Cytarabine

INDICATIONS AND USAGE: Cytarabine Injection in combination with other approved anti-cancer drugs is indicated for remission induction in acute non-lymphocytic leukemia of adults and pediatric patients. It has also been found useful in the treatment of acute non-lymphocytic leukemia and the blast phase of chronic myelocytic leukemia. Intrathecal administration of Cytarabine Injection (preservative free preparations only) is indicated in the prophylaxis and treatment of meningeal leukemia.

DOSAGE AND ADMINISTRATION Cytarabine Injection (non-preserved) can be administered by intravenous injection or infusion, subcutaneously, or intrathecally. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for intravenous infusion only. Intrathecal use of cytarabine requires the use of single-dose, unpreserved solutions only. Cytarabine Injection is not active orally. The schedule and method of administration varies with the program of therapy to be used. While Cytarabine Injection may be given by intravenous infusion or injection, or subcutaneously or intrathecally, THE PURPOSE OF THE PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF INTRAVENOUS INFUSIONS. Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In most instances, however, the drug has been well tolerated. Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion. This phenomenon is related to the drug's rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. Normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either. In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anti-cancer drugs is 100 mg/m 2 /day by continuous intravenous infusion (Days 1-7) or 100 mg/m 2 intravenous every 12 hours (Days 1-7). The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia. Intrathecal Use in Meningeal Leukemia : Cytarabine has been used intrathecally in acute leukemia in doses ranging from 5 mg/m 2 to 75 mg/m 2 of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m 2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy. If used intrathecally, do not use a solution containing benzyl alcohol. This pharmacy bulk package is not intended to be used for the preparation of intrathecal doses. Cytarabine given intrathecally may cause systemic toxicity and careful monitoring of the hemopoietic system is indicated. Modification of other anti-leukemia therapy may be necessary. Major toxicity is rare. The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported. Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has been reported. Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal cytarabine. When cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician. Focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine and may better be treated with radiotherapy. Chemical Stability of Infusion Solutions : Chemical stability studies were performed by a stability indicating HPLC assay on Cytarabine Injection in infusion solutions. These studies showed that when Cytarabine Injection was diluted with Water for Injection, 5% Dextros …

CONTRAINDICATIONS: Cytarabine Injection is contraindicated in those patients who are hypersensitive to the drug.

ADVERSE REACTIONS Expected Reactions Because cytarabine is a bone marrow suppressant, anemia, leukopenia, thrombocytopenia, megaloblastosis and reduced reticulocytes can be expected as a result of administration with Cytarabine Injection. The severity of these reactions are dose and schedule dependent. Cellular changes in the morphology of bone marrow and peripheral smears can be expected. Following 5-day constant infusions or acute injections of 50 mg/m 2 to 600 mg/m 2 , white cell depression follows a biphasic course. Regardless of initial count, dosage level, or schedule, there is an initial fall starting the first 24 hours with a nadir at days 7 to 9. This is followed by a brief rise which peaks around the twelfth day. A second and deeper fall reaches nadir at days 15 to 24. Then there is a rapid rise to above baseline in the next 10 days. Platelet depression is noticeable at 5 days with a peak depression occurring between days 12 to 15. Thereupon, a rapid rise to above baseline occurs in the next 10 days. Infectious Complications Injection Viral, bacterial, fungal, parasitic, or saprophytic infections, in any location in the body may be associated with the use of cytarabine injection alone or in combination with other immunosuppressive agents following immunosuppressant doses that affect cellular or humoral immunity. These infections may be mild, but can be severe and at times fatal. The Cytarabine (Ara-C) Syndrome A cytarabine syndrome has been described by Castleberry. It is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6 to 12 hours following drug administration. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome. If the symptoms of the syndrome are deemed treatable, corticosteroids should be contemplated as well as continuation of therapy with Cytarabine Injection. Most Frequent Adverse Reactions anorexia oral and anal inflammation rash nausea or ulceration thrombophlebitis vomiting hepatic dysfunction bleeding (all sites) diarrhea fever Nausea and vomiting are most frequent following rapid intravenous injection. Less Frequent Adverse Reactions sepsis sore throat conjunctivitis (may occur with rash) pneumonia esophageal ulceration dizziness cellulitis at injection site esophagitis alopecia skin ulceration chest pain anaphylaxis (see WARNINGS ) urinary retention pericarditis allergic edema renal dysfunction bowel necrosis pruritis neuritis abdominal pain shortness of breath neural toxicity pancreatitis urticaria freckling headache jaundice sinus bradycardia Experimental Doses Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine injection) has been reported following some experimental dose schedules of cytarabine injection. These reactions include reversible corneal toxicity and hemorrhagic conjunctivitis, which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction, including personality changes, somnolence and coma, usually reversible; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia; bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with experimental high dose therapy than with standard treatment programs using cytarabine. If experimental high dose therapy is used, do not use a preparation containing benzyl alcohol. Cases of cardiomyopathy with subsequent death have been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation. This cardiac toxicity may be schedule dependent. A syndrome of sudden respiratory distress …

4. Drug Interactions Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine injection or procarbazine. Steady-state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients may be considered as an alternative. An in vitro interaction study between gentamicin and cytarabine showed a cytarabine related antagonism for the susceptibility of K. pneumoniae strains. This study suggests that in patients on cytarabine being treated with gentamicin for a K. pneumoniae infection, the lack of a prompt therapeutic response may indicate the need for re-evaluation of antibacterial therapy. Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy during therapy with cytarabine injection. This may be due to potential competitive inhibition of its uptake.

DESCRIPTION Cytarabine Injection, an antineoplastic, is a sterile isotonic solution for intravenous and subcutaneous use, which contains no preservative and is available in 20 mg/mL (1000 mg/50 mL) Pharmacy Bulk Package. A Pharmacy Bulk Package is a container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion. Each mL contains 20 mg Cytarabine, USP and the following inactive ingredients: sodium chloride 0.68% and Water for Injection q.s. When necessary, the pH is adjusted with hydrochloric acid and/or sodium hydroxide to a target pH of 7.4. Each vial contains approximately 5.82 mEq sodium. Cytarabine is chemically 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone. The structural formula is: Cytarabine is an odorless, white to off-white, crystalline powder which is freely soluble in water and slightly soluble in alcohol and in chloroform. structural formula cytarabine injection

OVERDOSAGE There is no antidote for overdosage of Cytarabine Injection. Doses of 4.5 g/m 2 by intravenous infusion over 1 hour every 12 hours for 12 doses have caused an unacceptable increase in irreversible CNS toxicity and death. Single doses as high as 3 g/m 2 have been administered by rapid intravenous infusion without apparent toxicity.

HOW SUPPLIED Cytarabine Injection is available as follows: NDC No Pack Configuration 68083-343-05 Cytarabine Injection, 100 mg per 5 mL (20 mg per mL) Single Dose Vial packaged in a carton of 5. STORAGE CONDITIONS Protect from light. Retain in carton until time of use. Store at 20o to 25oC (68o to 77oF) [USP Controlled Room Temperature]. REFERENCES Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publications No.83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA, 1985; 2.53 (11): 1590–1592. National Study Commission on Cytotoxic Exposure – Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426–428. Jones RB, et al : Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer Journal of Clinicians, 1983; (Sept/Oct) 258–263. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp. Pharm, 1990; 47:1033–1049. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work Practice Guidelines), Am J. Health- Syst Pharm, 1996; 53:1669–1685. Manufactured by: Gland Pharma Limited Visakhapatnam-530049 Andhra Pradesh, India July 2020