Streptozocin (Systemic)
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VA CLASSIFICATION
Primary: AN200
Commonly used brand name(s): Zanosar.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antineoplastic—
Indications
Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.
Accepted
Carcinoma, islet cell (treatment) or
Carcinoma, pancreatic (treatment)—Streptozocin is indicated for treatment of symptomatic or progressive metastatic islet cell carcinoma of the pancreas (both functional and nonfunctional) {01} {04}. It is also indicated for treatment of metastatic [non–islet cell carcinoma of the pancreas]1 {05}.
[Tumors, gastrointestinal carcinoid (treatment)]1—Streptozocin also is indicated for treatment of malignant metastatic gastrointestinal carcinoid tumors. {02} {03}
1 Not included in Canadian product labeling.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
265.22
Mechanism of action/Effect:
Streptozocin is an alkylating agent of the nitrosourea type.
Streptozocin is considered cell cycle–phase nonspecific, although it particularly inhibits progression out of the G 2 phase of cell division.
The mechanism of streptozocin's antineoplastic action is not completely understood, but activity appears to occur as a result of formation of methylcarbonium ions, which alkylate or bind with many intracellular molecular structures including nucleic acids. Its cytotoxic action is probably due to cross-linking of strands of DNA, resulting in inhibition of DNA synthesis. Streptozocin has little effect on RNA or protein synthesis. Its alkylating activity is weak compared to that of other nitrosoureas.
Other actions/effects:
Streptozocin also has a diabetogenic or hyperglycemic effect as a result of selective uptake into and toxicity to pancreatic islet beta cells involving lowering of beta cell nicotinamide adenine dinucleotide (NAD). Irreversible damage to the cell results in degranulation and loss of insulin secretion.
Distribution:
Very little streptozocin crosses the blood-brain barrier, but metabolites do; 2 hours after administration, cerebrospinal fluid (CSF) concentrations are approximately equal to plasma concentrations.
Biotransformation:
Hepatic.
Half-life:
Initial:
Unchanged drug: 5 to 15 minutes.
Metabolites: 6 minutes.
Intermediate:
Metabolites: 3.5 hours.
Terminal:
Unchanged drug: 35 minutes.
Metabolites: 40 hours.
Elimination:
Renal (as unchanged drug and at least 3 identified metabolites, including methylnitrosoureas).
Fecal (less than 1%).
Significant respiratory excretion also occurs.
Precautions to Consider
Carcinogenicity/Mutagenicity/Tumorigenicity
Streptozocin administration has reportedly been followed by development of acute myelocytic leukemia in one patient. Streptozocin is mutagenic in bacteria, plants, and mammalian cells and has been shown to be tumorigenic (renal, hepatic, stomach, and pancreatic tumors) in animals and carcinogenic in mice. Topical exposure in rats has resulted in development of benign tumors at the site.
Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients receiving antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.
Streptozocin adversely affects fertility in male and female rats.
Pregnancy—
Streptozocin crosses the placenta. Studies in humans have not been done.
First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.
Other hazards to the fetus include adverse reactions seen in adults.
In general, use of a contraceptive is recommended during cytotoxic drug therapy.
Studies in animals have shown that streptozocin causes teratogenicity in rats and is abortifacient in rabbits.
FDA Pregnancy Category C.
Breast-feeding
It is not known whether streptozocin is distributed into breast milk. Although very little information is available regarding distribution of antineoplastic agents in breast milk, breast-feeding is not recommended during chemotherapy because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).
Pediatrics
Appropriate studies on the relationship of age to the effects of streptozocin have not been performed in the pediatric population.
Geriatrics
No information is available on the relationship of age to the effects of streptozocin in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving streptozocin.
Dental
The bone marrow depressant effects of streptozocin may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia and/or thrombocytopenia occur, dental work should be deferred until blood counts have returned to normal and patients should be instructed in proper oral hygiene including caution in use of regular toothbrushes, dental floss, and toothpicks.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Blood dyscrasia–causing medications (see Appendix II ) (leukopenic and/or thrombocytopenic effects of streptozocin may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of streptozocin, if necessary, should be based on blood counts)
Bone marrow depressants, other (see Appendix II ) or
Radiation therapy (additive bone marrow depression may occur, although myelosuppressive effects of streptozocin are rare; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)
(streptozocin may prolong the half-life of doxorubicin when used concurrently; dosage reduction of doxorubicin is recommended)
Corticosteroids, glucocorticoid or
Corticotropin (ACTH) (concurrent use may increase the hyperglycemic effect of streptozocin)
» Nephrotoxic medications (see Appendix II ) (concurrent use may result in enhanced nephrotoxicity and is not recommended)
Nicotinamide (concurrent use may reduce the diabetogenic effect of streptozocin but does not appear to alter the antitumor effect)
» Phenytoin (may protect pancreatic beta cells from the toxic effects of streptozocin, thus reducing its therapeutic effects; concurrent use is not recommended)
Vaccines, killed virus (because normal defense mechanisms may be suppressed by streptozocin therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)
» Vaccines, live virus (because normal defense mechanisms may be suppressed by streptozocin therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the streptozocin therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members)
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin and
Lactate dehydrogenase (LDH) (serum values may be increased, indicating hepatotoxicity)
Albumin concentrations in blood (may be decreased, indicating hepatotoxicity)
Blood urea nitrogen (BUN) concentrations and
Creatinine concentrations, plasma and
Protein concentrations, urinary (may be increased, indicating renal toxicity; usually transient, but permanent damage may occur)
Glucose (blood concentrations may be initially decreased because of sudden release of insulin)
Hematocrit (may rarely be mildly increased; reduction in hematocrit is generally more common than leukopenia or thrombocytopenia)
{01}
Phosphate (blood concentrations may be decreased, as an early indication of renal toxicity)
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
Bone marrow depression or
Infection (possible hematological toxicity, although this is rare)
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster (risk of severe generalized disease)
Diabetes mellitus (streptozocin causes hypoglycemia)
» Hepatic function impairment (reduced biotransformation and possible increased toxicity of streptozocin; streptozocin can have hepatotoxic effects)
» Renal function impairment (streptozocin causes severe renal toxicity {01})
Sensitivity to streptozocin
Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy.
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin concentrations, serum and
Lactate dehydrogenase (LDH) values, serum (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, and other agents being used concurrently)
» Blood urea nitrogen (BUN) concentrations and
» Creatinine clearance determinations and
» Creatinine concentrations, plasma and
» Electrolyte concentrations, serum and
» Urinalysis, serial, to detect proteinuria (recommended prior to, at least weekly during, and for 4 weeks following each course of therapy, to monitor for renal toxicity)
» Glucose concentrations, blood (recommended at periodic intervals)
Hematocrit or hemoglobin and
Leukocyte count, total and, if appropriate, differential and
Platelet count (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, and other agents being used concurrently)
Insulin concentrations, fasting (in patients with functional pancreatic tumors, serial monitoring allows a determination of biochemical response to therapy {01})
Uric acid concentrations, serum (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, and other agents being used concurrently)
Side/Adverse Effects
Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
—28 to 73%
Renal toxicity and failure (swelling of feet or lower legs; unusual decrease in urination)
Note: Renal toxicity (proteinuria, glycosuria, hypophosphatemia, azotemia, renal tubular acidosis) occurs frequently. Mild proteinuria is one of the first signs of renal toxicity {01}. Toxicity is dose-related and cumulative and may be fatal in some cases.
Incidence less frequent
Hypoglycemia (anxiety, nervousness, or shakiness; chills, cold sweats, or cool, pale skin; drowsiness or unusual tiredness or weakness; fast pulse; headache; unusual hunger)—occurring shortly after injection
pain or redness at site of injection —caused by rapid intravenous injection or extravasation
Note: Although streptozocin is diabetogenic, a sudden release of insulin may occur initially. Mild to moderate glucose tolerance abnormalities have been reported; they are usually reversible, although insulin shock with hypoglycemia has occurred.
Incidence rare
Hepatotoxicity —usually not symptomatic
leukopenia or infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic
Note: Hematological toxicity is rare but has been fatal in some cases.
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Nausea and vomiting
Note: Nausea and vomiting occur in most patients, usually within 2 to 4 hours after a dose and may be severe {01}; usually become progressively worse over a course of therapy; antiemetics have little effect.
Incidence less frequent
Diarrhea
Those indicating the need for medical attention if they occur after medication is discontinued
Renal toxicity (decrease in urination; swelling of feet or lower legs)
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Streptozocin (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to streptozocin
Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential, advisability of using contraception; telling physician immediately if pregnancy is suspected
Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially nephrotoxic medications or phenytoin
Other medical problems, especially chickenpox, herpes zoster, hepatic function impairment, or renal function impairment
Proper use of this medication
Importance of ample fluid intake and subsequent increase in urine output to aid excretion and reduce renal toxicity
Frequency of nausea and vomiting; importance of continuing medication despite stomach upset
» Proper dosing
Precautions while using this medication
» Importance of close monitoring by physician
» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth
» Possibility of local tissue injury and scarring if infiltration of intravenous solution occurs; telling doctor or nurse right away about redness, pain, or swelling at injection site
Side/adverse effects
Signs of potential side effects, especially renal toxicity and failure, hypoglycemia, pain or redness at site of injection caused by rapid intravenous injection or extravasation, hepatotoxicity, leukopenia, infection, and thrombocytopenia
Physician or nurse can help in dealing with side effects
General Dosing Information
Patients receiving streptozocin should be under supervision of a physician experienced in cancer chemotherapy.
A variety of dosage schedules and regimens of streptozocin, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature as well as the manufacturer's literature in choosing a specific dosage.
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response and appearance or severity of toxicity.
Streptozocin may be administered by rapid intravenous injection or as a short (over a 10- to 15-minute period) or long (over a 6-hour period) intravenous infusion.
Streptozocin has also been administered as a continuous, 5-day intravenous infusion. Although incidence of renal toxicity and nausea and vomiting appeared to be reduced, other side effects including lethargy, confusion, and depression were reported.
Care must be taken to avoid extravasation during administration because of the risk of severe ulceration and necrosis.
If extravasation of streptozocin occurs during intravenous administration, as indicated by local burning or stinging, the injection or infusion should be stopped immediately and resumed, completing the dose, in another vein.
Although the manufacturer does not recommend intra-arterial administration because of the possibility that renal toxicity may occur more rapidly, streptozocin has been administered intra-arterially by a number of investigators, for example, in patients with hepatic metastases.
It is recommended that intravenous dextrose be immediately available, especially when the first dose of streptozocin is administered, because of the risk of hypoglycemia due to a sudden release of insulin.
It is recommended that each course of streptozocin therapy be followed by a 4- to 6-week observation period in order to detect any renal toxicity.
It is recommended that dosage of streptozocin be reduced or treatment withdrawn if significant renal toxicity occurs. Subsequent doses should not be given until renal function returns to normal.
Concomitant hydration with each dose may reduce renal toxicity by promoting rapid excretion in a dilute urine.
Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include: • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
• Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
• Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.
Parenteral Dosage Forms
STREPTOZOCIN FOR INJECTION
Usual adult dose
Carcinoma, islet cell
Intravenous, 500 mg per square meter of body surface area per day for five consecutive days every six weeks or
Intravenous, 1 gram per square meter of body surface area once a week for two weeks, increased thereafter if necessary, up to a maximum dose of 1.5 grams per square meter of body surface area. {01}
Note: A single course usually consists of four to six once-a-week doses, but may be longer.
Usual adult prescribing limits
Up to 1.5 grams per square meter of body surface area as a single dose (because of the risk of azotemia) {01}.
Usual pediatric dose
Dosage has not been established.
Size(s) usually available:
U.S.—
1 gram (Rx) [Zanosar (citric acid anhydrous 220 mg)]
Canada—
1 gram (Rx) [Zanosar]
Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Protect from light.
Preparation of dosage form:
Streptozocin for injection is reconstituted for intravenous use by adding 9.5 mL of 5% dextrose injection or 0.9% sodium chloride injection to the vial, producing a clear, pale-gold solution containing 100 mg of streptozocin and 22 mg of citric acid per mL.
Reconstituted solutions may be further diluted with 5% dextrose injection or 0.9% sodium chloride injection for administration by intravenous infusion. Addition of the 100 mg of streptozocin per mL solution to 10 to 200 mL of 5% dextrose injection followed by administration over a 15-minute period by infusion may prevent local pain and phlebitis.
Stability:
Reconstituted solutions should be used within 12 hours if kept at room temperature.
Because the product contains no preservatives, the vial should not be used for more than one dose.
A change in color from pale gold to dark brown indicates decomposition.
Note: If accidental contact with skin or mucous membranes occurs, immediately wash the affected area with soap and water.
Revised: 09/30/1997
References
Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.
- Zanosar product information (Upjohn—US). In: PDR Physicians' desk reference. 46th ed. 1992. Montvale, NJ: Medical Economics Data; 1992.
- Gastrointestinal carcinoid tumor [7/97]. National Cancer Institute. Available from: URL: http://cancernet.nci.nih.gov
- Jensen RT, Norton JA. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT, Hellman S, Rosenberg SA. Cancer principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 1704-23.
- Zanosar product monograph (Upjohn—Canada), Rev 12/91.
- Reviewers' responses to Hematologic-Oncologic Disease Advisory Panel Memo #9 of 1/30/97.
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