Fludara

Fludarabine injection is also sometimes used to treat non-Hodgkin's lymphoma (NHL; cancer that begins in a type of white blood cell that normally fights infection) and mycosis fungoides (a type of lymphoma that affects the skin). Talk to your doctor about the risks of using this medication for your condition.

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

• Genzyme Corporation

Tell your healthcare provider if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy. Fludara falls into category D. It is not known if Fludara will harm your unborn baby. Because Fludara has the potential to harm your unborn baby, take precautions to avoid pregnancy during Fludara therapy and for at least 6 months after treatments.

Tell your healthcare provider right away if you become pregnant while receiving this medication.

The dose your doctor recommends will be determined based on your height and weight, your medical conditions, other medicines you take, and other factors.

The usual recommended Fludara dose is 25 mg per m² infused (injected into a vein) over 30 minutes, once daily, for five days in a row. This cycle may be repeated every 28 days.

Your doctor may recommend a lower dosage if you have kidney disease or a delay in treatment if you experience severe side effects.

Contraindications

• Known hypersensitivity to fludarabine and/or any ingredient in the formulation.1 95

Warnings/Precautions

Warnings

Severe, potentially irreversible or fatal neurologic effects (e.g., delayed, progressive encephalopathy and blindness, coma) reported;1 2 3 5 6 9 29 30 31 45 95 manifestations usually appear 21–60 days after completion of a course of therapy.1 2 29 30 31 95

Neurotoxicity appears to be dose related:1 2 3 6 9 29 30 31 45 95 usually occurring with dosages higher than those currently recommended for CLL.1 2 3 5 6 9 29 30 31 41 45 However, such toxicity may occur rarely at relatively low dosages.1 3 5 9 30 45 52 95

Monitoring for visual changes as evidence of neurotoxicity has been suggested.30

Risk of severe, cumulative, often reversible, myelosuppression (e.g., anemia, thrombocytopenia, neutropenia).1 2 3 4 5 6 9 22 23 39 95 95

Dosage adjustment and interruption of therapy and/or transfusions may be needed depending on severity of myelosuppression.9 Recovery of neutrophil and platelet count usually is complete within 5–7 weeks after discontinuance of therapy, but occasionally may require longer periods.87

Risk of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes fatal.1 95 Clinically significant cytopenia may last 2–12 months.1 95

Risk of life-threatening and sometimes fatal autoimmune hemolytic anemia, may recur upon rechallenge; close monitoring for hemolysis recommended.1 95 Not known whether corticosteroids are beneficial for management of these hemolytic episodes.1 95

Possible transfusion-associated graft-versus-host disease following transfusion of nonirradiated blood products.1 95 Consider use of irradiated blood products in patients requiring blood transfusions.1 95

Risk of severe and/or fatal pulmonary toxicity (e.g., pneumonitis) when administered concomitantly with pentostatin; do not use fludarabine with pentostatin.1 8 87 95 (See Specific Drugs under Interactions.)

May cause fetal harm (skeletal malformations, external deformities); avoid pregnancy during therapy.1 95

Use during pregnancy only in life-threatening situations or severe disease when safer drugs cannot be used or are ineffective.80 87

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 95

Sensitivity Reactions

Possible pulmonary hypersensitivity (diffuse interstitial pneumonitis characterized by dyspnea, hypoxia, cough, and pulmonary infiltrates).1 3 5 6 9 35 60 51 95

Interstitial pneumonitis usually delayed, occurring 3–28 days after administration of the third or later course of therapy.2 5 6 35 50

General Precautions

Highly toxic, very low therapeutic index; therapeutic response is unlikely without some evidence of toxicity.1 3 4 5 6 9 29 30 31 41 45 (See Boxed Warning.) Severe toxicity most likely in poor risk patients (e.g., geriatric patients, those with impaired renal or bone marrow function), but fatality may occur in those in relatively good condition.

Administer only under supervision of a qualified clinician experienced in the use of cytotoxic therapy.1 9 95

Closely observe for signs of hematologic and nonhematologic toxicity during therapy.1 30 65 95

If severe adverse effects occur, discontinue therapy or reduce dosage and institute appropriate measures as necessary.1 9 65 87 95

May occur as a result of CLL treatment.1 3 6 9 53 65 95

Increased risk in patients with large initial tumor burden.1 95

Closely monitor such patients and take appropriate precautions.1 95 Consider potential benefit of prophylactic allopurinol, adequate hydration, and/or urinary alkalinization.53 65 80 87

Specific Populations

Category D.

Not known whether fludarabine is distributed into milk.1 95 Discontinue nursing or the drug.1 95

Safety and efficacy not established.1 80 87 95

In clinical studies in a limited number of pediatric patients with certain cancers (e.g., acute leukemia, solid tumors),2 5 43 adverse effect profile generally was similar to that in adults.5 43 87

Bone marrow suppression (particularly thrombocytopenia), fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection were reported.1 95 Pulmonary hypersensitivity and peripheral neuropathy not reported.1 95

Safety and efficacy in geriatric patients have not been studied specifically to date; however, CLL, for which safety and efficacy have been established,1 2 3 4 6 9 14 15 20 21 58 occurs principally in patients >50 years of age.24 58 61

Possible increased risk of fludarabine-induced toxicity due to age-related decrease in renal function.1 26 95 Closely monitor such patients (especially those with advanced Rai stage CLL)4 and adjust dosage accordingly.1 95

Clearance of fludarabine directly correlates with creatinine clearance.1 41 80 87 95

Possible increased risk of fludarabine-induced toxicity;1 2 3 95 monitor closely for excessive toxicity.1 95

Adjust dosage carefully in patients with impaired renal function;1 41 80 87 95 reduce dosage in those with moderate renal impairment.1 95 Do not use fludarabine in patients with severe renal impairment.1 95 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea and/or vomiting,1 2 3 4 6 9 22 23 95 anorexia,1 9 95 diarrhea,1 3 4 6 22 95 GI bleeding,1 9 95 fever,1 3 4 22 95 chills,1 95 rash,1 2 3 4 6 9 22 95 urinary tract infection,1 9 95 edema,1 3 9 95 cough,1 4 95 dyspnea,1 4 95 upper respiratory infection,1 9 95 infection,1 3 4 22 38 95 weakness,1 3 9 95 pain,1 9 95 malaise,1 9 22 95 fatigue,1 9 22 95 paresthesia,1 3 9 95 visual disturbances.19 23 39

Storage

Parenteral

2–8°C.1 Do not store at room temperature.80

Use reconstituted and diluted solutions within 8 hours after preparation.1 11 80

2–8°C.95

Discard unused solution within 8 hours after initial entry into vial.95 80

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Drug Compatibility

• Importance of immediately informing clinician if fever, sore throat, or unusual bleeding or bruising occurs.80 87

• Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy, advise pregnant women of risk to the fetus.1 95 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1 95

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

• If you have an allergy to fludarabine or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have kidney disease.
• If you have a type of anemia called hemolytic anemia.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with Fludara.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.

Phase I studies in humans have demonstrated that Fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion. Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as approximately 20 hours. In vitro, plasma protein binding of Fludarabine ranged between 19% and 29%.

A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC).

Special Populations

Limited pharmacokinetic data for Fludara FOR INJECTION are available from a published study of children (ages 1-21 years) with refractory acute leukemias or solid tumors (Children’s Cancer Group Study 097). When Fludara FOR INJECTION was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early.

The total body clearance of the principal metabolite 2-fluoro-ara-A correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. Renal clearance represents approximately 40% of the total body clearance. Patients with creatinine clearance 30-79 mL/min should have their Fludara FOR INJECTION dose reduced and be monitored closely for excessive toxicity. Due to insufficient data, Fludara FOR INJECTION should not be administered to patients with creatinine clearance less than 30 mL/min. (See DOSAGE AND ADMINISTRATION section).

Very common adverse events include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, fatigue, weakness, infection, pneumonia, cough, nausea, vomiting, and diarrhea. Other commonly reported events include malaise, mucositis and anorexia. Serious opportunistic infections (such as latent viral reactivation, herpes zoster virus, Epstein-Barr virus, and progressive multifocal leukoencephalopathy) have occurred in CLL patients treated with Fludara FOR INJECTION.  Adverse events and those reactions which are more clearly related to the drug are arranged below according to body system.

Hematopoietic Systems

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with Fludara FOR INJECTION. During Fludara FOR INJECTION treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with Fludara FOR INJECTION.

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in post-marketing surveillance.  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.

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 in patients receiving Fludara FOR INJECTION (see WARNINGS section). The majority of patients rechallenged with Fludara FOR INJECTION developed a recurrence in the hemolytic process.

In post-marketing experience, cases of myelodysplastic syndrome and acute myeloid leukemia, mainly associated with prior, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors, or irradiation have been reported. 

Infections

Serious and sometimes fatal infections, including opportunistic infections and reactivations of latent viral infections such as VZV (herpes zoster), Epstein-Barr virus and JC virus (progressive multifocal leukoencephalopathy) have been reported in patients treated with Fludara FOR INJECTION.

Rare cases of Epstein-Barr virus (EBV) associated lymphoproliferative disorders have been reported in patients treated with Fludara FOR INJECTION.

In post-marketing experience, cases of progressive multifocal leukoencephalopathy have been reported. Most cases had a fatal outcome. Many of these cases were confounded by prior and/or concurrent chemotherapy. The time to onset has ranged from a few weeks to approximately one year after initiating treatment.

Of the 133 adult CLL patients in the two trials, there were 29 fatalities during study, approximately 50% of which were due to infection.

Metabolic

Tumor lysis syndrome has been reported in CLL patients treated with Fludara FOR INJECTION. This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and hematuria.

Nervous System

(see WARNINGS section)

Objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with Fludara FOR INJECTION at the recommended dose. Peripheral neuropathy has been observed in patients treated with Fludara FOR INJECTION and one case of wrist-drop was reported. There have been additional reports of cerebral hemorrhage though the frequency is not known.

Pulmonary System

Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16% and 22% of those treated with Fludara FOR INJECTION in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to Fludara FOR INJECTION characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed.

In post-marketing experience, cases of severe pulmonary toxicity have been observed with Fludara FOR INJECTION use which resulted in ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, pneumonitis and respiratory failure.  After an infectious origin has been excluded, some patients experienced symptom improvement with corticosteroids.

Gastrointestinal System

Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding and hemorrhage have been reported in patients treated with Fludara FOR INJECTION.  Elevations of pancreatic enzyme levels have also been reported.

Cardiovascular

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with Fludara FOR INJECTION. There have been additional reports of heart failure and arrhythmia though the frequency is rare.  No other severe cardiovascular events were considered to be drug related.

Genitourinary System

Rare cases of hemorrhagic cystitis have been reported in patients treated with Fludara FOR INJECTION.

Skin

Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with Fludara FOR INJECTION. Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and pemphigus have been reported, with fatal outcomes in some cases.

Neoplasms

Worsening or flare-up of pre-existing skin cancer lesions, as well as new onset of skin cancer, has been reported in patients during or after treatment with Fludara FOR INJECTION.

Hepatobiliary Disorders

Elevations of hepatic enzyme levels have been reported.

Data in the following table are derived from the 133 patients with CLL who received Fludara FOR INJECTION in the MDAH and SWOG studies.

More than 3000 adult patients received Fludara FOR INJECTION in studies of other leukemias, lymphomas, and other solid tumors. The spectrum of adverse effects reported in these studies was consistent with the data presented above.

High doses of Fludara FOR INJECTION (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 Fludara FOR INJECTION overdosage. Treatment consists of drug discontinuation and supportive therapy.