enters the cerebral spinal fluid (CSF), tissues that have the greatest contact with the CSF phosphorylate cytarabine. Liposomal cytarabine distributes well throughout the CSF and maintains cytotoxic concentrations for at least 2 weeks. The distribution between the lumbar and ventricular compartments is rapid following intralumbar administration. Systemic exposure following liposomal cytarabine administration is small due to the slow rate of transfer of cytarabine from the CSF to the plasma and the rapid deamination that occurs in the systemic circulation. In the CSF, cytarabine is negligibly transformed to Ara-U (1-beta-D-arabinofuranosyluracil), the systemic metabolite, due to low concentrations of cytidine deaminase in the CSF and central nervous system tissues. Therefore, the clearance of cytarabine from the CSF is due to CSF circulation, and the rate approximates the bulk flow rate of 0.24 mL/min.
 
Affected cytochrome P450 isoenzymes and drug transporter: none

Intrathecal Route
After a 50 mg induction dose, peak free cytarabine concentrations in the cerebral spinal fluid (CSF) occur within an hour and range from 30—50 micrograms/mL; the terminal half-life for the free CSF cytarabine ranges from 5.9—82.4 hours. Following intrathecal administration of liposome-encapsulated cytarabine 12.5—75 mg, the elimination half-life from the CSF was 141 hours (range, 100—263 hours). Liposomal cytarabine distributes well throughout the CSF and maintains cytotoxic concentrations for at least 2 weeks. The distribution between the lumbar and ventricular compartments is rapid following intralumbar administration.

Liposomal cytarabine is a FDA pregnancy risk category D drug; no adequate and well-controlled studies in pregnant women exist. Intravenous cytarabine is a known teratogen. Three anecdotal cases of major limb malformations in infants have been reported; their mothers received intravenous cytarabine monotherapy or in combination with other agents during the first trimester. Systemic exposure to cytarabine is negligible after intrathecal cytarabine liposomal administration, so the potential for fetal harm may be low. However, females of childbearing potential should be cautioned to avoid getting pregnant. If pregnancy occurs during liposomal cytarabine treatment, women should be counseled regarding risks and options for the pregnancy.

It is not known whether cytarabine is excreted in human milk following intrathecal administration of liposomal cytarabine. The systemic exposure to free cytarabine following intrathecal liposomal cytarabine is negligible. However, because of the potential for serious adverse effects in the infant, breast-feeding should be discontinued during liposomal cytarabine therapy. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.