Pharmacia & Upjohn
Action And Clinical Pharmacology: 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 definitively established; levels required to kill cells are considerably lower than those required to inhibit DNA synthesis or several of the enzymes involved in DNA synthesis. Streptozocin inhibits the progression of cells into mitosis but the agent does not apear to be specifically lethal to cells in a single phase of the cell cycle.
It is active in the L1210 leukemic mouse over a fairly wide range of parenteral dosage schedules. In many experimental animal species, streptozocin induces a diabetes that resembles human hyperglycemic nonketotic diabetes mellitus. This phenomenon, which has been extensively studied, is consequent upon histopathologic alteration of pancreatic islet beta cells.
The metabolism of streptozocin has not been fully studied. When given i.v. to mice or dogs, it disappears from the blood very rapidly. In all species tested, it concentrates in the liver and kidney. Less than 10% of the drug (or metabolites containing an N-nitrosourea group) is excreted by the kidney. Metabolic products have not been identified.
Indications And Clinical Uses: For 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.
Contra-Indications: In patients with known hypersensitivity to the drug.
Pre-existing renal disease is a strong contraindication to its use. Use of the drug in such a patient must be judged by the physician in terms of the potential benefit as opposed to the known risk.
Manufacturers’ Warnings In Clinical States: Streptozocin should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents (see Precautions). Renal, hepatic and hematologic evaluations should be done at regular intervals. Renal toxicity is dose related and cumulative and may be fatal.
Renal Toxicity: Many patients treated with streptozocin have experienced renal toxicity as evidenced by azotemia, anuria, hypophosphatemia, glycosuria and renal tubular acidosis. Such toxicity is dose-related and cumulative and may be severe or fatal. Renal function must be monitored before and after each course of therapy. Serial urinalysis, blood urea nitrogen, plasma creatinine, serum electrolytes and creatinine clearance should be obtained prior to, at least weekly during, and for 4 weeks after drug administration. Serial urinalysis is particularly important for the early detection of proteinuria and should be quantitated with a 24 hour collection when proteinuria is detected. Mild proteinuria is one of the first signs of renal toxicity and may herald further deterioration of renal function. Reduction of the dose or discontinuation of treatment is suggested in the presence of significant renal toxicity.
This drug should not be used in combination with or concomitantly with other potential nephrotoxins.
During therapy, 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.
Other 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.
Mutagenesis, Carcinogenesis, Impairment of Fertility: Streptozocin is mutagenic in bacteria, plants and mammalian cells. When administered parenterally, it has been shown to induce renal tumors in rats and to induce liver tumors and other tumors in hamsters. Stomach and pancreatic tumors were observed in rats treated orally with streptozocin. Streptozocin has also been shown to be carcinogenic in mice.
Streptozocin adversely affected fertility when administered to male and female rats.
When exposed dermally, some rats developed benign tumors at the site of application of streptozocin. Consequently, streptozocin may pose a carcinogenic hazard following topical exposure if not properly handled. If streptozocin powder or solution contacts the skin or mucosae, immediately wash the affected area with soap and water (see Handling Instructions).
Precautions: Patient Follow-up: Patients must be monitored closely, particularly for evidence of renal, hepatic, and hematopoietic toxicity. Serial urinalysis, blood urea nitrogen, and plasma creatinine levels, and creatinine clearance should be done prior to and at least once weekly during and for 4 weeks after drug administration (see Warnings).
Similarly, complete blood counts and liver function studies should be done weekly. Reduction of the dose or discontinuation of therapy is suggested in response to the appearance of renal, hepatic, or hematopoietic abnormalities, but must be weighed against the possible benefit of continued therapy of clinically progressive disease.
Pregnancy: Safe use during pregnancy has not been established. Streptozocin is mutagenic in bacteria and plants. By analogy with other nitrosoureas, it would be expected to exhibit teratogenic effects in animals.
When administered to pregnant monkeys, it appears promptly in the fetal circulation. It has been shown to induce renal tumors in rats, and liver and other tumors in hamsters. The physician must judge the possible benefit to the patient against these known toxic effects when considering the advisability of therapy in males or females who may contemplate the initiation of pregnancy or in pregnant females.
Reproduction studies revealed that streptozocin is teratogenic in the rat and has abortifacient effects in rabbits. There are no studies in pregnant women.
It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known whether streptozocin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, nursing should be discontinued in patients receiving streptozocin.
Children: No data on treatment of children are available.
Adverse Reactions: Renal: (see Warnings).
Many patients treated with streptozocin have experienced renal toxicity, as evidenced by azotemia, anuria, hypophosphatemia, and glycosuria, and renal tubular acidosis. Renal toxicity may be severe or fatal. Mild proteinuria is one of the first signs of renal toxicity and may herald further deterioration of renal function.
Two cases of nephrogenic diabetes insipidus following Zanosar therapy have been reported. One had spontaneous recovery and the second responded to indomethacin.
Gastrointestinal: Most patients have experienced severe nausea and vomiting, occasionally requiring discontinuation of drug therapy. Some patients experienced diarrhea. A number of patients have experienced hepatic toxicity, as characterized by elevated liver enzyme [AST (SGOT) and LDH] levels and hypoalbuminemia.
Metabolic: Mild to moderate abnormalities of glucose tolerance have been noted in some patients but these have generally been reversible.
Hematological: Hematological toxicity has been rare, most often involving mild decreases in hematocrit values. However, fatal hematological toxicity with substantial reductions in leukocyte and platelet count has been observed.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: No specific antidote is known.
Dosage And Administration: Streptozocin should be administered i.v. It is not active orally. Although it has been administered intra-arterially, this is not recommended pending further evaluation of the possibility that adverse renal effects may be evoked more readily by this route of administration.
Dosage Schedules: Two different dosage schedules have been employed successfully.
Daily Schedule: The recommended dose for daily i.v. administration is 500 mg/mof body surface area for 5 consecutive days every 6 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 i.v. administration is 1 000 mg/mof body surface area at weekly intervals for the first 2 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 1 500 mg/mbody 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 2 000 mg/mbody surface area and the median total dose to maximum response is about 4 000 mg/mbody surface area.
When streptozocin is used in combination with other chemotherapeutic agents, reduction of dosage is often necessary.
The ideal duration of maintenance therapy 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 non-functional tumors, response to therapy can be determined by measurable reductions of tumor size (reduction of organomegaly, masses, or lymph nodes).
Stability and Storage: Unopened vials should be stored at refrigeration temperatures (2 to 8°C) and protected from light (preferably stored in carton).
The total storage time for streptozocin after reconstitution should not exceed 48 hours at refrigeration temperatures (2 to 8°C) or 24 hours at room temperature. This product contains no preservatives and is not intended as a multiple-dose vial.
Further dilution of the reconstituted solution with 500 mL of Sodium Chloride Injection USP does not alter the solution stability.
Reconstitution: Reconstitute with 9.5 mL of Dextrose Injection USP, Sterile Water for Injection USP, or 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. When reconstituted as directed, the pH of the solution will be between 3.5 and 4.5.
Handling: The following precautionary measures are recommended in proceeding with the preparation and handling of cytotoxic agents such as streptozocin.
- The procedure should be carried out in a vertical laminar flow hood (biological Safety Cabinet – Class II);
- Personnel should wear: PVC gloves, safety glasses, disposable gowns and masks;
- All needles, syringes, vials, and other materials which have come in contact with streptozocin should be segregated and destroyed by incineration (sealed containers may explode).
Availability And Storage: Each off-white to pale yellow colored freeze-dried cake contains: streptozocin 1 g and citric acid anhydrous 220 mg. When necessary, pH was adjusted with hydrochloric acid and/or sodium hydroxide.
ZANOSAR® Pharmacia & Upjohn Streptozocin Antineoplastic Agent
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