Streptozocin

Dosage Forms

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

Solution Reconstituted, Intravenous:

Zanosar: 1 g (1 ea)

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Distribution

Concentrates in liver, kidney, and pancreatic beta cells

Metabolism

Rapid; primarily hepatic

Excretion

Urine (primarily; as parent drug and metabolites)

Onset of Action

1,500 mg/m² once weekly: Onset of response: 17 days; median time to maximum response: 35 days

Half-Life Elimination

<1 hour (Perry 2012)

Use: Labeled Indications

Pancreatic neuroendocrine tumors: Treatment of metastatic islet cell carcinoma of the pancreas (symptomatic or progressive disease)

Use: Off Label

Adrenocortical carcinoma, metastatica

Data from a randomized, controlled, open-label, parallel-group study supports the use of streptozocin in the treatment of metastatic adrenocortical carcinoma. In this phase III study comparing mitotane in combination with etoposide, doxorubicin, and cisplatin (EDP regimen), to streptozocin in combination with mitotane, the response rate and progression free survival were significantly better with the EDP arm, although there was no difference in overall survival between the groups Fassnacht 2012. Data from a phase II study evaluating streptozocin (in combination with mitotane) also supports the use of streptozocin in the treatment of metastatic adrenal carcinoma; either complete or partial response occurred in 36.4% of patients resulting in a 2 year survival of 70% and a 5 year survival rate of 32.5% Khan 2000.

Gastrointestinal neuroendocrine tumorsb

Data from a phase II/III randomized study supports the use of streptozocin (in combination with fluorouracil) in the treatment of gastrointestinal neuroendocrine (carcinoid) tumors Sun 2005 [LOE B]. Additionally, a small number of patients with gastrointestinal neuroendocrine tumors (GiNETs) were included in a study evaluating response to streptozocin (in combination with fluorouracil, leucovorin, and cisplatin) in patients with neuroendocrine tumors (including pancreatic and GI tumors); while patients with pancreatic neuroendocrine tumors had a higher response rate, patients with GiNETs also demonstrated objective responses and stable disease Turner 2010 [LOE C].

Contraindications

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

Dosage and Administration

Dosing: Adult

Note: Streptozocin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

Adrenocortical carcinoma, metastatic (off-label use): IV: 1,000 mg once daily for 5 days (cycle 1) followed by 2,000 mg on day 1 (subsequent cycles) every 3 weeks until disease progression or unacceptable toxicity (in combination with mitotane) (Fassnacht 2012; Khan 2000).

Gastrointestinal neuroendocrine tumors (off-label use): IV: 500 mg/m² on days 1 to 5 every 10 weeks (in combination with fluorouracil) until disease progression or unacceptable toxicity (Sun 2005) or 1,000 mg/m² once every 3 weeks for 3 cycles, if no progression may continue for up to a total of 6 cycles in the absence of unacceptable toxicity (in combination with leucovorin, fluorouracil and cisplatin) (Turner 2010).

Pancreatic neuroendocrine tumors (metastatic): IV:

Daily schedule: 500 mg/m² once daily for 5 consecutive days every 6 weeks (in combination with either doxorubicin or fluorouracil) until disease progression or unacceptable toxicity (Moertel 1992)

Weekly schedule: 1,000 mg/m² once weekly; if therapeutic response not achieved after 2 weeks, may escalate dose to a maximum of 1,500 mg/m² weekly

Alternate schedules (off-label dosing): 1,000 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) or 500 mg/m² on days 1 to 5 every 5 or 6 weeks (in combination with fluorouracil) for up to 1 year if best response is stable disease (Dilz 2015)

Dosing: Geriatric

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

Dosing: Adjustment for Toxicity

Bone marrow suppression: 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

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

IV: Streptozocin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).

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.

Storage

Store intact vials 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

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

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

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Consider therapy modification

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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Frequency not defined.

Endocrine & metabolic: Decreased glucose tolerance, glycosuria, hyperglycemia, hypoalbuminemia, hypoglycemia, hypophosphatemia, increased lactate dehydrogenase

Gastrointestinal: Diarrhea, nausea, vomiting

Genitourinary: Anuria, azotemia, nephrotoxicity, proteinuria

Hepatic: Increased serum transaminases

Local: Injection site reaction (includes burning sensation at injection site, erythema at injection site, inflammation at injection site, irritation at injection site, swelling at injection site, tenderness at injection site)

Renal: Increased blood urea nitrogen, increased serum creatinine, renal insufficiency, renal tubular acidosis

<1%, postmarketing, and/or case reports: Anemia, bone marrow depression (nadir: 2 to 3 weeks), confusion, depression, diabetes insipidus, hepatic insufficiency, lethargy, leukopenia, metastases, thrombocytopenia

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Hematologic toxicity has been observed. Mild bone marrow suppression (rare) may occur (usually mild anemia); 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: [US 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 (Dupuis 2011; Hesketh 2017; Roila 2016).
• Glucose intolerance: Mild-to-moderate glucose intolerance may occur; generally is reversible. Insulin shock with hypoglycemia has been observed.
• Hepatotoxicity: [US 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: [US 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: [US Boxed Warning]: Streptozocin is mutagenic; parenteral use is tumorigenic and carcinogenic in animals.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Experienced physician: [US 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

Pregnancy Considerations

Adverse 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 severe or persistent bleeding), signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating), severe nausea, vomiting, depression, confusion, severe loss of strength and energy, or severe injection site redness, pain, edema, 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 health care 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.