Zanosar

Streptozocin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• diarrhea
• feeling tired
• depression

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• pain, itching, redness, swelling, blisters, or sores in the place where the medication was injected.
• nausea
• vomiting
• shakiness
• dizziness or lightheadedness
• sweating
• confusion
• nervousness or irritability
• sudden changes in behavior or mood
• headache
• numbness or tingling around the mouth
• sudden hunger
• seizures
• excessive thirst
• frequent urination

Streptozocin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Streptozocin is injected into a vein through an IV. A healthcare provider will give you this injection.

Streptozocin can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Call your doctor for instructions if you miss an appointment for your streptozocin injection.

Streptozocin can lower the activity of your immune system making you susceptible to infections. Avoid contact with people who have colds, the flu, or other contagious illnesses and do not receive vaccines that contain live strains of a virus (e.g., live oral polio vaccine) during treatment with streptozocin. In addition, avoid contact with individuals who have recently been vaccinated with a live vaccine. There is a chance that the virus can be passed on to you.

Treatment with streptozocin may cause drowsiness or confusion. Use caution when driving, operating machinery, or performing other hazardous activities if drowsiness or confusion occurs.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Zanosar, there are no specific foo

ds that you must exclude from your diet when receiving this medication.

You should not receive streptozocin if you have kidney or liver disease, a bleeding or blood-clotting disorder, or bone marrow suppression.

Streptozocin can harm your liver or kidneys, and may also cause severe vomiting or diarrhea.

While receiving streptozocin, you should be able to get to a hospital or emergency room quickly in case you have a serious side effect. You may need frequent blood tests to make sure streptozocin is not causing harmful effects.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using streptozocin, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

This medicine can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Pancreatic Islet Cell Carcinoma

Treatment of metastatic islet cell carcinoma of the pancreas;4 136 used alone3 13 26 33 34 35 36 37 38 40 41 42 43 71 72 or in combination with other antineoplastic agents (e.g., doxorubicin, fluorouracil).36 37 39 136

Effective in patients with functional4 13 33 34 35 36 37 38 40 41 42 43 48 49 50 51 52 71 72 73 84 85 86 87 88 89 99 100 101 102 or nonfunctional4 33 37 39 and beta13 33 34 35 36 37 38 40 41 42 43 48 49 50 51 52 71 72 or non-beta37 73 84 85 86 87 88 89 99 100 101 102 103 104 105 islet cell tumors. Appears to be equally effective against functional or nonfunctional islet cell tumors.33 37

Currently the most active single agent for treatment of metastatic islet cell carcinoma of the pancreas.3 26 33 34 35 36 37 38 40 Combination therapy with fluorouracil associated with higher overall and complete response rates; however, effect on survival not established.36 37 81 85 100

Because tumor may be indolent,37 61 122 and because of streptozocin’s nephrotoxic4 33 and emetogenic122 potential, limit use to symptomatic or progressive metastatic disease.4 33 122

Carcinoid Tumor and Syndrome

Palliative treatment of metastatic carcinoid tumor† or syndrome†.3 13 36 39 43 59 63 92 93 94 106 136

Used alone36 43 59 106 or in combination with other antineoplastic agents3 63 94 136 (e.g., cyclophosphamide,94 fluorouracil,94 136 cyclophosphamide with fluorouracil and doxorubicin3 ).

When used alone, objective responses were partial and of short duration.36 43 59 106 Exact role in combination chemotherapy not established.3 94

Pancreatic Adenocarcinoma

Treatment of pancreatic adenocarcinoma†.3 36 40 43 59 62 69 70 74 75 76 77 78 110 111

Minimally effective as single agent.36 40 43 59 Role in combination chemotherapy regimens not yet determined.3 76 77 122

Warnings/Precautions

Warnings

Highly toxic, with low therapeutic index; therapeutic response not likely to occur without some evidence of toxicity.3 4 8 13 33 (See Boxed Warning.)

Renal toxicity occurs in 25–75% of patients.3 13 33 43 59 Dose limiting and cumulative; may be severe or fatal.3 4 13 33 43 53 54 55 56 57 58 59

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]).3 4 8 13 32 33 40 43 53 54 55 56 57 58 59 Hypokalemia and hypocalcemia also have occurred.3

Hypophosphatemia8 13 53 56 or mild proteinuria4 13 33 40 59 may be earliest sign of nephrotoxicity and may indicate impending further deterioration of renal function.3 4 40 53 Increased BUN and Scr may occur later if streptozocin is continued.13

Mild adverse renal effects (e.g., mild proteinuria) may be reversible if streptozocin is discontinued; 3 13 however, nephrotoxicity may be irreversible or fatal if drug is continued despite nephrotoxic manifestations.3 13 33 39 56 57 58

Intra-arterial† administration may increase risk and/or precipitate more rapid development of nephrotoxicity.33 b (See Intra-arterial Infusion under Dosage and Administration.)

Nephrogenic diabetes insipidus reported rarely.4 135

Long-term effects on renal function not fully known.58 Cumulative, delayed nephrotoxicity and chronic renal failure reported rarely following discontinuance of streptozocin.58

Manufacturer recommends obtaining serial urinalyses, Clcr, BUN, Scr, and electrolyte concentrations prior to and at least weekly during streptozocin therapy and then weekly for 4 weeks after discontinuance of drug.4 Alternatively, some clinicians suggest that assessment of renal function prior to each course of therapy is sufficient in most patients.122 Serial urinalysis is particularly important for early detection of proteinuria; if proteinuria is detected, quantify with a 24-hour urine collection.4

Adequate hydration may help reduce risk of nephrotoxicity to renal tubular epithelium by decreasing renal and urinary concentrations of streptozocin and/or metabolites;4 8 13 however, role of hydration not clearly established.13 122

Reduce dosage or discontinue streptozocin if substantial renal toxicity occurs.4

Use in patients with impaired renal function only when benefits outweigh known risk of nephrotoxicity.4 (See Renal Impairment under Cautions.)

Do not use in combination or concomitantly with other potential nephrotoxins.4 (See Nephrotoxic Drugs under Interactions.)

Possible carcinogenic hazard from topical exposure if improperly handled.4 132

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.4 Use during pregnancy only when potential benefits justify possible risks to fetus.4

Major Toxicities

Severe nausea and vomiting occur in most patients (>90%),137 usually beginning 1–4 hours following administration; may persist for ≥24 hours.3 13 33 May require discontinuance of streptozocin.3 4 13 33 37 137

Incidence and/or severity of nausea and vomiting may be reduced with 5-day continuous IV infusions compared with rapid, intermittent IV administration.60

Aggressive antiemetic therapy during early courses of emetogenic chemotherapy is the best way to prevent anticipatory nausea and vomiting.137 Behavioral therapy may be useful; benzodiazepines also may be useful, although evidence is lacking.137

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);137 currently available selective 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron) are comparably effective.137

To prevent delayed emesis, ASCO recommends administration of a 2-drug regimen (dexamethasone and aprepitant) following administration of highly emetogenic chemotherapy.137

Diarrhea has occurred occasionally.3 4 33 Duodenal ulcer reported rarely; however, not directly associated with streptozocin.40

Mild to moderate myelosuppression (e.g., leukopenia, thrombocytopenia, anemia [decreased hematocrit and hemoglobin]) reported; 3 4 13 33 severe myelosuppression (e.g., substantial leukopenia and thrombocytopenia) leading to sepsis and death reported rarely.4 13 33 Cumulative and usually reversible;3 4 13 33 may be more severe in patients previously treated with other antineoplastic agents or radiation therapy.3 13 67 68 Leukocyte and platelet nadirs usually occur at 1–2 weeks after administration.13

Asymptomatic eosinophilia also reported; disappears following discontinuance of streptozocin.13 43 60

Monitor CBC at least weekly.4 Adjust dosage or discontinue streptozocin as needed.4

Minimal, transient increases in serum AST, ALT, LDH, and/or alkaline phosphatase concentrations reported.4 13 32 33 37 Increased serum bilirubin concentration33 and hypoalbuminemia also reported.4 Severe and fatal hepatic effects reported rarely.61

Manufacturer recommends performing liver function tests at least weekly;4 alternatively, some clinicians recommend monitoring liver function just prior to initiating each course of therapy.133 Adjust dosage or discontinue streptozocin as needed.4

Mild to moderate, reversible abnormalities of glucose tolerance reported in some patients.3 4 32 33 43 Insulin shock with severe hypoglycemia, requiring treatment with IV dextrose, has occurred rarely in patients with insulinomas,4 8 33 61 usually within 24 hours after administration.33

Glycosuria without hyperglycemia reported in some patients.32 33 40 43

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.4 Severe tissue lesions and necrosis also reported following extravasation.4 62

Burning sensation, extending from site of injection up the arm, reported in some patients, especially following rapid IV injection.3 33 40

Confusion, lethargy, and depression reported with continuous IV infusion for 5 days;4 60 not associated with other methods of administration.3

General Precautions

Monitor closely, particularly for evidence of adverse renal, hematologic, and hepatic effects.4 (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.4 33

Specific Populations

Category D.4 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether streptozocin is distributed into milk.4 Discontinue nursing because of potential risk to nursing infants.b

Safety and efficacy not established.63 132

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.4 Select dosage with caution, usually starting at low end of dosage range. 4 (See Geriatric Patients under Dosage and Administration.)

Weigh benefit against risk of serious renal damage.4 (See Renal Effects under Cautions.) Dosage adjustments necessary based on degree of renal impairment.120 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Severe nausea and vomiting,3 4 13 33 37 137 nephrotoxicity,3 4 13 53 54 55 56 57 58 myelosuppression.3 4 13 33

Along with their needed effects, medicines like streptozocin can sometimes cause unwanted effects such as kidney problems and other side effects. These and others are described below. Also, because of the way these medicines act on the body, there is a chance that they might cause other unwanted effects that may not occur until months or years after the medicine is used. These delayed effects may include certain types of cancer, such as leukemia. Streptozocin has been shown to cause tumors (some cancerous) in animals. Discuss these possible effects with your doctor.

Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Anxiety, nervousness, or shakiness
• chills, cold sweats, or cool, pale skin
• drowsiness or unusual tiredness or weakness
• fast pulse
• headache
• pain or redness at place of injection
• unusual hunger

Check with your doctor immediately if any of the following side effects occur:

• Black, tarry stools
• blood in urine or stools
• cough or hoarseness
• fever or chills
• lower back or side pain
• painful or difficult urination
• pinpoint red spots on skin
• unusual bleeding or bruising

Check with your doctor as soon as possible if any of the following side effects occur:

• Swelling of feet or lower legs
• unusual decrease in urination

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Nausea and vomiting (usually occurs within 2 to 4 hours after receiving dose and may be severe)

• Diarrhea

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Decrease in urination
• swelling of feet or lower legs

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat pancreatic cancer.
• It may be given to you for other reasons. Talk with the doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Very upset stomach or throwing up.
• Low mood (depression).
• Feeling confused.
• Feeling very tired or weak.
• This medicine may cause tissue damage if the drug leaks from the vein. Tell your nurse if you have any redness, burning, pain, swelling, blisters, skin sores, or leaking of fluid where the drug is going into your body.

• If you need to store Zanosar at home, talk with your doctor, nurse, or pharmacist about how to store it.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Applies to streptozocin: intravenous powder for solution

Along with their needed effects, medicines like streptozocin (the active ingredient contained in Zanosar) can sometimes cause unwanted effects such as kidney problems and other side effects. These and others are described below. Also, because of the way these medicines act on the body, there is a chance that they might cause other unwanted effects that may not occur until months or years after the medicine is used. These delayed effects may include certain types of cancer, such as leukemia. Streptozocin has been shown to cause tumors (some cancerous) in animals. Discuss these possible effects with your doctor.

Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking streptozocin:

• Anxiety, nervousness, or shakiness
• chills, cold sweats, or cool, pale skin
• drowsiness or unusual tiredness or weakness
• fast pulse
• headache
• pain or redness at place of injection
• unusual hunger

Check with your doctor immediately if any of the following side effects occur while taking streptozocin:

• Black, tarry stools
• blood in urine or stools
• cough or hoarseness
• fever or chills
• lower back or side pain
• painful or difficult urination
• pinpoint red spots on skin
• unusual bleeding or bruising

Check with your doctor as soon as possible if any of the following side effects occur while taking streptozocin:

• Swelling of feet or lower legs
• unusual decrease in urination

Some side effects of streptozocin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Nausea and vomiting (usually occurs within 2 to 4 hours after receiving dose and may be severe)

• Diarrhea

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Decrease in urination
• swelling of feet or lower legs