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    Nitrosoureas

    BOXED WARNING

    Hypophosphatemia, nephrotoxicity, proteinuria, renal disease, renal failure, renal impairment, requires a specialized care setting, requires an experienced clinician

    Streptozocin-induced renal impairment is dose-related, cumulative, and may be severe or even fatal. Urinalysis, serum BUN and creatinine, and electrolyte concentrations as well as creatinine clearance should be assessed before, during, and for at least 4 weeks following therapy. Renal function should be determined before treatment initiation to avoid administering the drug to a patient with preexisting renal disease. Due to the additive and cumulative nature of streptozocin-induced nephrotoxicity, clinicians must judge the possible benefits of therapy versus risks in patients with renal impairment or renal failure. Hypophosphatemia and mild proteinuria are early signs of streptozocin-induced nephrotoxicity, which could lead to deterioration of kidney function. Adequate hydration may help reduce the risk of nephrotoxicity. Avoid use with other renal toxic agents. Dosage reduction or discontinuation should be considered if renal impairment develops. Adequate hydration may help reduce the risk of nephrotoxicity to renal tubular epithelium by decreasing renal and urinary concentration of the drug and its metabolites. Treatment requires an experienced clinician knowledgeable in the use of cancer chemotherapy. Administration requires a specialized care setting, where patients have access to facilities equipped and staffed with adequate laboratory and supportive medical services to monitor for drug toxicity and to care for patients compromised by these toxicities.

    Hepatic disease, hepatotoxicity

    Streptozocin should be used with caution in patients with hepatic disease. In animal models, streptozocin was found to accumulate in the liver and kidneys, and hepatotoxicity may occur. Liver function tests should be performed at least weekly, and dosage adjustments should be based upon toxicity. Only physicians experienced in the use of cancer chemotherapy should use streptozocin. Patients receiving streptozocin should have access to facilities equipped and staffed with adequate laboratory and supportive medical services to monitor for drug toxicity and to care for patients compromised by these toxicities.

    Chemotherapy-induced nausea/vomiting, diarrhea

    Severe chemotherapy-induced nausea/vomiting and diarrhea may be seen with the use of streptozocin and may be treatment-limiting.

    Accidental exposure, neoplastic disease, ocular exposure

    Streptozocin is mutagenic, and the risk of neoplastic disease should be considered prior to use. When administered parenterally, it has been found to be tumorigenic or carcinogenic in some rodent studies. Use care to avoid accidental exposure to streptozocin during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. Following skin or ocular exposure, skin and eyes should be thoroughly rinsed.

    DEA CLASS

    Rx

    DESCRIPTION

    Nitrosurea alkylating agent; natural product from Streptomyces achromogenes; seems to have specific activity in pancreatic cancers and some gastrointestinal tumors.

    COMMON BRAND NAMES

    Zanosar

    HOW SUPPLIED

    Zanosar Intravenous Inj Pwd F/Sol: 1g

    DOSAGE & INDICATIONS

    For the treatment of metastatic islet cell pancreatic cancer.
    NOTE: Due to the inherent toxicity of this agent, therapy with streptozocin should be limited to patients with symptomatic or progressive metastatic disease.
    Intravenous dosage
    Adults, Adolescents and Children

    500 mg/m2/day IV as a short daily or continuous infusion for 5 days every 4—6 weeks until the desired response or until toxicity has occurred. Daily doses above 500 mg/m2 are not recommended. Alternatively, a weekly course may be used as follows: 1000 mg/m2 IV weekly for first two weeks then maintained or increased as desired to no greater than 1500 mg/m2. A weekly course of 4—6 weeks is usually necessary.

    For the treatment of advanced carcinoid†.
    Intravenous dosage
    Adults

    500 mg/m2/day IV on days 1—5 every 10 weeks has been studied in combination with 5-fluorouracil (5-FU) 400 mg/m2/day IV on days 1—5 and 36—40, every 10 weeks. In a phase II/III clinical trial of 249 patients with unresectable advanced carcinoid tumor, streptozocin/5-FU improved overall survival compared to 5-FU/doxorubicin (24.3 months vs 15.7 months, p = 0.0267). The overall response rate (ORR) and progression-free survival were not significantly different. In clinical trials of various designs, ORR of 16—33% have been observed with streptozocin/5-FU.

    For the treatment of colorectal cancer†.
    Intravenous dosage
    Adults

    Dosage is not established. 500 mg/m2 IV weekly from day 1 in combination with methyl-CCNU 30 mg/m2/day on days 2—6, 5-fluorouracil (5-FU) 300 mg/m2/day IV on days 1—5 and 36—40, and vincristine 1 mg/m2 IV on days 1 and 36, repeated every 10 weeks, has been studied. Response rates in clinical trials of previously treated and previously untreated patients ranged from 10—34% with streptozocin based therapy. Significant nausea/vomiting and myelosuppression was observed in clinical trials.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1500 mg/m2/dose IV.

    Elderly

    1500 mg/m2/dose IV.

    Adolescents

    1500 mg/m2/dose IV.

    Children

    1500 mg/m2/dose IV.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; however, lower doses may be required to avoid excessive toxicity.

    Renal Impairment

    Dosage reduction or discontinuation of streptozocin treatment is recommended due to dose-related and cumulative nephrotoxicity.

    ADMINISTRATION

     
    CAUTION: Observe and exercise usual cautions for handling, preparing, and administering solutions of cytotoxic drugs.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Streptozocin is administered intravenously. Intra-arterial administration is not recommended because nephrotoxic effects may be evoked more rapidly.
    Adequate hydration may decrease nephrotoxic effects.
     
    Reconstitution:
    Reconstitute 1 g with 9.5 ml of D5W or NS injection to give a pale gold IV solution containing 100 mg/ml. May be further diluted with D5W, NS, or D5NS injection if desired.
     
    Direct IV injection
    Inject appropriate dose rapidly directly into a vein.
     
    Intermittent IV infusion
    Further dilute appropriate dose to allow infusion over 15 minutes to 6 hours.

    STORAGE

    Zanosar:
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Hypophosphatemia, nephrotoxicity, proteinuria, renal disease, renal failure, renal impairment, requires a specialized care setting, requires an experienced clinician

    Streptozocin-induced renal impairment is dose-related, cumulative, and may be severe or even fatal. Urinalysis, serum BUN and creatinine, and electrolyte concentrations as well as creatinine clearance should be assessed before, during, and for at least 4 weeks following therapy. Renal function should be determined before treatment initiation to avoid administering the drug to a patient with preexisting renal disease. Due to the additive and cumulative nature of streptozocin-induced nephrotoxicity, clinicians must judge the possible benefits of therapy versus risks in patients with renal impairment or renal failure. Hypophosphatemia and mild proteinuria are early signs of streptozocin-induced nephrotoxicity, which could lead to deterioration of kidney function. Adequate hydration may help reduce the risk of nephrotoxicity. Avoid use with other renal toxic agents. Dosage reduction or discontinuation should be considered if renal impairment develops. Adequate hydration may help reduce the risk of nephrotoxicity to renal tubular epithelium by decreasing renal and urinary concentration of the drug and its metabolites. Treatment requires an experienced clinician knowledgeable in the use of cancer chemotherapy. Administration requires a specialized care setting, where patients have access to facilities equipped and staffed with adequate laboratory and supportive medical services to monitor for drug toxicity and to care for patients compromised by these toxicities.

    Hepatic disease, hepatotoxicity

    Streptozocin should be used with caution in patients with hepatic disease. In animal models, streptozocin was found to accumulate in the liver and kidneys, and hepatotoxicity may occur. Liver function tests should be performed at least weekly, and dosage adjustments should be based upon toxicity. Only physicians experienced in the use of cancer chemotherapy should use streptozocin. Patients receiving streptozocin should have access to facilities equipped and staffed with adequate laboratory and supportive medical services to monitor for drug toxicity and to care for patients compromised by these toxicities.

    Chemotherapy-induced nausea/vomiting, diarrhea

    Severe chemotherapy-induced nausea/vomiting and diarrhea may be seen with the use of streptozocin and may be treatment-limiting.

    Bone marrow suppression, dental disease, dental work, herpes infection, infection, neutropenia, thrombocytopenia, varicella, viral infection

    Bone marrow suppression is modest when streptozocin is used alone. Patients with preexisting neutropenia and/or thrombocytopenia, should be allowed to regain normal hematopoiesis prior to initiating streptozocin therapy. Also, patients with an active infection should be treated prior to streptozocin therapy. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Complete blood counts should be done at least weekly; dosage adjustment should be based upon toxicity. Myelosuppressive effects of streptozocin can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Intramuscular injections

    Intramuscular injections should not be administered to patients with platelet counts < 50,000/mm3 who are receiving streptozocin. IM injections may cause bleeding, bruising, or hematomas due to streptozocin-induced thrombocytopenia.

    Diabetes mellitus

    Streptozocin should be used with caution in patients with diabetes mellitus. Streptozocin can cause hypoglycemia complicating diabetes therapy.

    Pregnancy

    Streptozocin, which crosses the placenta, is classified as FDA pregnancy risk category D. It is known to be teratogenic and/or abortifacient in laboratory animals. Additional hazards to the fetus include the possible effects of adverse reactions in the mother, similar adverse reactions in the fetus, and the known effects of alkylating agents on replicating cells. Streptozocin should only be used in pregnant women if the potential benefit justifies the potential risks to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking streptozocin.

    Breast-feeding

    Although it is unknown whether streptozocin is excreted into breast milk, its use during breast-feeding is generally not recommended due to the carcinogenic, teratogenic, and mutagenic effects of this agent.

    Accidental exposure, neoplastic disease, ocular exposure

    Streptozocin is mutagenic, and the risk of neoplastic disease should be considered prior to use. When administered parenterally, it has been found to be tumorigenic or carcinogenic in some rodent studies. Use care to avoid accidental exposure to streptozocin during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. Following skin or ocular exposure, skin and eyes should be thoroughly rinsed.

    Extravasation, intramuscular administration, subcutaneous administration

    Avoid extravasation of streptozocin during intravenous administration. Streptozocin is an irritant. Patients should be monitored for an injection site reaction during therapy with this agent. Intramuscular administration and subcutaneous administration of streptozocin should be avoided due to severe pain and irritation at the injection site.

    Vaccination

    Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy (such as streptozocin) should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    Driving or operating machinery

    Some patients may experience lethargy, confusion and depression following treatment with streptozocin. Patients should be warned to avoid driving or operating machinery until they know how the treatment will affect them.

    ADVERSE REACTIONS

    Severe

    diabetes insipidus / Delayed / 0-1.0
    renal tubular acidosis (RTA) / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    anuria / Delayed / Incidence not known
    insulin shock / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known

    Moderate

    thrombocytopenia / Delayed / 1.0-10.0
    neutropenia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    hypophosphatemia / Delayed / Incidence not known
    glycosuria / Early / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hypoalbuminemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    erythema / Early / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    vomiting / Early / 10.0
    nausea / Early / 10.0
    diarrhea / Early / Incidence not known
    skin irritation / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Aldesleukin, IL-2: (Moderate) The safety and efficacy of aldesleukin, IL 2 in combination with any antineoplastic agents have not been established. Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose aldesleukin, IL 2 and dacarbazine. Aldesleukin, IL 2 can decrease dacarbazine serum concentrations by increasing the volume of distribution of dacarbazine by 36 percent via an unknown mechanism.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Amikacin: (Moderate) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents, including aminoglycosides, could exacerbate the renal insult.
    Amiloride: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Aminoglycosides: (Moderate) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents, including aminoglycosides, could exacerbate the renal insult.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Atenolol; Chlorthalidone: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Azilsartan; Chlorthalidone: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Benazepril; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Bendroflumethiazide; Nadolol: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Bumetanide: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Candesartan; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Captopril; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely. Carbamazepine may potentially accelerate the hepatic metabolism of dacarbazine, DTIC.
    Celecoxib: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Chlorothiazide: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Chlorthalidone: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Chlorthalidone; Clonidine: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Cisplatin: (Moderate) Other nephrotoxic drugs, such as streptozocin, can aggravate the nephrotoxicity and electrolyte loss seen with cisplatin if given concurrently or shortly after cisplatin therapy.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Diclofenac: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diclofenac; Misoprostol: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diflunisal: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Diphenhydramine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diphenhydramine; Naproxen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Doxorubicin Liposomal: (Major) Streptozocin reduces doxorubicin's clearance possibly through inhibition of hepatic metabolism. Enhanced toxicity can be seen. Specific information regarding the affect on the clearance of liposomal doxorubicin formulations is not known.
    Doxorubicin: (Moderate) Streptozocin reduces doxorubicin's clearance possibly through inhibition of hepatic metabolism of doxorubicin. Enhanced toxicity can be seen.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Enalapril; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Esomeprazole; Naproxen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ethacrynic Acid: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Etodolac: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Famotidine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    Flurbiprofen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Foscarnet: (Moderate) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents, such as foscarnet, could exacerbate the renal insult.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Fosphenytoin: (Minor) In one case report, concomitant administration of phenytoin may diminish the cytotoxic activity of streptozocin on the pancreatic islet cells. Fosphenytoin may have similar effects.
    Furosemide: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Gentamicin: (Moderate) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents, including aminoglycosides, could exacerbate the renal insult.
    Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like streptozocin. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Losartan: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Moexipril: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Propranolol: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Quinapril: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Hydrocodone; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Oxycodone: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ifosfamide: (Moderate) Delayed renal clearance, and additive nephrotoxicity may occur in patients who have received or who are currently receiving nephrotoxic drugs, such as streptozocin, and are now receiving ifosfamide. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, kidney toxicity, and bone marrow suppression.
    Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like streptozocin. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Kanamycin: (Moderate) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents, including aminoglycosides, could exacerbate the renal insult.
    Ketoprofen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ketorolac: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lansoprazole; Naproxen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Loop diuretics: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Meloxicam: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Methyclothiazide: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Metolazone: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Nabumetone: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Sumatriptan: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Nonsteroidal antiinflammatory drugs: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Oxaprozin: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paromomycin: (Moderate) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents, including aminoglycosides, could exacerbate the renal insult.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy. Concurrent use of pegfilgrastim with nitrosoureas has not been evaluated.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenytoin: (Minor) Concomitant administration of phenytoin may diminish the cytotoxic activity of streptozocin on the pancreatic islet cells.
    Piroxicam: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Potassium-sparing diuretics: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Rofecoxib: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Sargramostim, GM-CSF: (Major) Sargramostim induces the proliferation of hematopoietic progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, sargramostim is contraindicated for use in patients during the 24 hours before or after cytotoxic chemotherapy.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Spironolactone: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Streptomycin: (Moderate) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents, including aminoglycosides, could exacerbate the renal insult.
    Sulindac: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Telavancin: (Moderate) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs such as streptozocin may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
    Thiazide diuretics: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Tobramycin: (Moderate) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents, including aminoglycosides, could exacerbate the renal insult.
    Tolmetin: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Torsemide: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Triamterene: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Valdecoxib: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Vancomycin: (Moderate) Concomitant use of parenteral vancomycin with other nephrotoxic drug, such as streptozocin, can lead to additive nephrotoxicity.

    PREGNANCY AND LACTATION

    Pregnancy

    Streptozocin, which crosses the placenta, is classified as FDA pregnancy risk category D. It is known to be teratogenic and/or abortifacient in laboratory animals. Additional hazards to the fetus include the possible effects of adverse reactions in the mother, similar adverse reactions in the fetus, and the known effects of alkylating agents on replicating cells. Streptozocin should only be used in pregnant women if the potential benefit justifies the potential risks to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking streptozocin.

    Although it is unknown whether streptozocin is excreted into breast milk, its use during breast-feeding is generally not recommended due to the carcinogenic, teratogenic, and mutagenic effects of this agent.

    MECHANISM OF ACTION

    Mechanism of Action: Streptozocin is considered a weak alkylating agent. Once injected, the drug undergoes rapid decomposition to form methylcarbonium ions, which alkylate DNA, causing interstrand crosslinking. Streptozocin also inhibits the synthesis of DNA by blocking the incorporation of a DNA precursor and by inhibiting cell proliferation. It has little effect on RNA synthesis. Due to the presence of a sugar moiety, streptozocin has a marked specificity for beta- and exocrine cells of the pancreas, and its uptake by these cells is enhanced.

    PHARMACOKINETICS

    Streptozocin is administered by IV injection and is rapidly decomposed to methylcarbonium ions. The metabolites tend to concentrate in the liver, kidneys, intestines, and pancreas. Although streptozocin does not appear to cross the blood-brain barrier, CSF concentrations of the drug's metabolites are equivalent to plasma concentrations. Streptozocin undergoes extensive metabolism in the liver and kidneys, and both unchanged drug and its metabolites are excreted in the urine, but only 15% of a dose is recovered. A small portion of a dose is excreted in expired air.

    Intravenous Route

    Following IV injection, streptozocin is rapidly decomposed to methylcarbonium ions. The metabolites tend to concentrate in the liver, kidneys, intestines, and pancreas.