Streptozocin (Monograph)

Brand name: Zanosar
Drug class: Antineoplastic Agents
VA class: AN200
Chemical name: 2-Deoxy-2-[[(methylnitrosoamino)carbonyl]amino]-d-glucose
Molecular formula: C₈H₁₅N₃O₇
CAS number: 18883-66-4

Introduction

Antineoplastic agent; a nitrosourea-derivative alkylating antibiotic.

Uses for Streptozocin

Pancreatic Islet Cell Carcinoma

Treatment of metastatic islet cell carcinoma of the pancreas; used alone or in combination with other antineoplastic agents (e.g., doxorubicin, fluorouracil).

Effective in patients with functional or nonfunctional and beta or non-beta islet cell tumors. Appears to be equally effective against functional or nonfunctional islet cell tumors.

Currently the most active single agent for treatment of metastatic islet cell carcinoma of the pancreas. Combination therapy with fluorouracil associated with higher overall and complete response rates; however, effect on survival not established.

Because tumor may be indolent, and because of streptozocin’s nephrotoxic and emetogenic potential, limit use to symptomatic or progressive metastatic disease.

Carcinoid Tumor and Syndrome

Palliative treatment of metastatic carcinoid tumor^{† [off-label]} or syndrome^{† [off-label]}.

Used alone or in combination with other antineoplastic agents (e.g., cyclophosphamide, fluorouracil, cyclophosphamide with fluorouracil and doxorubicin ).

When used alone, objective responses were partial and of short duration. Exact role in combination chemotherapy not established.

Pancreatic Adenocarcinoma

Treatment of pancreatic adenocarcinoma^{† [off-label]}.

Minimally effective as single agent. Role in combination chemotherapy regimens not yet determined.

Related/similar drugs

capecitabine, fluorouracil, Xeloda, gemcitabine, Lynparza, Afinitor

Streptozocin Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

• Use protective gloves during handling of streptozocin powder and preparation of solutions; topical contact may be carcinogenic hazard. (See Dermatologic Effects under Cautions.)

• If skin or mucosal contact occurs, wash affected area(s) immediately and thoroughly with soap and water.

• Use antiemetic therapy to prevent acute and delayed emesis. (See GI Effects under Cautions.)

• Measure response to therapy by monitoring for decrease or disappearance of signs or symptoms of disease. For functional or nonfunctional islet cell tumors, monitor for reductions in tumor size and/or organomegaly (e.g., pancreatic and/or extrapancreatic masses). For functional tumors, also may monitor appropriate polypeptide hormone concentrations (e.g., insulin, gastrin).

Administration

Administer by direct IV injection or by IV infusion. Intra-arterial^{† [off-label]} infusion not recommended. (See Intra-arterial Infusion under Dosage and Administration.)

Contains no preservatives; vials not intended for multiple-dose withdrawal.

IV Injection

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute vial containing 1 g of streptozocin with 9.5 mL of 5% dextrose or 0.9% sodium chloride injection to provide a solution containing 100 mg/mL.

Rate of Administration

Administer by rapid IV injection.

IV Infusion

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute vial containing 1 g of streptozocin with 9.5 mL of 5% dextrose or 0.9% sodium chloride injection to provide a solution containing 100 mg/mL.

Dilution

For IV infusion, may further dilute in 5% dextrose or 0.9% sodium chloride injection or in 5% dextrose and 0.9% sodium chloride injection.

Rate of Administration

Administer over a short or prolonged period.

Usually administered as intermittent IV infusions over 15 minutes to 6 hours.

Continuous 5-day IV infusions may be associated with increased CNS toxicity. (See CNS Effects under Cautions.)

Intra-arterial Infusion† [off-label]

Not recommended by manufacturer pending evaluation of possibility that adverse renal effects may be evoked more rapidly. (See Renal Effects under Cautions.)

Administered via an appropriately placed catheter using a controlled-infusion device.

Dilution

Dilute in 5% dextrose or 0.9% sodium chloride injection.

Rate of Administration

Infuse over 1–2 hours.

Dosage

Optimize results and minimize adverse effects by basing dosage on clinical, renal, hematologic, and hepatic responses and tolerance of the patient.

Consult published protocols for dosages of streptozocin and other chemotherapeutic agents and for method and sequence of administration.

Do not administer repeat course until renal, hematologic, and hepatic functions are within acceptable limits. (See Renal Effects, Hematologic Effects, and also Hepatic Effects under Cautions.)

Adults

Pancreatic Islet Cell Carcinoma

Consecutive-Day Regimen

IV

500 mg/m² daily for 5 consecutive days; repeat every 6 weeks until optimal benefit or treatment-limiting toxicity occurs. Do not exceed 500 mg/m² daily.

May produce more severe nausea and vomiting than weekly regimen; however, may be more tolerable and acceptable because of the longer interval between periods of treatment-induced nausea and vomiting.

Ideal duration of maintenance therapy unknown.

Weekly Regimen

IV

Initially, 1 g/m² once weekly for two weeks; then, may increase dose if therapeutic response is not achieved and no clinically important drug-related toxicity occurs. Do not exceed single dose of 1.5 g/m²; higher dosages may cause azotemia.

Median time to onset of therapeutic response is approximately 17 days; median total cumulative dose to onset of response is 2 g/m².

Median time to maximum therapeutic response is approximately 35 days; median total cumulative dose to achieve maximum response is 4 g/m².

Ideal duration of maintenance therapy unknown.

Intra-arterial Regimen†

Intra-arterial

1–4 g/m² once every 1–6 weeks for at least 1–4 courses of therapy. Safety not established. (See Intra-arterial Infusion under Dosage and Administration.)

Prescribing Limits

Adults

Pancreatic Islet Cell Carcinoma

Consecutive-Day Regimen

IV

Maximum 500 mg/m² daily.

Weekly Regimen

IV

Maximum 1.5 g/m² once weekly.

Special Populations

Renal Impairment

Cl_cr 10–50 mL/minute: 75% of usual dosage.

Cl_cr <10 mL/minute: 50% of usual dosage.

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. Start at lower end of dosage range. (See Geriatric Use under Cautions.)

Cautions for Streptozocin

Warnings/Precautions

Warnings

Highly toxic, with low therapeutic index; therapeutic response not likely to occur without some evidence of toxicity. (See Boxed Warning.)

Renal Effects

Renal toxicity occurs in 25–75% of patients. Dose limiting and cumulative; may be severe or fatal.

Renal toxicity may manifest as azotemia, anuria, proteinuria, hypophosphatemia, hyperchloremia, and proximal renal tubular acidosis (possibly associated with Fanconi-like syndrome [e.g., glycosuria, acetonuria, aminoaciduria]). Hypokalemia and hypocalcemia also have occurred.

Hypophosphatemia or mild proteinuria may be earliest sign of nephrotoxicity and may indicate impending further deterioration of renal function. Increased BUN and S_cr may occur later if streptozocin is continued.

Mild adverse renal effects (e.g., mild proteinuria) may be reversible if streptozocin is discontinued; however, nephrotoxicity may be irreversible or fatal if drug is continued despite nephrotoxic manifestations.

Intra-arterial^† administration may increase risk and/or precipitate more rapid development of nephrotoxicity. (See Intra-arterial Infusion under Dosage and Administration.)

Nephrogenic diabetes insipidus reported rarely.

Long-term effects on renal function not fully known. Cumulative, delayed nephrotoxicity and chronic renal failure reported rarely following discontinuance of streptozocin.

Manufacturer recommends obtaining serial urinalyses, Cl_cr, BUN, S_cr, and electrolyte concentrations prior to and at least weekly during streptozocin therapy and then weekly for 4 weeks after discontinuance of drug. Alternatively, some clinicians suggest that assessment of renal function prior to each course of therapy is sufficient in most patients. Serial urinalysis is particularly important for early detection of proteinuria; if proteinuria is detected, quantify with a 24-hour urine collection.

Adequate hydration may help reduce risk of nephrotoxicity to renal tubular epithelium by decreasing renal and urinary concentrations of streptozocin and/or metabolites; however, role of hydration not clearly established.

Reduce dosage or discontinue streptozocin if substantial renal toxicity occurs.

Use in patients with impaired renal function only when benefits outweigh known risk of nephrotoxicity. (See Renal Impairment under Cautions.)

Do not use in combination or concomitantly with other potential nephrotoxins. (See Nephrotoxic Drugs under Interactions.)

Dermatologic Effects

Possible carcinogenic hazard from topical exposure if improperly handled.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals. Use during pregnancy only when potential benefits justify possible risks to fetus.

Major Toxicities

GI Effects

Severe nausea and vomiting occur in most patients (>90%), usually beginning 1–4 hours following administration; may persist for ≥24 hours. May require discontinuance of streptozocin.

Incidence and/or severity of nausea and vomiting may be reduced with 5-day continuous IV infusions compared with rapid, intermittent IV administration.

Aggressive antiemetic therapy during early courses of emetogenic chemotherapy is the best way to prevent anticipatory nausea and vomiting. Behavioral therapy may be useful; benzodiazepines also may be useful, although evidence is lacking.

To prevent acute emesis associated with highly emetogenic chemotherapy (e.g., streptozocin), ASCO recommends premedication with a 3-drug antiemetic regimen (a selective 5-HT₃ receptor antagonist, dexamethasone, and aprepitant); currently available selective 5-HT₃ receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron) are comparably effective.

To prevent delayed emesis, ASCO recommends administration of a 2-drug regimen (dexamethasone and aprepitant) following administration of highly emetogenic chemotherapy.

Diarrhea has occurred occasionally. Duodenal ulcer reported rarely; however, not directly associated with streptozocin.

Hematologic Effects

Mild to moderate myelosuppression (e.g., leukopenia, thrombocytopenia, anemia [decreased hematocrit and hemoglobin]) reported; severe myelosuppression (e.g., substantial leukopenia and thrombocytopenia) leading to sepsis and death reported rarely. Cumulative and usually reversible; may be more severe in patients previously treated with other antineoplastic agents or radiation therapy. Leukocyte and platelet nadirs usually occur at 1–2 weeks after administration.

Asymptomatic eosinophilia also reported; disappears following discontinuance of streptozocin.

Monitor CBC at least weekly. Adjust dosage or discontinue streptozocin as needed.

Hepatic Effects

Minimal, transient increases in serum AST, ALT, LDH, and/or alkaline phosphatase concentrations reported. Increased serum bilirubin concentration and hypoalbuminemia also reported. Severe and fatal hepatic effects reported rarely.

Manufacturer recommends performing liver function tests at least weekly; alternatively, some clinicians recommend monitoring liver function just prior to initiating each course of therapy. Adjust dosage or discontinue streptozocin as needed.

Metabolic Effects

Mild to moderate, reversible abnormalities of glucose tolerance reported in some patients. Insulin shock with severe hypoglycemia, requiring treatment with IV dextrose, has occurred rarely in patients with insulinomas, usually within 24 hours after administration.

Glycosuria without hyperglycemia reported in some patients.

Local Effects

Manifestations of local inflammation (e.g., edema, erythema, burning, tenderness), usually resolving the same day or within a few days, reported following extravasation of streptozocin. Severe tissue lesions and necrosis also reported following extravasation.

Burning sensation, extending from site of injection up the arm, reported in some patients, especially following rapid IV injection.

CNS Effects

Confusion, lethargy, and depression reported with continuous IV infusion for 5 days; not associated with other methods of administration.

General Precautions

Adequate Patient Evaluation and Monitoring

Monitor closely, particularly for evidence of adverse renal, hematologic, and hepatic effects. (See Renal Effects, Hematologic Effects, and also Hepatic Effects under Cautions.)

Do not administer repeat course until renal, hematologic, and hepatic functions are within acceptable limits.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether streptozocin is distributed into milk. Discontinue nursing because of potential risk to nursing infants.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; clinical experience has not revealed age-related differences. Select dosage with caution, usually starting at low end of dosage range. (See Geriatric Patients under Dosage and Administration.)

Renal Impairment

Weigh benefit against risk of serious renal damage. (See Renal Effects under Cautions.) Dosage adjustments necessary based on degree of renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Severe nausea and vomiting, nephrotoxicity, myelosuppression.

Drug Interactions

Drugs that Decrease Hematopoiesis

Possible increased risk of hematologic toxicity.

Nephrotoxic Drugs

Possible cumulative nephrotoxicity; avoid combination or concomitant use.

Specific Drugs

Streptozocin Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed following oral administration. Not active orally; must be administered IV.

Distribution

Extent

Following IV or intraperitoneal administration in animals, rapidly distributed into liver, kidneys, intestine, and pancreas; lower concentrations in skeletal muscle, spleen, lungs, heart, and thymus.

Does not appear to cross the blood-brain barrier; however, metabolites readily distribute into CSF.

Readily crosses the placenta in monkeys. Not known whether streptozocin crosses the placenta or is distributed into milk in humans.

Elimination

Metabolism

Extensively metabolized, probably in the liver and kidneys.

Elimination Route

Excreted principally in urine as unchanged drug (10%) and metabolites (60–70%). May be excreted in expired air (5%) or in feces (<1%).

Half-life

Biphasic; terminal half-life is approximately 35–40 minutes for streptozocin or >40 hours for metabolites.

Stability

Storage

Parenteral

Powder for Injection

2–8°C; protect from light. Store in carton.

Reconstituted or diluted solution (i.e., diluted with 5% dextrose and 0.9% sodium chloride injection to final concentration of 2 mg/mL) stable for 48 hours at room temperature or for ≥96 hours at 2–8°C. However, because product contains no preservatives, manufacturer recommends discarding reconstituted or diluted solution within 12 hours after preparation.

Compatibility

Drug Compatibility

Actions

• Active against gram-positive and gram-negative bacteria; cytotoxicity precludes use as an anti-infective agent.

• Precise mechanism unknown. Alkylates DNA, causing interstrand cross-linking. Weak alkylator compared with other nitrosoureas.

• Inhibits DNA synthesis in bacterial and mammalian cells. Blocks progression of cells into mitosis; however, cycle-phase nonspecific. Does not inhibit RNA or protein synthesis.

• Marked specificity for pancreatic beta and exocrine cells.

Advice to Patients

• Risk of adverse renal, GI, hematologic, and hepatic effects. Importance of adherence to medical and laboratory appointment schedules.

• Possible confusion, lethargy, and depression if receiving continuous IV infusion for 5 days. Potential risk in driving or using complex machinery.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., renal disease).

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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