Fludarabine

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.

Do not receive a "live" vaccine while using fludarabine, 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.

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

Other drugs may interact with fludarabine, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

(See BOXED WARNINGS)

Dose Dependent Neurologic Toxicities

There are clear dose-dependent toxic effects seen with FLUDARA (fludarabine) FOR INJECTION. Dose levels approximately 4 times greater (96 mg/m²/day for 5 to 7 days) than that recommended for CLL (25 mg/m²/day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 to 60 days following the last dose. Thirteen of 36 patients (36%) who received FLUDARA (fludarabine) FOR INJECTION at high doses (96 mg/m²/day for 5 to 7 days) developed this severe neurotoxicity. Similar severe central nervous system toxicity, including coma, seizures, agitation and confusion, has been reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.

In postmarketing experience neurotoxicity has been reported to occur either earlier or later than in clinical trials (range 7 to 225 days).

The effect of chronic administration of FLUDARA (fludarabine) FOR INJECTION on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy.

Bone Marrow Suppression

Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with FLUDARA (fludarabine) FOR INJECTION. In a Phase I study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3-25 days) for granulocytes and 16 days (range, 2-32) for platelets. Most patients had hematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of FLUDARA (fludarabine) FOR INJECTION requires careful hematologic monitoring.

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients.

Autoimmune Reactions

Instances of life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur after one or more cycles of treatment with FLUDARA (fludarabine) FOR INJECTION in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs' test and who may or may not be in remission from their disease. Steroids may or may not be effective in controlling these hemolytic episodes. The majority of patients rechallenged with FLUDARA (fludarabine) FOR INJECTION developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified. Patients undergoing treatment with FLUDARA (fludarabine) FOR INJECTION should be evaluated and closely monitored for hemolysis. Discontinuation of therapy with FLUDARA (fludarabine) FOR INJECTION is recommended in case of hemolysis.

Transfusion Associated Graft-Versus-Host Disease

Transfusion-associated graft-versus-host disease has been observed after transfusion of nonirradiated blood in FLUDARA (fludarabine) FOR INJECTION treated patients. Fatal outcome as a consequence of this disease has been reported. Therefore, to minimize the risk of transfusionassociated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received, treatment with FLUDARA (fludarabine) FOR INJECTION should receive irradiated blood only.

Pulmonary Toxicity

In a clinical investigation using FLUDARA (fludarabine) FOR INJECTION in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of FLUDARA (fludarabine) FOR INJECTION in combination with pentostatin is not recommended.

Pregnancy Category D

Based on its mechanism of action, fludara (fludarabine) bine phosphate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of FLUDARA FOR INJECTION in pregnant women. Fludara (fludarabine) bine administered to rats and rabbits during organogenesis caused an increase in resorptions, skeletal and visceral malformations and decreased fetal body weights. If FLUDARA (fludarabine) FOR INJECTION 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.

Male Fertility and Reproductive Outcomes

Males with female sexual partners of childbearing potential should use contraception during and after cessation of FLUDARA FOR INJECTION therapy. Fludara (fludarabine) bine may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain. [See PRECAUTIONS, Impairment of Fertility]

Fludarabine is a prescription medication used to treat adult patients with chronic lymphocytic leukemia (CLL). Chronic lymphocytic leukemia is a type of cancer of the white blood cells.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information. 

Before receiving fludarabine, tell your doctor about all your medical conditions including if you have:

• kidney disease
• previously been treated with other chemotherapy medications or radiation therapy

Tell your doctor if you are:

• allergic to any ingredient in fludarabine or any other medication
• pregnant or breastfeeding

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Do not use fludarabine if you are pregnant. It could harm the unborn baby.

Use birth control to prevent pregnancy while you are receiving fludarabine, whether you are a man or a woman. Fludarabine use by either parent may cause birth defects.

Before you receive fludarabine, tell your doctor if you have kidney disease, bone marrow problems or a weak immune system, any active infection, a history of skin cancer, or a history of a viral infection such as herpes zoster (shingles), Epstein-Barr, or a virus affecting the central nervous system.

If you need to have a blood transfusion, tell your caregivers ahead of time that you are being treated with fludarabine.

Fludarabine can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often. Visit your doctor regularly.

Do not receive a "live" vaccine while using fludarabine, 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.

Contact your doctor at once if you develop signs of infection such as fever, chills, sore throat, flu symptoms, easy bruising or bleeding (nosebleeds, bleeding gums), loss of appetite, nausea and vomiting, mouth sores, or unusual weakness.

It is very important that your doctor check your progress at regular visits to make sure that fludarabine is working properly. Blood tests may be needed to check for unwanted effects.

Fludarabine can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection (e.g., pneumonia). It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of an infection or bleeding:

• If you can, avoid people with infections. Check with your doctor right away if you think you are getting an infection or if you have fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination; shortness of breath; or unusual bleeding or bruising.
• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

You should not use fludarabine if you are also taking pentostatin (Nipent®). Taking it together with fludarabine may increase the chance of serious side effects.

fludarabine may cause a serious type of reaction called tumor lysis syndrome. Your doctor may give you a medicine to help prevent this. Call your doctor right away if you have a decrease or change in urine amount; joint pain, stiffness, or swelling; lower back, side, or stomach pain; a rapid weight gain; swelling of the feet or lower legs; or unusual tiredness or weakness.

Using fludarabine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. You should not become pregnant while you are taking fludarabine and for 6 months after stopping it. If you think you have become pregnant while using the medicine, tell your doctor right away.

High doses of Fludarabine phosphate, USP (see WARNINGS section) have been associated with an irreversible central nervous system toxicity characterized by delayed blindness, coma, and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for Fludarabine phosphate, USP overdosage. Treatment consists of drug discontinuation and supportive therapy.

Usual Dose: The recommended adult dose of Fludarabine Phosphate for Injection, USP is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days. Each 5 day course of treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

A number of clinical settings may predispose to increased toxicity from Fludarabine phosphate, USP. These include advanced age, renal insufficiency, and bone marrow impairment. Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of Fludarabine phosphate, USP be administered following the achievement of a maximal response and then the drug should be discontinued.

Renal Insufficiency: Adult patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have a 20% dose reduction of Fludarabine phosphate, USP. Fludarabine phosphate, USP should not be administered to patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m2).

Preparation of Solutions: Fludarabine Phosphate for Injection, USP should be prepared for parenteral use by aseptically adding Sterile Water for Injection, USP. When reconstituted with 2 mL of Sterile Water for Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg of Fludarabine phosphate, USP, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2 to 8.2. In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection, USP or 0.9% Sodium Chloride, USP.

Reconstituted Fludarabine Phosphate for Injection, USP contains no antimicrobial preservative and thus should be used within 8 hours of reconstitution. Care must be taken to assure the sterility of prepared solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Fludarabine Phosphate for Injection, USP should not be mixed with other drugs.

Handling and Disposal: Procedures for proper handling and disposal should be considered. Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published.1-4

Caution should be exercised in the handling and preparation of Fludarabine Phosphate for Injection, USP solution. The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.

• 2F-ara-AMP
• Fludara
• Fludarabine Monophosphate
• Fludarabine Phosphate

Reconstitute lyophilized powder with 2 mL SWFI to a concentration of 25 mg/mL.

Dilute for infusion in 100 to 125 mL D5W or NS.

IV: The manufacturer recommends administering over ~30 minutes (for the treatment of CLL). Continuous infusions and IV bolus over 15 minutes have been used for some off-label protocols (refer to individual studies for infusion rate details).

Oral: Tablet [Canadian product] may be administered with or without food; should be swallowed whole with water; do not chew, break, or crush.