Vial container label

Vial carton label

Product name

Fludarabine Phosphate Injection 50 mg/2 mL

PrFludarabine Phosphate Injection, USP 50 mg/2 mL

Route of administration

For Intravenous use only

For Intravenous use only

Specific information

Cytotoxic agent

Cytotoxic

Ingredients

Each mL contains 25 mg of the active ingredient fludarabine phosphate, 1.78 mg disodium phosphate dihydrate, water for injection and sodium hydroxide to adjust pH to 7.5. The pH range for the final product is 7.3 to 7.7. Fludarabine Phosphate Injection is a sterile solution intended for intravenous administration.

Each mL contains 25 mg of the active ingredient fludarabine phosphate, 25 mg mannitol, 62.5 mg of disodium hydrogen phosphate dehydrate and water for injection. The pH range of the final solution is 6.0-7.1. FLUDARABINE PHOSPHATE INJECTION, USP is supplied as a colourless to slightly brown yellow, sterile solution for intravenous administration.

Compatibility and storage

Fludarabine Phosphate Injection contains no antimicrobial preservative and should be used within 8 hours of opening. Care must be taken to assure sterility of infusion solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The product must be further diluted for intravenous infusion administration in PVC bags to a concentration of 1 mg/mL in 5% Dextrose Injection USP, or in 0.9% Sodium Chloride Injection USP. Use within 24 hours when kept at room temperature and 72 hours when refrigerated. FLUDARABINE PHOSPHATE INJECTION, USP contains no antimicrobial preservative and thus care must be taken to ensure the sterility of prepared solutions.

Incompatibilities

Fludarabine Phosphate Injection should not be mixed with other drugs.

The formulation for intravenous use must not be mixed with other drugs.

Storage condition

Store in a refrigerator between 2° and 8°C (36° to 46°F).

Store FLUDARABINE PHOSPHATE INJECTION, USP under refrigeration between 2°C and 8°C. Do not freeze. Discard unused portion.

How supplied

Fludarabine Phosphate Injection is supplied as a sterile solution containing 25 mg of fludarabine phosphate in a single use vial.

NDC 66758-046-01 one carton containing 1 vial of Fludarabine Phosphate Injection.

FLUDARABINE PHOSPHATE INJECTION, USP is supplied in a 2 mL, single dose, clear glass vial with orange flip-off seal, packaged individually.

Indication

Fludarabine Phosphate Injection is indicated for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating agent containing regimen. The safety and effectiveness of Fludarabine Phosphate Injection in previously untreated or nonrefractory patients with CLL have not been established.

FLUDARABINE PHOSPHATE INJECTION, USP is indicated for:

• Second line treatment in patients with chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (Lg-NHL) who have failed other conventional therapies.

Recommended dose

The recommended adult dose of Fludarabine Phosphate Injection is 25 mg/m 2 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 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 Phosphate Injection be administered following the achievement of a maximal response and then the drug should be discontinued.

The usual starting dose of FLUDARABINE PHOSPHATE INJECTION, USP (fludarabine phosphate) is 25 mg/m 2 administered intravenously over a period of approximately 30 minutes, daily for five days every 28 days. Dosage may be decreased based on evidence of hematologic or nonhematologic toxicity.

Note that in patients with decreased renal function (creatinine clearance between 30 and 70 mL/min) the dose should be reduced by up to 50%. FLUDARABINE PHOSPHATE INJECTION, USP (fludarabine phosphate) treatment is contraindicated, if creatinine clearance is < 30 mL/min. (See WARNINGS AND PRECAUTIONS).

The duration of treatment depends on the treatment success and the tolerability of the drug.

FLUDARABINE PHOSPHATE INJECTION, USP should be administered until the achievement of a maximal response (complete or partial remission, usually 6 cycles) and then the drug should be discontinued.

Contraindications

None

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• Renally impaired patients with creatinine clearance <30 mL/min.
• Patients with decompensated hemolytic anemia
• In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory CLL, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of FLUDARABINE PHOSPHATE INJECTION, USP in combination with pentostatin is contraindicated.

Drug Interactions

Pentostatin: The use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended due to the risk of fatal pulmonary toxicity. [see Warnings and Precautions (5.5)]

Serious Drug Interactions: In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory CLL, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of FLUDARABINE PHOSPHATE INJECTION, USP in combination with pentostatin is contraindicated.

Higher than recommended doses of fludarabine phosphate have been associated with leukoencephalopathy, acute toxic leukoencephalopathy, or posterior reversible encephalopathy syndrome (PRES)/ reversible posterior leukoencephalopathy syndrome (RPLS). Symptoms, which may be delayed and irreversible, may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, altered sensorium, focal neurological deficits, coma, and death. Additional effects may include optic neuritis, and papillitis, confusion, somnolence, agitation, paraparesis/ quadriparesis, muscle spasticity and incontinence. High doses are also associated with bone marrow suppression manifested by thrombocytopenia and neutropenia.

There is no known specific antidote for fludarabine phosphate overdosage. Treatment consists of drug discontinuation and supportive therapy.

Boxed Warning

SEVERE BONE MARROW SUPPRESSION, CNS TOXICITY, HEMOLYTIC ANEMIA, AND PULMONARY TOXICITY

Fludarabine Phosphate Injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Fludarabine phosphate injection can severely suppress bone marrow function. When used at high doses in dose-ranging studies in patients with acute leukemia, fludarabine phosphate injection was associated with severe neurologic effects, including blindness, coma, and death. This severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m 2/day for 5 to 7 days) than the recommended dose. 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. [see Warnings and Precautions (5.2)]

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 fludarabine phosphate injection. Patients undergoing treatment with Fludarabine Phosphate Injection should be evaluated and closely monitored for hemolysis. [see Warnings and Precautions (5.3)]

In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended [see Warnings and Precautions (5.5)]

Serious Warnings and Precautions

FLUDARABINE PHOSPHATE INJECTION, USP should be administered under the supervision of, or prescribed by, a qualified physician experienced in the use of antineoplastic therapy.

Fludarabine phosphate is associated with:

• Myelosuppression, including fatal cases (see WARNINGS AND PRECAUTIONS - Hematologic)
• Irreversible CNS effects, including fatal cases (see WARNINGS AND PRECAUTIONS - Neurologic)
• Auto-immune hemolytic anemia, including fatal cases (see WARNINGS AND PRECAUTIONS - Hematologic)

In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory CLL, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of FLUDARABINE PHOSPHATE INJECTION, USP in combination with pentostatin is contraindicated.

Warnings and Precautions

5 WARNINGS AND PRECAUTIONS

5.1 Dose Dependent Neurologic Toxicities

There are clear dose dependent toxic effects seen with fludarabine phosphate. Dose levels approximately 4 times greater (96 mg/m 2/day for 5 to 7 days) than that recommended for CLL (25 mg/m 2/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 fludarabine phosphate at high doses (96 mg/m 2/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 fludarabine phosphate on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy.

Fludarabine phosphate may reduce the ability to drive or use mechanical equipment, since fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.

5.2 Bone Marrow Suppression

Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate. In a Phase I study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32 days) 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 Fludarabine Phosphate 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.

5.3 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 fludarabine phosphate 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 fludarabine phosphate 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 Fludarabine Phosphate Injection should be evaluated and closely monitored for hemolysis. Discontinuation of therapy with Fludarabine Phosphate Injection is recommended in case of hemolysis.

5.4 Transfusion Associated Graft-Versus-Host Disease

Transfusion-associated graft-versus-host disease has been observed after transfusion of non-irradiated blood in fludarabine phosphate treated patients. Fatal outcome as a consequence of this disease has been reported. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received, treatment with Fludarabine Phosphate Injection should receive irradiated blood only.

5.5 Pulmonary Toxicity

In a clinical investigation using fludarabine phosphate 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 Fludarabine Phosphate Injection in combination with pentostatin is not recommended.

5.6 Pregnancy

Pregnancy Category D

Based on its mechanism of action, fludarabine phosphate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of fludarabine phosphate injection in pregnant women, Fludarabine phosphate was embryolethal and teratogenic in rats and rabbits. 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. [see Use in Specific Populations (8.1)]

5.7 Male Fertility and Reproductive Outcomes

Males with female sexual partners of childbearing potential should use contraception during and after cessation of fludarabine phosphate therapy. Fludarabine phosphate 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 Nonclinical Toxicology (13.1)]

5.8 Tumor Lysis

Tumor lysis syndrome has been associated with fludarabine phosphate treatment. This syndrome has been reported in CLL patients with large tumor burdens. Since fludarabine phosphate can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.

5.9 Renal Impairment

Fludarabine Phosphate Injection must be administered cautiously in patients with renal impairment. The total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with creatinine clearance 30 to 79 mL/min should have their fludarabine phosphate dose reduced and be monitored closely for excessive toxicity. Fludarabine phosphate should not be administered to patients with creatinine clearance less than 30 mL/min. [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)]

In patients aged 65 years or older, creatinine clearance should be measured before start of treatment.

5.10 Vaccination

During and after treatment with Fludarabine Phosphate Injection, vaccination with live vaccines should be avoided.

General

FLUDARABINE PHOSPHATE INJECTION, USP is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of hematologic and nonhematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the development of neutropenia, thrombocytopenia, anemia and leukopenia.

Vaccination with live vaccines should be avoided during and after treatment with FLUDARABINE PHOSPHATE INJECTION, USP.

Carcinogenesis and Mutagenesis

Disease progression and transformation (eg, Richters Syndrome) have been commonly reported in CLL patients (see WARNINGS AND PRECAUTIONS - Skin).

Endocrine and Metabolism

Tumor lysis syndrome associated with fludarabine phosphate treatment has been reported in CLL patients with large tumor burdens. Since FLUDARABINE PHOSPHATE INJECTION, USP can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.

Gastrointestinal

In clinical trials with oral fludarabine phosphate, nausea/vomiting and/or diarrhea were reported in approximately 38% of patients. In most cases, the severity was mild to moderate (WHO toxicity grading). Only a small percentage of patients, approximately 1 % with nausea/vomiting and 5% with diarrhea, required therapy. Patients with prolonged, clinically relevant, nausea/vomiting and diarrhea should be closely monitored to avoid dehydration.

Hematologic

In patients with an impaired state of health, FLUDARABINE PHOSPHATE INJECTION, USP should be given with caution and after careful risk/benefit consideration. This applies especially to patients with severe impairment of bone marrow function (thrombocytopenia, anemia, and/or granulocytopenia), immunodeficiency or with a history of opportunistic infection. Prophylactic treatment should be considered in patients at increased risk of developing opportunistic infections (see ADVERSE REACTIONS).

Severe bone marrow suppression, notably thrombocytopenia, anemia, leukopenia and neutropenia, may occur with administration of FLUDARABINE PHOSPHATE INJECTION, USP and requires careful hematologic monitoring. In a Phase I study in solid tumor patients, the median time to nadir counts was 13 days (range, 3- 25 days) for granulocytes and 16 days (range, 2-32 days) 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 FLUDARABINE PHOSPHATE INJECTION, USP 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 cases reported has ranged from approximately 2 months to approximately 1 year. These episodes have occurred in both previously treated and untreated patients.

Instances of life-threatening and sometimes fatal autoimmune phenomena (e.g. autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, acquired hemophilia and Evans' syndrome) have been reported to occur during or after treatment with fludarabine phosphate in patients with or without a previous history of autoimmune processes 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. One study was performed with 31 patients with hemolytic anemia related to the administration of fludarabine phosphate. Since the majority (90%) of these patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process, rechallenge with FLUDARABINE PHOSPHATE INJECTION, USP should be avoided. The mechanisms which predispose patients to the development of this complication have not been identified. Patients undergoing treatment with FLUDARABINE PHOSPHATE INJECTION, USP should be evaluated and closely monitored for signs of autoimmune hemolytic anemia (a decline in hemoglobin linked with hemolysis and a positive Coombs' test). Discontinuation of therapy with FLUDARABINE PHOSPHATE INJECTION, USP is recommended in the event of hemolysis. The transfusion of irradiated blood and the administration of corticosteroids are the most common treatment measures for autoimmune hemolytic anemia.

Hepatic/Biliary/Pancreatic

No data are available concerning the use of fludarabine phosphate in patients with hepatic impairment. In this group of patients, FLUDARABINE PHOSPHATE INJECTION, USP should be used with caution and administered if the perceived benefit outweighs any potential risk.

Immune

Transfusion-associated graft-versus-host disease (reaction by the transfused immunocompetent lymphocytes to the host) has been observed after transfusion of nonirradiated blood in patients treated with fludarabine phosphate. Fatal outcome as a consequence of this disease has been reported with a high frequency. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing or who have received treatment with FLUDARABINE PHOSPHATE INJECTION, USP should receive irradiated blood only.

Neurologic

Administration of fludarabine phosphate can be associated with leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL), or posterior reversible encephalopathy syndrome (PRES)/ reversible posterior leukoencephalopathy syndrome (RPLS).

LE, ATL or PRES/RPLS may occur:

• at the recommended dose, most commonly
• • when fludarabine phosphate is given following, or in combination with, medications known to be associated with LE, ATL or PRES/RPLS, or
  • when fludarabine phosphate is given in patients with cranial or total body irradiation, Graft versus Host Disease, renal impairment, or following Hematopoietic Stem Cell Transplantation.
• at doses higher than the recommended dose.

When high doses of fludarabine phosphate were administered in dose-ranging studies in acute leukemia patients, a syndrome with delayed onset, characterized by blindness, coma, and death was identified. Symptoms appeared from 21 to 60 days post dosing (however, in post marketing experience, cases of neurotoxicity have been reported to occur both earlier and later than seen in clinical trials). Demyelination, especially of the occipital cortex of the brain was noted. The majority of these cases occurred in patients treated intravenously with doses approximately four times greater (96 mg/m 2/day for 5-7 days) than the recommended dose. Thirteen of 36 patients (36.1%) who received fludarabine phosphate at high doses ( 96 mg/m 2/day for 5 to 7 days per course) developed severe neurotoxicity, while only one of 443 patients (0.2%) who received the drug at low doses ( 40 mg/m2/day for 5 days per course) developed the toxicity. In patients treated at doses in the range of the dose recommended for CLL, Lg-NHL, severe central nervous system toxicity occurred rarely (coma, seizures and agitation) or uncommonly (confusion).

LE, ATL or PRES/RPLS symptoms may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, altered sensorium, and focal neurological deficits. Additional effects may include optic neuritis, and papillitis, confusion, somnolence, agitation, paraparesis/quadriparesis, muscle spasticity, incontinence, and coma.

The onset of the neurologic symptoms can be delayed and may occur after discontinuation of fludarabine. Late-occurring encephalopathy has been reported up to 4.8 years following fludarabine.

LE/ ATL/ PRES/RPLS may be irreversible, life-threatening, or fatal.

The effect of chronic administration of fludarabine phosphate on the central nervous system is unknown. In some studies, however, patients tolerated the recommended dose, for relatively long treatment periods (up to 26 courses of therapy).

Periodic neurological assessments are recommended. Whenever LE, ATL or PRES/RPLS is suspected, FLUDARABINE PHOSPHATE INJECTION, USP treatment should be stopped. Patients should be monitored and should undergo brain imaging, preferably utilizing MRI. If the diagnosis is confirmed, FLUDARABINE PHOSPHATE INJECTION, USP therapy should be permanently discontinued.

Renal

The total body clearance of the principal plasma metabolite 2F-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Patients with reduced renal function demonstrated an increased total body exposure (AUC of 2F-ara-A). Limited clinical data are available in patients with impairment of renal function (creatinine clearance below 70 mL/min). Therefore, if renal impairment is clinically suspected, or in patients over the age of 70 years, creatinine clearance should be measured. If creatinine clearance is between 30 and 70 mL/min, the dose should be reduced by up to 50% and close hematological monitoring should be used to assess toxicity.

FLUDARABINE PHOSPHATE INJECTION, USP treatment is contraindicated, if creatinine clearance is < 30 mL/min. (See DOSAGE AND ADMINISTRATION).

Sexual Function/Reproduction

Preclinical toxicology studies in mice, rats and dogs have demonstrated dose-related adverse effects on the male reproductive system. Observations consisted of a decrease in mean testicular weights in dogs and degeneration and necrosis of spermatogenic epithelium of the testes in mice, rats and dogs. The possible adverse effects on fertility in males and females in humans have not been adequately evaluated. Therefore, it is recommended that men and women of child-bearing potential take contraceptive measures during FLUDARABINE PHOSPHATE INJECTION, USP therapy, and for at least 6 months after the cessation of FLUDARABINE PHOSPHATE INJECTION, USP therapy.

Skin

The worsening or flare-up of pre-existing skin cancer lesions, as well as new onset of skin cancer, has been reported to occur in patients during or after intravenous (i.v.) fludarabine phosphate therapy.

Special Populations

Pregnant Women:

There are very limited data of fludarabine phosphate use in pregnant women in the first trimester: one newborn has been described with absent bilateral radii and normal thumbs, thrombocytopenia, fossa ovalis aneurysm and a small patent ductus arteriosus. Early pregnancy loss has been reported in fludarabine phosphate monotherapy as well as in combination therapy. Premature delivery has been reported.

FLUDARABINE PHOSPHATE INJECTION, USP should not be used during pregnancy unless clearly necessary (e.g., life-threatening situation, no alternative safer treatment available without compromising the therapeutic benefit, treatment cannot be avoided). It has the potential to cause fetal harm. Prescribers may only consider it to be used if the potential benefits justify the potential risks to the fetus. Women of childbearing potential must be apprised of the potential hazard to the fetus.

Women should avoid becoming pregnant while on FLUDARABINE PHOSPHATE INJECTION, USP therapy. Women of childbearing potential or fertile males must take effective contraceptive measures during and at least for 6 months after cessation of therapy.

Nursing Women:

Breast-feeding should not be initiated during FLUDARABINE PHOSPHATE INJECTION, USP treatment. Nursing women should discontinue breastfeeding.

It is not known whether this drug is excreted in human milk. There is evidence from preclinical data that after intravenous administration to rats that fludarabine phosphate and/or metabolites transfer from maternal blood to milk.

Pediatrics: The safety and effectiveness of fludarabine phosphate in children have not been established.

Geriatrics (> 75 years of age): Since there are limited data for the use of fludarabine phosphate in elderly persons (> 75 years), caution should be exercised with the administration of FLUDARABINE PHOSPHATE INJECTION, USP in these patients. The total body clearance of the principal plasma metabolite 2F-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Patients with reduced kidney function demonstrated an increased total body exposure (AUC of 2F-ara-A). Limited clinical data are available in patients with impairment of renal function (creatinine clearance below 70 mL/min). Since renal impairment is frequently present in patients over the age of 70 years, creatinine clearance should be measured. If creatinine clearance is between 30 and 70 mL/min, the dose should be reduced by up to 50%, and close hematologic monitoring should be used to assess toxicity. FLUDARABINE PHOSPHATE INJECTION, USP treatment is contraindicated if creatinine clearance is < 30 mL/min. (See DOSAGE AND ADMINISTRATION).

Monitoring and Laboratory Tests

During treatment, the patient's hematologic (particularly neutrophils and platelets) and serum chemistry profiles should be monitored regularly.

Effects on Ability to Drive or Operate Machines

FLUDARABINE PHOSPHATE INJECTION, USP may reduce the ability to drive or use machines, since fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.