Nano Pharma

Purpose: The purpose of this monograph is to reference and provide an in depth understanding of a medication in a new delivery system. This product review summarizes the current data available in a concise manner to help enhance the availability, use and generate more optimistic outcomes for the patient and the health care professionals. Introduction: On April 20th, 2007, cytarabine liposome injection (DepoCyt) was approved by the FDA for the treatment of lymphomatous meningitis 1 . This medication gained approval under the Accelerated Approval regulations by the FDA.

The rapid approval was due to a preliminary showing of “increased complete response rate compared to un-encapsulated cytarabine”1. Cytarabine liposome injection (DepoCyt) is the injectable form of the antimetabolite of cytarabine that is encapsulated into multi-vesicular lipid based particles 2. This medication is classified as an antineoplastic agent and Pyrimidine Antagonist 3. Other medications in this category include capecitabine, floxuridine, 5-FU, gemcitabine 4. Currently DepoCyt is recognized as being used in adults for Lymphomatous meningitis.

However, DepoCyt is has been used off-label for Hodgkin’s disease, bone marrow transplant, acute leukemia, acute non-lymphocytic leukemia, hematopoietic stem cell transplants, and refractory acute leukemia or lymphomas. Cytarabine liposomal injection (DepoCyt) is approved as a suspension that is administered by the intrathecal route 3 . Dosage Form: Suspension: •Intrathecal Suspension 10 mg/ml (50 mg Vial) The suspension is available as a 5 mL ingle vial dose that contains 50 mg of cytarabine. It is formulated as a non-pyrogenic, sterile, white to off white suspension in NaCl 0.

9% w/v in water for intrathecal injections. In addition, inactive ingredients include cholesterol (4. 4 mg/mL), triloein (1. 2 mg/mL), DOPC (5. 7 mg/mL) and DPPG (1 mg/mL). The pH of the suspension is 5. 5-8. 5 3. Intrathecal Cytarabine Dosing in Children According to Age5 Patient ageIntrathecal cytarabine dose < 1 year20 mg 1 to 2 years30 mg 2 to 3 years50 mg > 3 years70 to 75 mg Indication: Cytarabine liposome injection (DepoCyt) is indicated by the FDA to be used for malignant meningitis lymphomatous.

•Treatment of Malignant meningitis intrathecal route has shown an increase in response rate compared to standard cytarabine (un-encapsulated). In a phase II randomized trial, patients receiving liposomal cytarabine resulted in a response rate of 71 % (liposomal) vs. 15% (un-encapsulated) 5. •In another study, better quality of life (QOL) was observed with DepoCyt (Liposomal cytarabine) vs. free cytarabine when given on an every 2 week schedule 6. Preclinical / Clinical Efficacy: MOA / Pharmacology: DepoCyt is a sustained release version of cytarabine.

It is designed for intrathecal administration into the CSF. Cytarabine is cell phase specific and affects cells only during the S-phase portion of cell division. Once in the cell, cytarabine, converts into cytarabine 5 triphosphate (ara-CTP). It is thought that the MOA of ara-CTP, the primary active metabolite, works by prevention of DNA polymerase2,3. ADME: •Induction phase peak levels of DepoCyt 50 mg peak levels of free cytarabine observed in 1 hour. •Peak levels of cytarabine liposomal injection was observed about 5 hours after injection in the ventricle or the lumbar sac.

oLevels of biphasic elimination profiles with a terminal phase half-life of 100-263 hours. The range dose for the T1/2 was 12. 5 mg to 75 mg. oCmax: 30-50 mcg/mL oTmax: 1 hour •Primary route of elimination of cytarabine is the metabolism to the inactive metabolite ara-U. Ara-U is metabolized and excreted via urination. oUnlike systemic cytarabine, DepoCyt conversion to ara-U is negligible in the CSF after injection due to the lower quantity of cytidine deaminase in the CSF and CNS tissue.

oCSF clearance of cytarabine is 0. 24 mL/min. oElimination T1/2 : 5. 9 to 82. 4 hours. Contraindications: Cytarabine liposome injection (DepoCyt) is contraindicated in patients with: •Active meningeal infection •Known hypersensitivity to cytarabine or any component of the formulation. Warnings and Adverse Effects Hematologic DepoCyt is a potent bone-marrow suppressant with risks of neutropenia (10%) and anemia (12%) . Therapy should be started cautiously in patients with preexisting drug-induced bone marrow suppression.

Patients should be under medical supervision and have daily leukocyte and platelet counts drawn. Examination of bone marrow should also be performed and facilities administering DepoCyt should have be able to manage the complications of bone marrow suppression, such as infection or hemorrhage. Central Nervous System •Chemical arachnoiditis is the most common adverse effect of DepoCyt (100% without steroid therapy). Patients receiving intrathecal cytarabine should be treated concurrently with dexamethasone to prevent the symptoms of chemical arachnoiditis.

Presentation of arachnoiditis usually occurs within 5 days of treatment and presents as nausea, vomiting, headaches, and fever. •Neuropathy and myelopathy (rarely, irreversible) have been reported. •Other CNS effects include cerebral and cerebellar dysfunction, including personality changes, somnolence and coma. Weakness has been observed in a large fraction of patients (40%). Visual Disturbances Side effects include reversible corneal toxicity and hemorrhagic conjunctivitis. Incidence of conjunctivitis can be reduced with prophylactic ocular corticosteroid drops. Hepatic Toxicity.

Liver abscesses and damage due to increased hyperbilirubinemia has been reported with experimental doses of DepoCyt. Cost Comparison Lymphomatous meningitis: DrugStrengthRouteCost / unitCost / treatment ($) DepoCyt50 mg/ 5 ml vialIntrathecal$3114$18684 Cytarabine 500 mg/ 25 mlIntrathecal$146$300 Methotrexate100 mg/ 4 mlIntrathecal$12$120 •Depocyt Induction therapy:50 mg administered intrathecally every 14 days for 2 doses(weeks 1 and 3). Consolidation therapy :50 mg administered intrathecally every 14 days for 3 doses(weeks 5, 7, and 9), followed by 1 additional dose at week .

•Cytarabine Since liposomal form is now the only used form for meningitis, the calculation uses a dose of 50 mg biweekly for 9 weeks, which is the dose for meningeal lymphoma of an average adult. Conclusion Cytarabine Liposomal Injection (DepoCyt) is a new treatment option for lymphomatous meningitis. In clinical trials of DepoCyt and ara-C, intrathecally administered DepoCyt has been found to more effective in improving quality of life, has shown an increased response rate of 71% for DepoCyt and 15% for ara-C, and allowed all patients to complete the planned 1 month therapy regiment.

In one clinical trial, DepoCyt increased medial survival time by one month, from 63 days to 100 days in patients, however due to the rarity of the illness, the trial was only powered to assess quality of life5. Compared to the alternative chemotherapy for lymphomatous meningitis, methotrexate, given twice a week, DepoCyt increased the response rate, increased the medial survival time and the time to neurological progression, and offered a more comfortable dosing schedule.

A 2003 clinical study showed that within the 12-month follow-up, the average patient receiving DepoCyt (compared with the methotrexate arm) achieved 71 more days of neurologic progression-free survival and 52 more days of overall survival7. Although the actual chemotherapy cost of DepoCyt is far more than cytarabine or methotrexate, the benefit in savings from 3 lumbar punctures every 2 weeks ($192. 15 each puncture, $600 every 2 weeks) increase the economic viability of the liposomal injection and improve patient comfort, which account into quality of life assessment models.

It is feasible to recommend this drug to patients who have a longer prognosis in order to improve outcomes and continue high dose experimental testing with concomitant steroid administration. References 1. FDA Grants Full Approval for DepoCyt(R) for the Treatment of Lymphomatous Meningitis, Enzon Pharmaceuticals Inc. http://investor. enzon. com/releasedetail. cfm? ReleaseID=238805 2. Hamada A, Kawaguchi T, Nakano M. Clinical Pharmacokinetics of Cytarabine Formulations. Clin Pharmacokinet.

2002;41(10):705-18. 3. Rose HS, Rando RR. Pharmacology of Nucleotide Synthesis in Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4. Torchilin V. Recent Advances with Liposomes as Pharmaceutical Carriers. Nat Rev Drug Discov. 2005 Feb;4(2):145-60. 5. Glants M, LaFollete S, Jaeckle K. Randomized Trial of a Slow-Release Versus a Standard Formulation of Cytarabine for the Intrathecal Treatment of Lymphomatous Meningitis. JCO October 1999 vol. 17 no. 10 3110-3116.

6. Jabbour E , O’Brien S, Kantarjian H. Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia. Blood. 2007 Apr 15;109(8):3214-8. Epub 2007 Jan 5. 7. Jaeckle K, Batchelor T. An Open Label Trial of Sustained-release Cytarabine (DepoCyt™) for the Intrathecal Treatment of Solid Tumor Neoplastic Meningitis. J NEURO ONCOLOG. 57:3 (2002).

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