In Treatment of:
Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia, producing higher response rates than alkylating agents such as chlorambucil alone. Fludarabine is used in various combinations with cyclophosphamide, mitoxantrone, dexamethasone and rituximab in the treatment of indolent non-Hodgkins lymphomas. As part of the FLAG regimen, fludarabine is used together with cytarabine and granulocyte colony-stimulating factor in the treatment of acute myeloid leukaemia. Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to non myeloablative allogeneic stem cell transplant.
Fludarabine is associated with profound lymphopenia, and as a consequence, increases the risk of opportunistic infections significantly. Patients who have been treated with fludarabine will usually be asked to take co-trimoxazole or to use monthly nebulised pentamidine to prevent Pneumocystis jiroveci pneumonia. The profound lymphopenia caused by fludarabine renders patients susceptible to transfusion-associated graft versus host disease, a fatal complication of blood transfusion. For this reason, all patients who have ever received fludarabine should only be given irradiated blood components.
Fludarabine causes anemia, thrombocytopenia and neutropenia, requiring regular blood count monitoring. Some patients require blood and platelet transfusion, or G-CSF injections to boost neutrophil counts.
Fludarabine is associated with the development of severe autoimmune hemolytic anemia in a proportion of patients.
Difficulties are often encountered when harvesting peripheral blood stem cells from patients previously treated with fludarabine.
Check with your physician if you have any of the following:
Feeling Restless, Toxic Effect on Brain or Spinal Cord Function, Immune Reaction Causing Low Platelet Count, Problems with Eyesight, Sudden Blindness and Pain Upon Moving the Eye, Disease of the Optic Nerve, Progressive Disease in the White Matter of the Brain, Acquired Factor VIII Deficiency Disease, Evans' Syndrome, Infection caused by Bacteria, Abnormal Heart Rhythm, Suddenly Serious Symptoms of Heart Failure, Shingles, Inflammation in Lungs caused by Allergic Reaction, Interstitial Pneumonitis, Uric Acid Kidney Stones, Serious Kidney Problems, Mild to Moderate Kidney Impairment, Coma, Seizures, Visible Water Retention, Abnormal Liver Function Tests, Pregnancy, A Mother who is Producing Milk and Breastfeeding, Infection caused by a Fungus, Severe Infection, Increased Uric Acid due to Cancer Chemotherapy, Destruction of Red Blood Cells by Body's Own Antibodies, Acquired Low Blood Count due to Destruction of Red Cells, Acquired Decrease of All Cells in the Blood, Decreased Function of Bone Marrow, Anemia, Low Platelet Count and Bleeding from Immune Response, Decreased Neutrophils a Type of White Blood Cell, Confused
Before starting fludarabine treatment, make sure you tell your doctor about any other medications you are taking (including prescription, over-the-counter, vitamins, herbal remedies, etc.). Do not take aspirin, or products containing aspirin unless your doctor specifically permits this.
Do not receive any kind of immunization or vaccination without your doctor's approval while taking fludarabine.
Inform your health care professional if you are pregnant or may be pregnant prior to starting this treatment. Pregnancy category D (fludarabine may be hazardous to the fetus. Women who are pregnant or become pregnant must be advised of the potential hazard to the fetus).
For both men and women: Do not conceive a child (get pregnant) while taking fludarabine. Barrier methods of contraception, such as condoms, are recommended. Discuss with your doctor when you may safely become pregnant or conceive a child after therapy.
Do not breast feed while taking this medication.
You may be at risk of infection so try to avoid crowds or people with colds and those not feeling well, and report fever or any other signs of infection immediately to your health care provider.
Wash your hands often.
Use an electric razor and a soft toothbrush to minimize bleeding.
Avoid contact sports or activities that could cause injury.
To reduce nausea, take anti-nausea medications as prescribed by your doctor, and eat small, frequent meals.
Drink at least two to three quarts of fluid every 24 hours, unless you are instructed otherwise.
In general, drinking alcoholic beverages should be kept to a minimum or avoided completely. You should discuss this with your doctor.
Acetaminophen or ibuprophen may help relieve discomfort from fever, headache and/or generalized aches and pains. However, be sure to talk with your doctor before taking it.
Get plenty of rest.
Maintain good nutrition.
If you experience symptoms or side effects, be sure to discuss them with your health care team. They can prescribe medications and/or offer other suggestions that are effective in managing such problems.
Monitoring and testing:
You will be checked regularly by your health care professional while you are taking fludarabine, to monitor side effects and check your response to therapy. Periodic blood work to monitor your complete blood count (CBC) as well as the function of other organs (such as your kidneys and liver) will also be ordered by your doctor.
Usual Adult Dose for Chronic Lymphocytic Leukemia
25 mg/m2 IV once over 30 minutes for 5 days every 28 days. Following a maximal tumor response, 3 additional cycles are recommended.
40 mg/m2 once daily for 5 days every 28 days
Fludarabine phosphate can be taken either on an empty stomach or with food. The tablets have to be swallowed whole with water; they should not be chewed or broken.
Usual Adult Dose for non-Hodgkin's Lymphoma
25 mg/m2/day for 5 days every 28 days
Usual Pediatric Dose for Malignant Disease
Solid tumors: 7 to 9 mg/m2 IV bolus followed by 20 to 27 mg/m2/day continuous IV infusion for 5 days
Usual Pediatric Dose for Leukemia
Acute leukemia: 10 mg/m2 IV once over 15 minutes followed by continuous IV infusion of 30.5 mg/m2/day for 5 days or 10.5 mg/m2 IV once over 15 minutes followed by continuous IV infusion of 30.5 mg/m2/day for 2 days followed by cytarabine.
Usual Pediatric Dose for Stem Cell Transplant Conditioning
Reduced-intensity conditioning regimen prior to allogenic hematopoietic stem cell transplantation: 30 mg/m2/day for 5 days
Renal Dose Adjustments
CrCl 30-70 mL/min/1.73 m2:
Reduce dose by 20% and monitor closely for toxicity
CrCl less than 30 mL/min/1.73 m2:
IV: Not recommended for use
Oral (adults): Administer 50% of dose.
Liver Dose Adjustments
Caution is recommended
The recommended dose of fludarabine may depend on whether other cytotoxic agents are coadministered. Reference to specific protocols is recommended.
Delay or decrease doses in cases of hematologic or other serious toxicities. In case of hemolysis, treatment should be discontinued.
Neurotoxicity: Consider treatment delay or discontinuation
Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia have been associated with the use of fludarabine.
There are no data specifically regarding use in dialysis. However, the following guidelines should be noted:
CrCl less than 30 mL/min/1.73 m2:
IV: Not recommended for use
Oral (adults): Administer 50% of dose
The recommended adult dose of fludarabine FOR INJECTION 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 FOR INJECTION. These include advanced age, renal impairment, 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 FOR INJECTION be administered following the achievement of a maximal response and then the drug should be discontinued.
Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30-79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. fludarabine FOR INJECTION should not be administered to patients with creatinine clearance less than 30 mL/min.
Starting Dose Adjustment for Renal Impairment
CREATININE CLEARANCE STARTING DOSE
≥ 80 mL/min 25 mg/m² (full dose)
50 - 79 mL/min 20 mg/m²
30 - 49 mL/min 15 mg/m²
< 30 mL/min do not administer
Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.
Preparation of Solutions
Fludarabine FOR INJECTION 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 bine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2-8.2. 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 FOR INJECTION 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 FOR INJECTION 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 FOR INJECTION 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.