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Streptozocin

Pronunciation

(strep toe ZOE sin)

Index Terms

  • Streptozotocin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Zanosar: 1 g (1 ea)

Brand Names: U.S.

  • Zanosar

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Alkylating Agent (Nitrosourea)

Pharmacology

Inhibits DNA synthesis by alkylation and cross-linking the strands of DNA, and by possible protein modification; cell cycle nonspecific

Distribution

Concentrates in liver, kidney, and pancreatic beta cells

Metabolism

Rapid; primarily hepatic

Excretion

Urine (primarily; as parent drug and metabolites)

Onset of Action

1500 mg/m2 once weekly: Onset of response: 17 days; median time to maximum response: 35 days

Half-Life Elimination

<1 hour

Use: Labeled Indications

Treatment of metastatic islet cell carcinoma of the pancreas (symptomatic or progressive disease)

Use: Unlabeled

Treatment of metastatic adrenal carcinoma

Contraindications

There are no contraindications listed within the manufacturer’s labeling.

Dosing: Adult

Note: Streptozocin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch, 2011; Roila, 2010).

Pancreatic islet cell carcinoma, metastatic: IV:

Daily schedule: 500 mg/m2/day for 5 consecutive days every 6 weeks until maximum benefit or until unacceptable toxicity

Weekly schedule: 1000 mg/m2 once weekly; if therapeutic response not achieved after 2 weeks, may escalate dose to a maximum of 1500 mg/m2 weekly

Off-label dosing: 1000 mg/m2 once every 3 weeks for up to 6 cycles (in combination with leucovorin, fluorouracil and cisplatin) (Turner, 2010) or 400 mg/m2 days 1 to 5 every 4 weeks (in combination with fluorouracil and doxorubicin) until disease progression or unacceptable toxicity (Kouvaraki, 2004)

Adrenal carcinoma, metastatic (off-label use): IV: 1000 mg once daily for 5 days (cycle 1) followed by 2000 mg on day 1 (subsequent cycles) every 3 weeks (in combination with mitotane) (Fassnacht, 2012; Khan 2000)

Dosing: Geriatric

Refer to adult dosing. Select dose cautiously, beginning at the lower end of dosing range.

Dosing: Renal Impairment

No dosage adjustment provided in the manufacturer’s labeling; however, it is recommended to use clinical judgment weighing benefit vs risk of renal toxicity in patients with pre-existing renal impairment. The following dosing adjustments have been recommended (Aronoff, 2007): Adults (based on a usual dose of 500 mg/m2):

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 10-50 mL/minute: Administer 75% of dose

CrCl <10 mL/minute: Administer 50% of dose

Dosing: Hepatic Impairment

No dosage adjustment provided in the manufacturer’s labeling. However, streptozocin is rapidly hepatically metabolized; dose should be decreased in patients with severe liver disease.

Dosing: Adjustment for Toxicity

Bone marrow suppression or hepatic dysfunction: May require dosage reduction or discontinuation.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Reconstitute powder with 9.5 mL D5W or NS to a concentration of 100 mg/mL. May further dilute for infusion in D5W or NS.

Administration

Streptozocin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch, 2011; Dupuis, 2011; Roila, 2010).

Administer as either a rapid IV injection or as short or prolonged infusion.

Irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in D5W, NS.

Y-site administration: Incompatible with allopurinol, aztreonam, piperacillin/tazobactam.

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. The manufacturer recommends use within 12 hours of reconstitution; vial does not contain a preservative.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Frequency not defined:

Endocrine & metabolic: Glucose intolerance, hyper-/hypoglycemia, hypoalbuminemia, hypophosphatemia

Gastrointestinal: Diarrhea, nausea, vomiting

Hepatic: LDH increased, transaminases increased

Local: Injection site reactions (burning, edema, erythema, inflammation, irritation, tenderness)

Renal: Anuria, azotemia, BUN increased, creatinine increased, glycosuria, nephrotoxicity, proteinuria, renal dysfunction, renal tubular acidosis

Infrequent, postmarketing, and/or case reports: Anemia, confusion, depression, diabetes insipidus, lethargy, leukopenia, myelosuppression (nadir: at 2-3 weeks), secondary malignancies, thrombocytopenia, liver dysfunction, secondary malignancy

ALERT: U.S. Boxed Warning

Experienced physician:

Streptozocin sterile powder 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 a laboratory and supportive resources sufficient to monitor drug tolerance and to protect and maintain a patient compromised by drug toxicity. 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 streptozocin. The physician should be familiar with the following text before making a judgment and beginning treatment.

Drug toxicities:

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.

Secondary malignancy:

Streptozocin is mutagenic. When administered parenterally, it has been found to be tumorigenic or carcinogenic in some rodents.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [U.S. Boxed Warning]: Hematologic toxicity has been observed. Mild bone marrow suppression (rare) may occur; monitor blood counts weekly. May require dosage reduction or discontinuation.

• CNS effects: May cause confusion, lethargy or depression; caution patients about performing tasks that require mental alertness (eg, operating machinery or driving).

• Extravasation/tissue irritation: Streptozocin is an irritant with vesicant-like properties. Avoid extravasation. Local tissue irritation or inflammation (burning, edema, erythema, tenderness) may occur, but usually resolves within a few days.

• Gastrointestinal events: [U.S. Boxed Warning]: Diarrhea has been observed. May cause severe nausea and vomiting. Streptozocin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch, 2011; Dupuis, 2011; Roila, 2010).

• Glucose intolerance: Mild-to-moderate glucose intolerance may occur; generally is reversible.

• Hepatotoxicity: [U.S. Boxed Warning]: Liver dysfunction has been observed. Hepatotoxicity may be characterized by elevated transaminases and LDH, or by hypoalbuminemia; monitor liver function weekly. Hepatic dysfunction may require dosage reduction or discontinuation.

• Renal toxicity: [U.S. Boxed Warning]: Renal toxicity is dose-related and cumulative; may be severe or fatal. Azotemia, anuria, hypophosphatemia, glycosuria and renal tubular acidosis have been reported. Adequate hydration may reduce the risk for nephrotoxicity. Monitor renal function (BUN, serum creatinine, and serial urinalysis) and electrolytes prior to, weekly during, and after each treatment course. Mild proteinuria is an early sign of renal toxicity; if proteinuria is detected with urinalysis, obtain 24-hour urine collection. Avoid use in combination with other nephrotoxic medications. Use with caution in patients with pre-existing renal disease.

• Secondary malignancy: [U.S. Boxed Warning]: Streptozocin is mutagenic; parenteral use is tumorigenic and carcinogenic in animals.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician. Administer in a facility with sufficient access to lab and supportive resources for monitoring toxicities.

Monitoring Parameters

Renal function tests, including BUN, serum creatinine, and serial urinalysis, and serum electrolytes (at baseline, weekly during, and for 4 weeks after treatment); 24-hour urine collection if proteinuria is detected on urinalysis; liver function tests (weekly), CBC with differential and platelets (weekly), blood glucose; monitor infusion site

Pregnancy Risk Factor

D

Pregnancy Considerations

Teratogenic events have been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), severe nausea, vomiting, depression, confusion, loss of strength and energy, or severe injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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