ZANOSAR should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.

A patient need not be hospitalized but should have access to a facility with laboratory and supportive resources sufficient to monitor drug tolerance and to protect and maintain a patient compromised by drug toxicity. Renal toxicity is dose-related and cumulative and may be severe or fatal. Other major toxicities are nausea and vomiting which may be severe and at times treatment-limiting. In addition, liver dysfunction, diarrhea, and hematological changes have been observed in some patients. Streptozocin is mutagenic. When administered parenterally, it has been found to be tumorigenic or carcinogenic in some rodents.

The physician must judge the possible benefit to the patient against the known toxic effects of this drug in considering the advisability of therapy with ZANOSAR. The physician should be familiar with the following text before making a judgment and beginning treatment.

Each vial of ZANOSAR contains 1 g of the active ingredient streptozocin 2-deoxy-2 [[(methylnitrosoamino)carbonyl]amino]-α (and ß)-D-glucopyranose and 220 mg citric acid anhydrous. ZANOSAR is available as a sterile, pale yellow, freeze-dried preparation for intravenous administration. The pH was adjusted with sodium hydroxide. When reconstituted as directed, the pH of the solution will be between 3.5 and 4.5. Streptozocin is a synthetic antineoplastic agent that is chemically related to other nitrosoureas used in cancer chemotherapy. Streptozocin is an ivory-colored crystalline powder with a molecular weight of 265.2. It is very soluble in water or physiological saline and is soluble in alcohol. The structural formula is represented below:

Chemical Structure

Streptozocin inhibits DNA synthesis in bacterial and mammalian cells. In bacterial cells, a specific interaction with cytosine moieties leads to degradation of DNA. The biochemical mechanism leading to mammalian cell death has not been definitely established; streptozocin inhibits cell proliferation at a considerably lower level than that needed to inhibit precursor incorporation into DNA or to inhibit several of the enzymes involved in DNA synthesis. Although streptozocin inhibits the progression of cells into mitosis, no specific phase of the cell cycle is particularly sensitive to its lethal effects.

Streptozocin is active in the L1210 leukemic mouse over a fairly wide range of parenteral dosage schedules. In experiments in many animal species, streptozocin induced a diabetes that resembles human hyperglycemic nonketotic diabetes mellitus. This phenomenon, which has been extensively studied, appears to be mediated through a lowering of beta cell nicotinamide adenine dinucleotide (NAD) and consequent histopathologic alteration of pancreatic islet beta cells.

The metabolism and the chemical dissociation of streptozocin that occurs under physiologic conditions has not been extensively studied. When administered intravenously to a variety of experimental animals, streptozocin disappears from the blood very rapidly. In all species tested, it was found to concentrate in the liver and kidney. As much as 20% of the drug (or metabolites containing an N-nitrosourea group) is metabolized and/or excreted by the kidney. Metabolic products have not yet been identified.

ZANOSAR is indicated in the treatment of metastatic islet cell carcinoma of the pancreas. Responses have been obtained with both functional and nonfunctional carcinomas. Because of its inherent renal toxicity, therapy with this drug should be limited to patients with symptomatic or progressive metastatic disease.

No specific antidote for ZANOSAR is known.

ZANOSAR sterile powder should be administered intravenously by rapid injection or short/prolonged infusion. It is not active orally. Although it has been administered intraarterially, this is not recommended pending further evaluation of the possibility that adverse renal effects may be evoked more rapidly by this route of administration.

Two different dosage schedules have been employed successfully with ZANOSAR.

Daily Schedule—The recommended dose for daily intravenous administration is 500 mg/m² of body surface area for five consecutive days every six weeks until maximum benefit or until treatment-limiting toxicity is observed. Dose escalation on this schedule is not recommended.

Weekly Schedule—The recommended initial dose for weekly intravenous administration is 1000 mg/m² of body surface area at weekly intervals for the first two courses (weeks). In subsequent courses, drug doses may be escalated in patients who have not achieved a therapeutic response and who have not experienced significant toxicity with the previous course of treatment. However, A SINGLE DOSE OF 1500 mg/m² BODY SURFACE AREA SHOULD NOT BE EXCEEDED as a greater dose may cause azotemia. When administered on this schedule, the median time to onset of response is about 17 days and the median time to maximum response is about 35 days. The median total dose to onset of response is about 2000 mg/m² body surface area and the median total dose to maximum response is about 4000 mg/m² body surface area.

The ideal duration of maintenance therapy with ZANOSAR has not yet been clearly established for either of the above schedules.

For patients with functional tumors, serial monitoring of fasting insulin levels allows a determination of biochemical response to therapy. For patients with either functional or nonfunctional tumors, response to therapy can be determined by measurable reductions of tumor size (reduction of organomegaly, masses, or lymph nodes).

Reconstitute ZANOSAR with 9.5 mL of dextrose injection, USP, or 0.9% sodium chloride injection, USP. The resulting pale-gold solution will contain 100 mg of streptozocin and 22 mg of citric acid per mL. Where more dilute infusion solutions are desirable, further dilution in the above vehicles is recommended. The total storage time for streptozocin after it has been placed in solution should not exceed 12 hours. This product contains no preservatives and is not intended as a multiple-dose vial.

Caution in the handling and preparation of the powder and solution should be exercised, and the use of gloves is recommended. If the sterile powder of ZANOSAR or a solution prepared from ZANOSAR contacts the skin or mucosae, immediately wash the affected area with soap and water.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.^1–7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

ZANOSAR is supplied as follows:

Unopened vials of ZANOSAR should be stored at refrigeration temperatures (2°C to 8°C) and protected from light (preferably stored in carton).