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 non-refractory patients with CLL have not been established.

The recommended adult dose of fludarabine phosphate 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 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.

Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30 to 79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. Fludarabine Phosphate Injection should not be administered to patients with creatinine clearance less than 30 mL/min.

Starting Dose Adjustment for Renal Impairment

<div class="scrollingtable"><table> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td> <p class="First"> <span class="Bold">Creatinine Clearance</span> </p> </td><td> <p class="First"> <span class="Bold">Starting Dose</span> </p> </td> </tr> <tr> <td> <p class="First">≥ 80 mL/min</p> </td><td> <p class="First">25 mg/m<span class="Sup">2</span> (full dose) </p> </td> </tr> <tr> <td> <p class="First">50 to 79 mL/min</p> </td><td> <p class="First">20 mg/m<span class="Sup">2</span> </p> </td> </tr> <tr> <td> <p class="First">30 to 49 mL/min</p> </td><td> <p class="First">15 mg/m<span class="Sup">2</span> </p> </td> </tr> <tr class="Last"> <td> <p class="First">&lt; 30 mL/min</p> </td><td> <p class="First">Do not administer</p> </td> </tr> </tbody> </table></div>

Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.

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.

Fludarabine Phosphate Injection should not be mixed with other drugs.

Fludarabine Phosphate Injection is supplied as a 50 mg per 2 mL (25 mg per mL) sterile solution.

{ "type": "p", "children": [], "text": "Fludarabine Phosphate Injection is supplied as a 50 mg per 2 mL (25 mg per mL) sterile solution." }

None

{ "type": "p", "children": [], "text": "None" }

There are clear dose dependent toxic effects seen with fludarabine phosphate. 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 fludarabine phosphate 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 post-marketing 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.

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.

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.

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.

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.

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)].

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)].

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.

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.

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

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with fludarabine phosphate. During fludarabine phosphate 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 fludarabine phosphate.

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 anemias, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur in patients receiving fludarabine phosphate [see Warnings and Precautions (5.3)]. The majority of patients rechallenged with fludarabine phosphate 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.

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 fludarabine phosphate.

Rare cases of Epstein-Barr (EBV) associated lymphoproliferative disorders have been reported in patients treated with fludarabine phosphate.

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 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.

Tumor lysis syndrome has been reported in CLL patients treated with fludarabine phosphate. 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.

Objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with fludarabine phosphate at the recommended dose. Peripheral neuropathy has been observed in patients treated with fludarabine phosphate and one case of wrist-drop was reported. There have been additional reports of cerebral hemorrhage though the frequency is not known [see Warnings and Precautions (5)].

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

In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine phosphate 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 disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis, and hemorrhage have been reported in patients treated with fludarabine phosphate. Elevations of pancreatic enzyme levels have also been reported.

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine phosphate. There have been reports of heart failure and arrhythmia. No other severe cardiovascular events were considered to be drug related.

Hemorrhagic cystitis has been reported in patients treated with fludarabine phosphate.

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

Worsening or flare-up of preexisting skin cancer lesions, as well as new onset of skin cancer, has been reported in patients during or after treatment with fludarabine phosphate.

Elevations of hepatic enzyme levels have been reported.

Data in Table 1 are derived from the 133 patients with CLL who received fludarabine phosphate in the MDAH and SWOG studies.

TABLE 1: PERCENT OF CLL PATIENTS REPORTING NON-HEMATOLOGIC ADVERSE REACTIONS

<div class="scrollingtable"><table> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">ADVERSE REACTIONS</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">MDAH</span> </p> <p> <span class="Bold">(N=101)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">SWOG</span> </p> <p> <span class="Bold">(N=32)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ANY ADVERSE REACTION</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">88%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">91%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">BODY AS A WHOLE</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">72</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">84</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">FEVER</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">60</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">69</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CHILLS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">19</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">FATIGUE</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">38</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">INFECTION</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">33</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">44</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PAIN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">22</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">MALAISE</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">DIAPHORESIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ALOPECIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ANAPHYLAXIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">HEMORRHAGE</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">HYPERGLYCEMIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">DEHYDRATION</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">NEUROLOGICAL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">69</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">WEAKNESS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">65</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PARESTHESIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">HEADACHE</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">VISUAL DISTURBANCE</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">15</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">HEARING LOSS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">SLEEP DISORDER</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">DEPRESSION</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CEREBELLAR SYNDROME</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">IMPAIRED MENTATION</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PULMONARY</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">35</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">69</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">COUGH</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">44</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PNEUMONIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">22</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">DYSPNEA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">22</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">SINUSITIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PHARYNGITIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">UPPER RESPIRATORY INFECTION</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ALLERGIC PNEUMONITIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">EPISTAXIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">HEMOPTYSIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">BRONCHITIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">HYPOXIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">GASTROINTESTINAL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">46</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">63</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">NAUSEA/VOMITING</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">36</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">31</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">DIARRHEA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ANOREXIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">34</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">STOMATITIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">GI BLEEDING</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ESOPHAGITIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">MUCOSITIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">LIVER FAILURE</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ABNORMAL LIVER FUNCTION TEST</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CHOLELITHIASIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CONSTIPATION</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">DYSPHAGIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CUTANEOUS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">18</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">RASH</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">15</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PRURITUS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">SEBORRHEA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">GENITOURINARY</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">22</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">DYSURIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">URINARY INFECTION</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">15</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">HEMATURIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">RENAL FAILURE</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ABNORMAL RENAL FUNCTION TEST</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PROTEINURIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">HESITANCY</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CARDIOVASCULAR</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">38</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">EDEMA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">19</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ANGINA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CONGESTIVE HEART FAILURE</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ARRHYTHMIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">SUPRAVENTRICULAR TACHYCARDIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">MYOCARDIAL INFARCTION</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">DEEP VENOUS THROMBOSIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PHLEBITIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">TRANSIENT ISCHEMIC ATTACK</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ANEURYSM</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CEREBROVASCULAR ACCIDENT</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">MUSCULOSKELETAL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">MYALGIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">OSTEOPOROSIS</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">ARTHRALGIA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">TUMOR LYSIS SYNDROME</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

More than 3000 adult patients received fludarabine phosphate 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.

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)].

[See Warnings and Precautions (5.6)].

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. In rats, repeated intravenous doses of fludarabine phosphate at 2.4 times and 7.2 times the recommended human intravenous dose (25 mg/m 2) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights. Maternal toxicity was not apparent at 2.4 times the human intravenous dose, and was limited to slight body weight decreases at 7.2 times the human intravenous dose. In rabbits, repeated intravenous doses of fludarabine phosphate at 3.8 times the human intravenous dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels (≥ 0.5 times the human intravenous dose). 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.

It is not known whether fludarabine phosphate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions including tumorigenicity in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy.

Fludarabine phosphate was evaluated in 62 pediatric patients (median age 10, range 1 to 21) with refractory acute leukemia (45 patients) or solid tumors (17 patients). Limited pharmacokinetic data for fludarabine phosphate are available in children (ages 1 to 21 years). When fludarabine phosphate was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early.

The fludarabine phosphate regimen tested for pediatric lymphocytic leukemia (ALL) patients was a loading bolus of 10.5 mg/m2/day followed by a continuous infusion of 30.5 mg/m2/day for 5 days. In 12 pediatric patients with solid tumors, dose-limiting myelosuppression was observed with a loading dose of 8 mg/m2/day followed by a continuous infusion of 23.5 mg/m2/day for 5 days. The maximum tolerated dose was a loading dose of 7 mg/m2/day followed by a continuous infusion of 20 mg/m2/day for 5 days. Treatment toxicity included bone marrow suppression. Platelet counts appeared to be more sensitive to the effects of fludarabine phosphate than hemoglobin and white blood cell counts. Other adverse events included fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection. There were no reported occurrences of peripheral neuropathy or pulmonary hypersensitivity reaction.

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 to 79 mL/min should have their fludarabine phosphate dose reduced and be monitored closely for excessive toxicity. Due to insufficient data, fludarabine phosphate should not be administered to patients with creatinine clearance less than 30 mL/min [see Dosage and Administration (2.2), Warnings and Precautions (5.9)].

High doses of fludarabine phosphate [see Warnings and Precautions (5)] 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 overdosage. Treatment consists of drug discontinuation and supportive therapy.

{ "type": "p", "children": [], "text": "High doses of fludarabine phosphate \n [see Warnings and Precautions (5)] 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 overdosage. Treatment consists of drug discontinuation and supportive therapy.\n " }

Fludarabine Phosphate Injection contains fludarabine phosphate, a nucleotide metabolic inhibitor. Fludarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9- ß-D-arabinofuranosyladenine (ara-A), that is relatively resistant to deamination by adenosine deaminase.

{ "type": "p", "children": [], "text": "Fludarabine Phosphate Injection contains fludarabine phosphate, a nucleotide metabolic inhibitor. Fludarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-\n ß-D-arabinofuranosyladenine (ara-A), that is relatively resistant to deamination by adenosine deaminase.\n " }

The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0- phosphono- ß-D-arabinofuranosyl)(2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is C 10H 13FN 5O 7P (MW 365.2) and the structure is provided in Figure 1.

{ "type": "p", "children": [], "text": "The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0- phosphono-\n ß-D-arabinofuranosyl)(2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is C\n 10H\n 13FN\n 5O\n 7P (MW 365.2) and the structure is provided in Figure 1.\n " }

Figure 1: Chemical Structure of Fludarabine Phosphate

{ "type": "p", "children": [], "text": "\nFigure 1: Chemical Structure of Fludarabine Phosphate\n" }

Each mL contains 25 mg of the active ingredient fludarabine phosphate, 25 mg of mannitol, water for injection, q.s.; and sodium hydroxide to adjust pH to 6.8. The pH range for the final product is 6.0 to 7.1. Fludarabine Phosphate Injection is a sterile solution intended for intravenous administration.

{ "type": "p", "children": [], "text": "Each mL contains 25 mg of the active ingredient fludarabine phosphate, 25 mg of mannitol, water for injection, q.s.; and sodium hydroxide to adjust pH to 6.8. The pH range for the final product is 6.0 to 7.1. Fludarabine Phosphate Injection is a sterile solution intended for intravenous administration." }

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-fluoroara-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).

No animal carcinogenicity studies with fludarabine have been conducted.

Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberrations in the presence of metabolic activation) and induced sister chromatid exchanges both with and without metabolic activation. In addition, fludarabine phosphate was clastogenic in vivo (mouse micronucleus assay) but was not mutagenic to germ cells (dominant lethal test in male mice). Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells (HGRPT assay in Chinese hamster ovary cells) either in the presence or absence of metabolic activation.

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 mice and rats with a trend toward decreased 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 humans have not been adequately evaluated [see Warnings and Precautions (5.7)].

Two single-arm open-label studies of fludarabine phosphate have been conducted in adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In a study conducted by M.D. Anderson Cancer Center (MDAH), 48 patients were treated with a dose of 22 to 40 mg/m2 daily for 5 days every 28 days. Another study conducted by the Southwest Oncology Group (SWOG) involved 31 patients treated with a dose of 15 to 25 mg/m2 daily for 5 days every 28 days. The overall objective response rates were 48% and 32% in the MDAH and SWOG studies, respectively. The complete response rate in both studies was 13%; the partial response rate was 35% in the MDAH study and 19% in the SWOG study. These response rates were obtained using standardized response criteria developed by the National Cancer Institute CLL Working Group and were achieved in heavily pretreated patients. The ability of fludarabine phosphate to induce a significant rate of response in refractory patients suggests minimal cross-resistance with commonly used anti-CLL agents.

The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1 to 68 weeks) and 21 weeks (range of 1 to 53 weeks), respectively. The median duration of disease control was 91 weeks (MDAH) and 65 weeks (SWOG). The median survival of all refractory CLL patients treated with fludarabine phosphate was 43 weeks and 52 weeks in the MDAH and SWOG studies, respectively.

Rai stage improved to Stage II or better in 7 of 12 MDAH responders (58%) and in 5 of 7 SWOG responders (71%) who were Stage III or IV at baseline. In the combined studies, mean hemoglobin concentration improved from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in a subgroup of anemic patients. Similarly, average platelet count improved from 63,500/mm3 to 103,300/mm 3 at the time of response in a subgroup of patients who were thrombocytopenic at baseline.

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.

{ "type": "p", "children": [], "text": "1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165." }

2. OSHA Technical Manual, TED 1-0.l5A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otim_vi_2.html

{ "type": "p", "children": [], "text": "2. OSHA Technical Manual, TED 1-0.l5A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otim_vi_2.html\n" }

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:172-1193.

{ "type": "p", "children": [], "text": "3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs.\nAm J Health-Syst Pharm. 2006; 63:172-1193." }

4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society

{ "type": "p", "children": [], "text": "4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society" }

Fludarabine Phosphate Injection, USP is supplied as a sterile solution containing 50 mg/2 mL (25 mg/mL) of fludarabine phosphate in a 2 mL single use vial.

NDC 0527-1242-02 one carton containing 1 vial of Fludarabine Phosphate Injection.

Store refrigerated between 2° and 8°C (36° and 46°F).

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 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.

Patients should be informed of the importance of periodic assessment of their blood count to detect the development of anemia, neutropenia and thrombocytopenia.

During treatment, the patient's hematologic profile (particularly neutrophils, red blood cells, and platelets) should be monitored regularly to determine the degree of hematopoietic suppression [see Warnings and Precautions (5.2)].

Fludarabine phosphate can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant [see Warnings and Precautions (5.6)].

Distributed by:Lannett Company, Inc.Philadelphia, PA 19136

Made in Italy

L7324 Rev. 05/2022

NDC 0527-1242-02

{ "type": "p", "children": [], "text": "\nNDC 0527-1242-02\n" }

FludarabinePhosphateInjection, USP

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50 mg/2 mL(25 mg/mL)

{ "type": "p", "children": [], "text": "\n50 mg/2 mL(25 mg/mL)\n" }

CAUTION: Cytotoxic AgentFor Intravenous Use

{ "type": "p", "children": [], "text": "\nCAUTION: Cytotoxic AgentFor Intravenous Use\n" }

Rx Only2 mLSingle Dose Vial

{ "type": "p", "children": [], "text": "\nRx Only2 mLSingle Dose Vial\n" }

Lannett

{ "type": "p", "children": [], "text": "\nLannett\n" }

NDC 0527-1242-02

{ "type": "p", "children": [], "text": "\nNDC 0527-1242-02\n" }

FludarabinePhosphateInjection, USP

{ "type": "p", "children": [], "text": "\nFludarabinePhosphateInjection, USP\n" }

50 mg/2 mL(25 mg/mL)

{ "type": "p", "children": [], "text": "\n50 mg/2 mL(25 mg/mL)\n" }

CAUTION: Cytotoxic AgentFor Intravenous Use

{ "type": "p", "children": [], "text": "\nCAUTION: Cytotoxic AgentFor Intravenous Use\n" }

Rx Only2 mLSingle Dose Vial

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Lannett

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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 non-refractory patients with CLL have not been established.

The recommended adult dose of fludarabine phosphate 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 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.

Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30 to 79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. Fludarabine phosphate injection should not be administered to patients with creatinine clearance less than 30 mL/min.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="49.900%"/> <col align="left" width="50.100%"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule" colspan="2" valign="top"><span class="Bold">Starting Dose Adjustment for Renal Impairment</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Creatinine Clearance</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Starting Dose</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">≥ 80 mL/min </td><td align="center" class="Botrule Rrule" valign="top">25 mg/m<span class="Sup">2</span> (full dose) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">50 to 79 mL/min </td><td align="center" class="Botrule Rrule" valign="top">20 mg/m<span class="Sup">2</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">30 to 49 mL/min </td><td align="center" class="Botrule Rrule" valign="top">15 mg/m<span class="Sup">2</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&lt; 30 mL/min </td><td align="center" class="Botrule Rrule" valign="top">Do not administer </td> </tr> </tbody> </table></div>

Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.

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.

Fludarabine phosphate injection should not be mixed with other drugs.

Fludarabine Phosphate Injection, USP is supplied as a 50 mg per 2 mL (25 mg per mL) sterile solution.

{ "type": "p", "children": [], "text": "Fludarabine Phosphate Injection, USP is supplied as a 50 mg per 2 mL (25 mg per mL) sterile solution.\n" }

None

{ "type": "p", "children": [], "text": "None\n" }

There are clear dose dependent toxic effects seen with fludarabine phosphate. 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 fludarabine phosphate 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 post-marketing 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.

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 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.

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

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 should receive irradiated blood only.

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 in combination with pentostatin is not recommended.

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 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)].

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)].

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.

Fludarabine phosphate 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.

During and after treatment with fludarabine phosphate, vaccination with live vaccines should be avoided.

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with fludarabine phosphate. During fludarabine phosphate 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 fludarabine phosphate.

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 anemias, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur in patients receiving fludarabine phosphate [see Warnings and Precautions (5.3)]. The majority of patients rechallenged with fludarabine phosphate 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.

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 fludarabine phosphate.

Rare cases of Epstein-Barr (EBV) associated lymphoproliferative disorders have been reported in patients treated with fludarabine phosphate.

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 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.

Tumor lysis syndrome has been reported in CLL patients treated with fludarabine phosphate. 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.

Objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with fludarabine phosphate at the recommended dose. Peripheral neuropathy has been observed in patients treated with fludarabine phosphate and one case of wrist-drop was reported. There have been additional reports of cerebral hemorrhage though the frequency is not known [see Warnings and Precautions (5)].

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

In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine phosphate 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 disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis, and hemorrhage have been reported in patients treated with fludarabine phosphate. Elevations of pancreatic enzyme levels have also been reported.

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine phosphate. There have been reports of heart failure and arrhythmia. No other severe cardiovascular events were considered to be drug related.

Hemorrhagic cystitis has been reported in patients treated with fludarabine phosphate.

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

Worsening or flare-up of preexisting skin cancer lesions, as well as new onset of skin cancer, has been reported in patients during or after treatment with fludarabine phosphate.

Elevations of hepatic enzyme levels have been reported.

Data in Table 1 are derived from the 133 patients with CLL who received fludarabine phosphate in the MDAH and SWOG studies.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 1: PERCENT OF CLL PATIENTS REPORTING NON-HEMATOLOGIC ADVERSE REACTIONS </span> </caption> <col align="left" width="54.385%"/> <col align="left" width="24.441%"/> <col align="left" width="21.174%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule" valign="top"><span class="Bold">ADVERSE REACTIONS</span></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">MDAH</span></td><td align="center" class="Rrule Toprule" valign="top"><span class="Bold">SWOG</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=101)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N=32)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">ANY ADVERSE REACTION </td><td align="center" class="Botrule Rrule" valign="top">88% </td><td align="center" class="Botrule Rrule" valign="top">91% </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">BODY AS A WHOLE </td><td align="center" class="Botrule Rrule" valign="top">72 </td><td align="center" class="Botrule Rrule" valign="top">84 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       FEVER </td><td align="center" class="Botrule Rrule" valign="top">60 </td><td align="center" class="Botrule Rrule" valign="top">69 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       CHILLS </td><td align="center" class="Botrule Rrule" valign="top">11 </td><td align="center" class="Botrule Rrule" valign="top">19 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       FATIGUE </td><td align="center" class="Botrule Rrule" valign="top">10 </td><td align="center" class="Botrule Rrule" valign="top">38 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       INFECTION </td><td align="center" class="Botrule Rrule" valign="top">33 </td><td align="center" class="Botrule Rrule" valign="top">44 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       PAIN </td><td align="center" class="Botrule Rrule" valign="top">20 </td><td align="center" class="Botrule Rrule" valign="top">22 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       MALAISE </td><td align="center" class="Botrule Rrule" valign="top">8 </td><td align="center" class="Botrule Rrule" valign="top">6 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       DIAPHORESIS </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">13 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ALOPECIA </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ANAPHYLAXIS </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       HEMORRHAGE </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       HYPERGLYCEMIA </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">6 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       DEHYDRATION </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">NEUROLOGICAL </td><td align="center" class="Botrule Rrule" valign="top">21 </td><td align="center" class="Botrule Rrule" valign="top">69 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       WEAKNESS </td><td align="center" class="Botrule Rrule" valign="top">9 </td><td align="center" class="Botrule Rrule" valign="top">65 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       PARESTHESIA </td><td align="center" class="Botrule Rrule" valign="top">4 </td><td align="center" class="Botrule Rrule" valign="top">12 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       HEADACHE </td><td align="center" class="Botrule Rrule" valign="top">3 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       VISUAL DISTURBANCE </td><td align="center" class="Botrule Rrule" valign="top">3 </td><td align="center" class="Botrule Rrule" valign="top">15 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       HEARING LOSS </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">6 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       SLEEP DISORDER </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       DEPRESSION </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       CEREBELLAR SYNDROME </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       IMPAIRED MENTATION </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">PULMONARY </td><td align="center" class="Botrule Rrule" valign="top">35 </td><td align="center" class="Botrule Rrule" valign="top">69 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       COUGH </td><td align="center" class="Botrule Rrule" valign="top">10 </td><td align="center" class="Botrule Rrule" valign="top">44 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       PNEUMONIA </td><td align="center" class="Botrule Rrule" valign="top">16 </td><td align="center" class="Botrule Rrule" valign="top">22 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       DYSPNEA </td><td align="center" class="Botrule Rrule" valign="top">9 </td><td align="center" class="Botrule Rrule" valign="top">22 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       SINUSITIS </td><td align="center" class="Botrule Rrule" valign="top">5 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       PHARYNGITIS </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">9 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       UPPER RESPIRATORY INFECTION </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">16 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ALLERGIC PNEUMONITIS </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">6 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       EPISTAXIS </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       HEMOPTYSIS </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">6 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       BRONCHITIS </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       HYPOXIA </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">GASTROINTESTINAL </td><td align="center" class="Botrule Rrule" valign="top">46 </td><td align="center" class="Botrule Rrule" valign="top">63 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       NAUSEA/VOMITING </td><td align="center" class="Botrule Rrule" valign="top">36 </td><td align="center" class="Botrule Rrule" valign="top">31 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       DIARRHEA </td><td align="center" class="Botrule Rrule" valign="top">15 </td><td align="center" class="Botrule Rrule" valign="top">13 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ANOREXIA </td><td align="center" class="Botrule Rrule" valign="top">7 </td><td align="center" class="Botrule Rrule" valign="top">34 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       STOMATITIS </td><td align="center" class="Botrule Rrule" valign="top">9 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       GI BLEEDING </td><td align="center" class="Botrule Rrule" valign="top">3 </td><td align="center" class="Botrule Rrule" valign="top">13 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ESOPHAGITIS </td><td align="center" class="Botrule Rrule" valign="top">3 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       MUCOSITIS </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       LIVER FAILURE </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ABNORMAL LIVER FUNCTION TEST </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       CHOLELITHIASIS </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       CONSTIPATION </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       DYSPHAGIA </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CUTANEOUS </td><td align="center" class="Botrule Rrule" valign="top">17 </td><td align="center" class="Botrule Rrule" valign="top">18 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       RASH </td><td align="center" class="Botrule Rrule" valign="top">15 </td><td align="center" class="Botrule Rrule" valign="top">15 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       PRURITUS </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       SEBORRHEA </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">GENITOURINARY </td><td align="center" class="Botrule Rrule" valign="top">12 </td><td align="center" class="Botrule Rrule" valign="top">22 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       DYSURIA </td><td align="center" class="Botrule Rrule" valign="top">4 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       URINARY INFECTION </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">15 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       HEMATURIA </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       RENAL FAILURE </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ABNORMAL RENAL FUNCTION TEST </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       PROTEINURIA </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       HESITANCY </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CARDIOVASCULAR </td><td align="center" class="Botrule Rrule" valign="top">12 </td><td align="center" class="Botrule Rrule" valign="top">38 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       EDEMA </td><td align="center" class="Botrule Rrule" valign="top">8 </td><td align="center" class="Botrule Rrule" valign="top">19 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ANGINA </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">6 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       CONGESTIVE HEART FAILURE </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ARRHYTHMIA </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       SUPRA VENTRICULAR TACHYCARDIA </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       MYOCARDIAL INFARCTION </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       DEEP VENOUS THROMBOSIS </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       PHLEBITIS </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       TRANSIENT ISCHEMIC ATTACK </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ANEURYSM </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       CEREBROVASCULAR ACCIDENT </td><td align="center" class="Botrule Rrule" valign="top">0 </td><td align="center" class="Botrule Rrule" valign="top">3 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">MUSCULOSKELETAL </td><td align="center" class="Botrule Rrule" valign="top">7 </td><td align="center" class="Botrule Rrule" valign="top">16 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       MYALGIA </td><td align="center" class="Botrule Rrule" valign="top">4 </td><td align="center" class="Botrule Rrule" valign="top">16 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       OSTEOPOROSIS </td><td align="center" class="Botrule Rrule" valign="top">2 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">       ARTHRALGIA </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">TUMOR LYSIS SYNDROME </td><td align="center" class="Botrule Rrule" valign="top">1 </td><td align="center" class="Botrule Rrule" valign="top">0 </td> </tr> </tbody> </table></div>

More than 3000 adult patients received fludarabine phosphate 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.

The use of fludarabine phosphate in combination with pentostatin is not recommended due to the risk of fatal pulmonary toxicity [see Warnings and Precautions (5.5)].

Teratogenic Effects

Pregnancy Category D [see Warnings and Precautions (5.6)].

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 in pregnant women. In rats, repeated intravenous doses of fludarabine phosphate at 2.4 times and 7.2 times the recommended human IV dose (25 mg/m2) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights. Maternal toxicity was not apparent at 2.4 times the human IV dose, and was limited to slight body weight decreases at 7.2 times the human IV dose. In rabbits, repeated intravenous doses of fludarabine phosphate at 3.8 times the human IV dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels (≥ 0.5 times the human IV dose). 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.

It is not known whether fludarabine phosphate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions including tumorigenicity in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy.

Fludarabine phosphate was evaluated in 62 pediatric patients (median age 10, range 1 to 21) with refractory acute leukemia (45 patients) or solid tumors (17 patients). Limited pharmacokinetic data for fludarabine phosphate are available in children (ages 1 to 21 years). When fludarabine phosphate was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early.

The fludarabine phosphate regimen tested for pediatric lymphocytic leukemia (ALL) patients was a loading bolus of 10.5 mg/m2/day followed by a continuous infusion of 30.5 mg/m2/day for 5 days. In 12 pediatric patients with solid tumors, dose-limiting myelosuppression was observed with a loading dose of 8 mg/m2/day followed by a continuous infusion of 23.5 mg/m2/day for 5 days. The maximum tolerated dose was a loading dose of 7 mg/m2/day followed by a continuous infusion of 20 mg/m2/day for 5 days. Treatment toxicity included bone marrow suppression. Platelet counts appeared to be more sensitive to the effects of fludarabine phosphate than hemoglobin and white blood cell counts. Other adverse events included fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection. There were no reported occurrences of peripheral neuropathy or pulmonary hypersensitivity reaction.

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 to 79 mL/min should have their fludarabine phosphate dose reduced and be monitored closely for excessive toxicity. Due to insufficient data, fludarabine phosphate should not be administered to patients with creatinine clearance less than 30 mL/min [see Dosage and Administration (2.2), Warnings and Precautions (5.9)].

High doses of fludarabine phosphate [see Warnings and Precautions (5)] 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 overdosage. Treatment consists of drug discontinuation and supportive therapy.

{ "type": "p", "children": [], "text": "High doses of fludarabine phosphate [see Warnings and Precautions (5)] 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 overdosage. Treatment consists of drug discontinuation and supportive therapy.\n" }

Fludarabine Phosphate Injection, USP contains fludarabine phosphate, USP, a nucleotide metabolic inhibitor. Fludarabine phosphate, USP is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-ß-D-arabinofuranosyladenine (ara-A), that is relatively resistant to deamination by adenosine deaminase.

{ "type": "p", "children": [], "text": "Fludarabine Phosphate Injection, USP contains fludarabine phosphate, USP, a nucleotide metabolic inhibitor. Fludarabine phosphate, USP is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-ß-D-arabinofuranosyladenine (ara-A), that is relatively resistant to deamination by adenosine deaminase.\n" }

The chemical name for fludarabine phosphate, USP is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-ß-D-arabinofuranosyl)(2-fluoro-ara-AMP).

{ "type": "p", "children": [], "text": "The chemical name for fludarabine phosphate, USP is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-ß-D-arabinofuranosyl)(2-fluoro-ara-AMP).\n\n" }

Figure 1: Chemical Structure of Fludarabine Phosphate

{ "type": "p", "children": [], "text": "\nFigure 1: Chemical Structure of Fludarabine Phosphate\n" }

Each mL contains 25 mg of the active ingredient fludarabine phosphate, USP, 25 mg of mannitol, water for injection, qs; and sodium hydroxide to adjust pH to 6.8. The pH range for the final product is 6.0 to 7.1. Fludarabine Phosphate Injection, USP is a sterile solution intended for intravenous administration.

{ "type": "p", "children": [], "text": "Each mL contains 25 mg of the active ingredient fludarabine phosphate, USP, 25 mg of mannitol, water for injection, qs; and sodium hydroxide to adjust pH to 6.8. The pH range for the final product is 6.0 to 7.1. Fludarabine Phosphate Injection, USP is a sterile solution intended for intravenous administration.\n" }

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-fluoroara-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).

No animal carcinogenicity studies with fludarabine have been conducted.

Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberrations in the presence of metabolic activation) and induced sister chromatid exchanges both with and without metabolic activation. In addition, fludarabine phosphate was clastogenic in vivo (mouse micronucleus assay) but was not mutagenic to germ cells (dominant lethal test in male mice). Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells (HGRPT assay in Chinese hamster ovary cells) either in the presence or absence of metabolic activation.

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 mice and rats with a trend toward decreased 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 humans have not been adequately evaluated [see Warnings and Precautions (5.7)].

Two single-arm open-label studies of fludarabine phosphate have been conducted in adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In a study conducted by M.D. Anderson Cancer Center (MDAH), 48 patients were treated with a dose of 22 to 40 mg/m2 daily for 5 days every 28 days. Another study conducted by the Southwest Oncology Group (SWOG) involved 31 patients treated with a dose of 15 to 25 mg/m2 daily for 5 days every 28 days. The overall objective response rates were 48% and 32% in the MDAH and SWOG studies, respectively. The complete response rate in both studies was 13%; the partial response rate was 35% in the MDAH study and 19% in the SWOG study. These response rates were obtained using standardized response criteria developed by the National Cancer Institute CLL Working Group and were achieved in heavily pretreated patients. The ability of fludarabine phosphate to induce a significant rate of response in refractory patients suggests minimal cross-resistance with commonly used anti-CLL agents.

The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1 to 68 weeks) and 21 weeks (range of 1 to 53 weeks), respectively. The median duration of disease control was 91 weeks (MDAH) and 65 weeks (SWOG). The median survival of all refractory CLL patients treated with fludarabine phosphate was 43 weeks and 52 weeks in the MDAH and SWOG studies, respectively.

Rai stage improved to Stage II or better in 7 of 12 MDAH responders (58%) and in 5 of 7 SWOG responders (71%) who were Stage III or IV at baseline. In the combined studies, mean hemoglobin concentration improved from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in a subgroup of anemic patients. Similarly, average platelet count improved from 63,500/mm3 to 103,300/mm3 at the time of response in a subgroup of patients who were thrombocytopenic at baseline.

{ "type": "", "children": [], "text": "" }

Fludarabine Phosphate Injection, USP is supplied as follows:

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="20.600%"/> <col align="left" width="54.733%"/> <col align="left" width="24.667%"/> <tbody class="Headless"> <tr> <td align="left" valign="top"><span class="Bold">NDC</span></td><td align="left" valign="top"><span class="Bold">Fludarabine Phosphate Injection, USP (25 mg per mL)</span></td><td align="left" valign="top"><span class="Bold">Package Factor</span></td> </tr> <tr> <td align="left" valign="top">25021-242-02 </td><td align="left" valign="top">50 mg per 2 mL Single-Dose Vial </td><td align="left" valign="top">1 vial per carton </td> </tr> </tbody> </table></div>

Fludarabine Phosphate Injection, USP is a clear, sterile solution.

Each mL of Fludarabine Phosphate Injection, USP contains 25 mg of fludarabine phosphate, USP, 25 mg of mannitol, water for injection, qs; and sodium hydroxide to adjust pH to 6.8. The pH range for the final product is 6.0 to 7.1.

Store refrigerated between 2° and 8°C (36° and 46°F).

Protect from light. Retain in carton until time of use.

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 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.

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.

Patients should be informed of the importance of periodic assessment of their blood count to detect the development of anemia, neutropenia and thrombocytopenia.

During treatment, the patient's hematologic profile (particularly neutrophils, red blood cells, and platelets) should be monitored regularly to determine the degree of hematopoietic suppression [see Warnings and Precautions (5.2)].

Fludarabine phosphate can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant [see Warnings and Precautions (5.6)].

SAGENT® Mfd. for SAGENT PharmaceuticalsSchaumburg, IL 60195 (USA)Made in India©2021 Sagent Pharmaceuticals, Inc.

Revised: July 2021

SAGENT Pharmaceuticals®

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

{ "type": "p", "children": [], "text": "PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label\n" }

NDC 25021-242-02

{ "type": "p", "children": [], "text": "NDC 25021-242-02\n" }

Rx only

{ "type": "p", "children": [], "text": "Rx only\n" }

FLUDARABINE PHOSPHATE INJECTION, USP

{ "type": "p", "children": [], "text": "FLUDARABINE PHOSPHATE INJECTION, USP\n" }

50 mg per 2 mL

{ "type": "p", "children": [], "text": "50 mg per 2 mL\n" }

(25 mg per mL)

{ "type": "p", "children": [], "text": "(25 mg per mL)\n" }

For Intravenous Use Only

{ "type": "p", "children": [], "text": "For Intravenous Use Only\n" }

2 mL Single-Dose Vial

{ "type": "p", "children": [], "text": "2 mL Single-Dose Vial\n" }

Caution: Cytotoxic Agent

{ "type": "p", "children": [], "text": "Caution: Cytotoxic Agent\n" }

Fludarabine phosphate is indicated as a single agent for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) whose disease has not responded to or has progressed during or after treatment with at least one standard alkylating-agent containing regimen. Studies demonstrating clinical benefit such as prolongation of survival or relief of symptoms have not been performed. Studies providing a direct comparison of the clinical efficacy and safety of orally administered fludarabine phosphate relative to intravenously administered fludarabine phosphate have not been performed.

{ "type": "p", "children": [], "text": "Fludarabine phosphate is indicated as a single agent for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) whose disease has not responded to or has progressed during or after treatment with at least one standard alkylating-agent containing regimen. Studies demonstrating clinical benefit such as prolongation of survival or relief of symptoms have not been performed. Studies providing a direct comparison of the clinical efficacy and safety of orally administered fludarabine phosphate relative to intravenously administered fludarabine phosphate have not been performed." }

The oral dose is different than the intravenous dose.

The recommended adult dose of fludarabine phosphate is 40 mg/m2 administered by mouth 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. Fludarabine phosphate film-coated tablets 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.

The following table provides guidance for determining the number of tablets of fludarabine phosphate to be administered based on body surface area (BSA):

<div class="scrollingtable"><table frame="box" width="650"> <caption> <span>TABLE 1: SUGGESTED NUMBER OF TABLETS TO BE ADMINISTERED</span> </caption> <thead> <tr class="First Last"> <td align="center" class="BotruleLruleRruleToprule" valign="top"><span class="Bold">Body Surface Area (BSA)</span></td><td align="center" class="BotruleLruleRruleToprule" valign="top"><span class="Bold">Calculated Total Dose Equivalent to </span> <br/> <span class="Bold">40 mg/m</span><span class="Bold"><span class="Sup">2</span></span><span class="Bold"> BSA (rounded up or down </span> <br/> <span class="Bold">to nearest 10 mg)</span></td><td align="center" class="BotruleLruleRruleToprule" valign="top"><span class="Bold">Total Number of Tablets</span></td> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="BotruleLruleRruleToprule" valign="top">0.75 – 0.88</td><td align="center" class="BotruleLruleRruleToprule" valign="top">30 mg</td><td align="center" class="BotruleLruleRruleToprule" valign="top">3</td> </tr> <tr> <td align="center" class="BotruleLruleRruleToprule" valign="top">0.89 – 1.13</td><td align="center" class="BotruleLruleRruleToprule" valign="top">40 mg</td><td align="center" class="BotruleLruleRruleToprule" valign="top">4</td> </tr> <tr> <td align="center" class="BotruleLruleRruleToprule" valign="top">1.14 – 1.38</td><td align="center" class="BotruleLruleRruleToprule" valign="top">50 mg</td><td align="center" class="BotruleLruleRruleToprule" valign="top">5</td> </tr> <tr> <td align="center" class="BotruleLruleRruleToprule" valign="top">1.39 – 1.63</td><td align="center" class="BotruleLruleRruleToprule" valign="top">60 mg</td><td align="center" class="BotruleLruleRruleToprule" valign="top">6</td> </tr> <tr> <td align="center" class="BotruleLruleRruleToprule" valign="top">1.64 – 1.88</td><td align="center" class="BotruleLruleRruleToprule" valign="top">70 mg</td><td align="center" class="BotruleLruleRruleToprule" valign="top">7</td> </tr> <tr> <td align="center" class="BotruleLruleRruleToprule" valign="top">1.89 – 2.13</td><td align="center" class="BotruleLruleRruleToprule" valign="top">80 mg</td><td align="center" class="BotruleLruleRruleToprule" valign="top">8</td> </tr> <tr> <td align="center" class="BotruleLruleRruleToprule" valign="top">2.14 – 2.38</td><td align="center" class="BotruleLruleRruleToprule" valign="top">90 mg</td><td align="center" class="BotruleLruleRruleToprule" valign="top">9</td> </tr> <tr class="Last"> <td align="center" class="BotruleLruleRruleToprule" valign="top">2.39 – 2.50</td><td align="center" class="BotruleLruleRruleToprule" valign="top">100 mg</td><td align="center" class="BotruleLruleRruleToprule" valign="top">10</td> </tr> </tbody> </table></div>

A number of clinical settings may predispose to increased toxicity from fludarabine phosphate. 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 be administered following the achievement of a maximal response and then the drug should be discontinued.

10 mg film-coated tablets that are capsule shaped and salmon pink in color, marked on one side with ‘LN’ in a regular hexagon.

{ "type": "p", "children": [], "text": "10 mg film-coated tablets that are capsule shaped and salmon pink in color, marked on one side with ‘LN’ in a regular hexagon." }

None

{ "type": "p", "children": [], "text": "None" }

Dose-dependent neurotoxicity has been observed with fludarabine phosphate. Dose levels approximately 4 times greater (96 mg/m2/day for 5 days to 7 days) than the recommended intravenous dose (25 mg/m2/day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 days to 60 days following the last dose. Thirteen of 36 patients (36.1%) who received fludarabine phosphate intravenously at high doses (≥ 96 mg/m2/day for 5 days to 7 days per course) developed severe neurotoxicity, while only one of 443 patients (0.2%) who received the drug intravenously at low doses (≤ 40 mg/m2/day for 5 days per course) developed toxicity. In the pivotal clinical study conducted with fludarabine phosphate film-coated tablets administered at 40 mg/m2, severe impairment of consciousness was reported in one patient. 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. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate. In a study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3 days to 25 days) for granulocytes and 16 days (range, 2 days 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 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. One case of pancytopenia was reported in the pivotal clinical study conducted with oral fludarabine phosphate tablets.

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia 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 should be evaluated and closely monitored for hemolysis.

A high incidence of fatal pulmonary toxicity was observed in a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults. Therefore, the use of fludarabine phosphate in combination with pentostatin is not recommended.

Of 133 adult patients with CLL who received intravenous fludarabine phosphate in two clinical trials, there were 29 fatalities during study. Approximately 50% of the fatalities were due to infection and 25% due to progressive disease. Of 183 adult patients with CLL that received oral fludarabine phosphate in two clinical trials, there were 13 deaths. Approximately 50% of the deaths were due to progressive disease, while two patient deaths (15%) were attributed to infection. Monitor for signs and symptoms of infection.

Tumor lysis syndrome associated with fludarabine phosphate treatment has been reported in patients with CLL 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.

Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of non-irradiated blood in fludarabine phosphate treated patients. Consideration should, therefore, be given to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with fludarabine phosphate.

Fludarabine phosphate must be administered cautiously in patients with renal impairment. Following dosing of the intravenous product, the total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with mild to moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have their oral fludarabine phosphate dose reduced by 20% and be monitored closely. Patients with severe impairment of renal function (creatinine clearance < 30 mL/min/1.73 m2) should have their oral fludarabine phosphate dose reduced by 50% and be monitored closely.

Fludarabine phosphate is an 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 anemia, neutropenia and thrombocytopenia.

During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression.

Patients treated with fludarabine phosphate appear to be at an increased risk of infection. Monitor for signs and symptoms of infection.

Based on its mechanism of action, fludarabine phosphate can cause fetal harm when administered to a pregnant woman. Fludarabine phosphate administered to rats and rabbits during organogenesis caused an increase in resorptions, skeletal and visceral malformation, and decreased fetal body weights. If fludarabine phosphate 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. Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy. [see Use in Specific Populations (8.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to fludarabine phosphate tablets in 159 patients exposed to the drug. Fludarabine phosphate tablets were studied primarily in Study 1 in 78 patients with CLL who received prior therapy and in Study 2 in 81 patients with CLL who had not received prior therapy.

Based on experience with the intravenous and oral use of fludarabine phosphate, the most common adverse reactions include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, infection, and nausea and vomiting. Other commonly reported events include malaise, fatigue, anorexia, and weakness. Serious opportunistic infections have occurred in patients with CLL treated with fludarabine phosphate. The most frequently reported adverse reactions and those reactions which are more clearly related to the drug, as reported in clinical studies conducted with intravenous and oral fludarabine phosphate, are arranged below according to body system.

Hematopoietic Systems

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of patients with CLL treated with fludarabine phosphate. During intravenous fludarabine phosphate 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%. Among 78 patients with B-CLL who were treated with oral fludarabine phosphate, the absolute neutrophil count decreased to less than 500/mm3 in 37% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 14%, and platelet count decreased from pretreatment values by at least 50% in 17% of patients. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with fludarabine phosphate intravenously. In the pivotal oral fludarabine phosphate study (Study 1), there was one report of a non-fatal case of pancytopenia. Similarly, there was one case of non-fatal pancytopenia reported among the 133 patients with CLL treated with intravenous fludarabine phosphate.

Life-threatening and sometimes fatal autoimmune hemolytic anemias have been reported to occur in patients receiving fludarabine phosphate. [See Warnings and Precautions (5.2)] The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process.

Metabolic

Tumor lysis syndrome has been reported in patients with CLL treated with fludarabine phosphate 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

Objective weakness, agitation, confusion, visual disturbances, and coma have occurred in patients with CLL treated with fludarabine phosphate at the recommended dose. Peripheral neuropathy and one case of wrist-drop have been observed with intravenous administration of fludarabine phosphate. In Study 1 for oral fludarabine phosphate, there was one report of severe impairment of consciousness that presented concurrent with hemolytic anemia. This patient had enrolled in the study with pre-existing peripheral neurotoxicity. [See Warnings and Precautions (5.1)]

Pulmonary System

Pneumonia, a frequent manifestation of infection in patients with CLL, was observed in two clinical trials conducted with intravenous fludarabine phosphate (16% and 22%) and in two clinical trials with oral fludarabine phosphate (8% and 3%). Pulmonary hypersensitivity reactions to fludarabine phosphate characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed. In Study 1 conducted with oral fludarabine phosphate, severe pulmonary toxicity was reported in 5 of 78 patients, often in conjunction with respiratory or pulmonary infections and hence not regarded as isolated drug related pulmonary toxicity.

Gastrointestinal System

Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding have been reported in patients treated with fludarabine phosphate. Nausea and vomiting occurred in up to 38% of patients following treatment with oral fludarabine phosphate in the clinical trials.

Cardiovascular

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine phosphate. No other severe cardiovascular events were considered to be drug related.

Genitourinary System

Hemorrhagic cystitis has been reported in patients treated intravenously with fludarabine phosphate.

Skin

Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with oral and intravenous fludarabine phosphate.

Data in Table 2 are derived from the 159 patients with CLL who received fludarabine phosphate in Study 1 and Study 2.

<div class="scrollingtable"><table frame="void" width="600"> <caption> <span>TABLE 2: Incidence (≥5%) of Non-Hematologic Adverse Reactions in Patients with CLL Treated with Fludarabine Phosphate Tablets</span> </caption> <thead> <tr class="First Last"> <td align="center" valign="top"><span class="Bold Underline">ADVERSE REACTIONS</span></td><td align="center" valign="top"><span class="Bold Underline">Study 1</span> <br/>(N=78)<br/>%</td><td align="center" valign="top"><span class="Bold Underline">Study 2</span> <br/>(N=81)<br/>%</td> </tr> </thead> <tbody> <tr class="First"> <td valign="top">ANY ADVERSE REACTION</td><td align="center" valign="top">82</td><td align="center" valign="top">89</td> </tr> <tr> <td valign="top">BODY AS A WHOLE</td><td align="center" valign="top">59</td><td align="center" valign="top">77</td> </tr> <tr> <td valign="top">   FEVER</td><td align="center" valign="top">26</td><td align="center" valign="top">11</td> </tr> <tr> <td valign="top">   INFECTION</td><td align="center" valign="top">12</td><td align="center" valign="top">17</td> </tr> <tr> <td valign="top">   PAIN</td><td align="center" valign="top">5</td><td align="center" valign="top">19</td> </tr> <tr> <td valign="top">   FLU SYNDROME</td><td align="center" valign="top">8</td><td align="center" valign="top">5</td> </tr> <tr> <td valign="top">   DIAPHORESIS</td><td align="center" valign="top">8</td><td align="center" valign="top">0</td> </tr> <tr> <td valign="top">NEUROLOGICAL</td><td align="center" valign="top">19</td><td align="center" valign="top">41</td> </tr> <tr> <td valign="top">   WEAKNESS/FATIGUE (ASTHENIA)</td><td align="center" valign="top">13</td><td align="center" valign="top">31</td> </tr> <tr> <td valign="top">   SWEATING INCREASED</td><td align="center" valign="top">0</td><td align="center" valign="top">14</td> </tr> <tr> <td valign="top">   HEADACHE</td><td align="center" valign="top">9</td><td align="center" valign="top">9</td> </tr> <tr> <td valign="top">PULMONARY</td><td align="center" valign="top">37</td><td align="center" valign="top">53</td> </tr> <tr> <td valign="top">   COUGH</td><td align="center" valign="top">21</td><td align="center" valign="top">0</td> </tr> <tr> <td valign="top">   COUGH INCREASED</td><td align="center" valign="top">0</td><td align="center" valign="top">6</td> </tr> <tr> <td valign="top">   PNEUMONIA</td><td align="center" valign="top">8</td><td align="center" valign="top">3</td> </tr> <tr> <td valign="top">   DYSPNEA</td><td align="center" valign="top">1</td><td align="center" valign="top">5</td> </tr> <tr> <td valign="top">   SINUSITIS</td><td align="center" valign="top">1</td><td align="center" valign="top">5</td> </tr> <tr> <td valign="top">   UPPER RESPIRATORY INFECTION</td><td align="center" valign="top">9</td><td align="center" valign="top">14</td> </tr> <tr> <td valign="top">   RHINITIS</td><td align="center" valign="top">3</td><td align="center" valign="top">11</td> </tr> <tr> <td valign="top">   BRONCHITIS</td><td align="center" valign="top">6</td><td align="center" valign="top">9</td> </tr> <tr> <td valign="top">METABOLIC AND NUTRITIONAL</td><td align="center" valign="top">3</td><td align="center" valign="top">31</td> </tr> <tr> <td valign="top">   WEIGHT DECREASED</td><td align="center" valign="top">1</td><td align="center" valign="top">6</td> </tr> <tr> <td valign="top">   LACTIC DEHYDROGENASE INCREASED</td><td align="center" valign="top">0</td><td align="center" valign="top">6</td> </tr> <tr> <td valign="top">   PERIPHERAL EDEMA</td><td align="center" valign="top">0</td><td align="center" valign="top">7</td> </tr> <tr> <td valign="top">GASTROINTESTINAL</td><td align="center" valign="top">41</td><td align="center" valign="top">28</td> </tr> <tr> <td valign="top">   NAUSEA</td><td align="center" valign="top">5</td><td align="center" valign="top">1</td> </tr> <tr> <td valign="top">   DIARRHEA</td><td align="center" valign="top">6</td><td align="center" valign="top">5</td> </tr> <tr> <td valign="top">   ANOREXIA</td><td align="center" valign="top">19</td><td align="center" valign="top">0</td> </tr> <tr> <td valign="top">   ABDOMINAL PAIN</td><td align="center" valign="top">8</td><td align="center" valign="top">10</td> </tr> <tr> <td valign="top">CUTANEOUS</td><td align="center" valign="top">22</td><td align="center" valign="top">25</td> </tr> <tr> <td valign="top">   RASH</td><td align="center" valign="top">5</td><td align="center" valign="top">4</td> </tr> <tr> <td valign="top">   SKIN DISORDER</td><td align="center" valign="top">0</td><td align="center" valign="top">6</td> </tr> <tr> <td valign="top">   HERPES SIMPLEX</td><td align="center" valign="top">8</td><td align="center" valign="top">7</td> </tr> <tr> <td valign="top">GENITOURINARY</td><td align="center" valign="top">8</td><td align="center" valign="top">14</td> </tr> <tr> <td valign="top">   URINARY TRACT INFECTION</td><td align="center" valign="top">4</td><td align="center" valign="top">5</td> </tr> <tr> <td valign="top">CARDIOVASCULAR</td><td align="center" valign="top">14</td><td align="center" valign="top">17</td> </tr> <tr> <td valign="top">   CHEST PAIN</td><td align="center" valign="top">0</td><td align="center" valign="top">5</td> </tr> <tr> <td valign="top">MUSCULOSKELETAL</td><td align="center" valign="top">10</td><td align="center" valign="top">19</td> </tr> <tr class="Last"> <td valign="top">   BACK PAIN</td><td align="center" valign="top">4</td><td align="center" valign="top">9</td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post approval use of oral fludarabine phosphate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possibly to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematopoietic Systems

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.

Nervous System

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 median time to onset was approximately one year.

Pulmonary System

In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine phosphate use which resulted in acute respiratory distress syndrome, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, and respiratory failure. After exclusion of an infectious origin, some patients experienced symptom improvement with corticosteroids.

The use of fludarabine phosphate in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity. [See Warnings and Precautions (5.6)]

“Pregnancy Category D. See ‘Warnings and Precautions’ section.”

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 in pregnant women. Fludarabine phosphate was embryolethal and teratogenic in both rats and rabbits. If fludarabine phosphate 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. Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy.

In rats, repeated intravenous doses of fludarabine phosphate at 1.5 times and 4.5 times the recommended human oral dose (40 mg/m2) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights. Maternal toxicity was not apparent at 1.5 times the human oral dose, and was limited to slight body weight decreases at 4.5 times the human oral dose. In rabbits, repeated intravenous doses of fludarabine phosphate at 2.4 times the human oral dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels (≥ 0.3 times the human oral dose).

It is not known whether fludarabine phosphate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions including tumorgenicity in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

Of 78 previously treated patients with B-CLL treated with oral fludarabine phosphate 50% were ≥ age 65 and 3% were ≥ age 75. The response rate was generally lower among patients age 65 and older.  Among previously treated patients (Study 1) age 65 and older, the overall objective response, according to standardized response criteria developed by the National Cancer Institute CLL Working Group (NCI criteria), was 41%. The safety profile among younger and older patients on study was similar. Other reported clinical experience has not identified differences in responses or safety between older and younger patients.

In patients receiving intravenous fludarabine phosphate, the total body clearance of the metabolite 2-fluoro-ara-adenine (2F-ara-A) correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. Renal clearance represented approximately 40% of the total body clearance. Patients with mild to moderate renal impairment (30 to 70 mL/min/1.73 m2) receiving 20% reduced fludarabine phosphate dose had a similar exposure compared to patients with normal renal function receiving the recommended dose (AUC; 21 nM•h/mL versus 20 nM•h/mL). Two patients with severe renal impairment (< 30 mL/min/1.73 m2) receiving 40% reduced fludarabine phosphate dose had a 40% increase in exposure compared to patients with normal renal function receiving the recommended dose. The mean total body clearance was 172 mL/min for patients with normal renal function, 124 mL/min for patients with mild to moderately impaired renal function, and 71 mL/min for the two patients with severe renal impairment.

High doses of fludarabine phosphate [See Indications and Usage (1.1) and Warnings and Precautions (5.1)] 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 overdosage. Treatment consists of drug discontinuation and supportive therapy. In Study 2, two patients ingested an overdose of 20% to 33% of oral fludarabine phosphate. No serious side effects were reported.

{ "type": "p", "children": [], "text": "High doses of fludarabine phosphate [See Indications and Usage (1.1) and Warnings and Precautions (5.1)] 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 overdosage. Treatment consists of drug discontinuation and supportive therapy. In Study 2, two patients ingested an overdose of 20% to 33% of oral fludarabine phosphate. No serious side effects were reported." }

The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-ß-D-arabinofuranosyl)(2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is C10H13FN5O7P (MW 365.2) and the structure is provided in Figure 1

{ "type": "p", "children": [], "text": "The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-ß-D-arabinofuranosyl)(2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is C10H13FN5O7P (MW 365.2) and the structure is provided in Figure 1" }

Fludarabine phosphate film-coated tablets for oral administration contain fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-beta -D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Each tablet contains 10 mg of the active ingredient fludarabine phosphate. The tablet core consists of microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, croscarmellose sodium and magnesium stearate. The film-coat contains hypromellose, talc, titanium dioxide (E171) and ferric oxide pigment (red/E172, yellow/E172).

{ "type": "p", "children": [], "text": "Fludarabine phosphate film-coated tablets for oral administration contain fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-beta -D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Each tablet contains 10 mg of the active ingredient fludarabine phosphate. The tablet core consists of microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, croscarmellose sodium and magnesium stearate. The film-coat contains hypromellose, talc, titanium dioxide (E171) and ferric oxide pigment (red/E172, yellow/E172)." }

Fludarabine phosphate (2F-ara-AMP) is a synthetic purine nucleotide antimetabolite agent. Upon administration, 2F-ara-AMP is rapidly dephosphorylated in the plasma to 2F-ara-A, which then enters into the cell. Intracellularly, 2F-ara-A is converted to the 5'-triphosphate, 2-fluoro-ara-ATP (2F-ara-ATP). 2F-ara-ATP competes with deoxyadenosine triphosphate for incorporation into DNA. Once incorporated into DNA, 2F-ara-ATP functions as a DNA chain terminator, inhibits DNA polymerase alpha, gamma, and delta, and inhibits ribonucleoside diphosphate reductase. 2F-ara-A also inhibits DNA primase and DNA ligase I. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.

Cardiac Electrophysiology

In a randomized, uncontrolled, open-label, parallel study, patients with B-cell CLL were administered a single dose of oral fludarabine phosphate 40 mg/m2 (n = 42) or intravenous fludarabine phosphate 25 mg/m2 (n=14). The maximum increase in the baseline-corrected mean change in QTcI (individual-corrected QT interval) following treatment with oral fludarabine phosphate was less than 10 milliseconds.

Studies with the intravenous product have demonstrated that fludarabine phosphate is converted to the active metabolite, 2F-ara-A. Clinical pharmacology studies have focused on 2F-ara-A pharmacokinetics.

Following administration of the intravenous product, systemic plasma clearance of 2F-ara-A is approximately 117 mL/min to 145 mL/min. After five daily 30 minute intravenous infusions of 25 mg 2F-ara- AMP/m2 to cancer patients, trough concentrations of 2F-ara-A increased by a factor of about 2. The terminal half-life of 2F-ara-A was approximately 20 hours. Plasma protein binding of 2F-ara-A was approximately 19% to 29%. A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC).

2F-ara-A exhibits dose proportional increases in AUC and Cmax after single oral doses of 50 mg, 70 mg or 90 mg of 2F-ara-AMP. Cmax of 2F-ara-A occurs 1 hour to 2 hours after single or multiple oral doses and is approximately 20 % to 30 % of the maximum plasma concentrations produced at the end of a 30 minute intravenous infusion of the same dose. The absolute oral bioavailability of 2F-ara-A is 50 - 65% following single and repeated doses of the immediate release tablet formulation. Similar systemic exposure (AUC) was observed after a single 40 mg/m2 fludarabine phosphate oral dose and a single 25 mg/m2 fludarabine phosphate intravenous dose. The terminal half-life of 2F-ara-A was similar to that following intravenous administration; approximately 20 hours. The Cmax, AUC and terminal half-life of 2F-ara-A are unaffected when administered with a high fat meal, although Tmax is slightly delayed from 1.3 hours to 2.2 hours.

Following intravenous administration, renal clearance of 2F-ara-A represents approximately 40% of the total body clearance of fludarabine phosphate, and total body clearance is inversely correlated with serum creatinine and creatinine clearance. In two patients with median creatinine clearance of 22 mL/min/1.73 m2, 2F-ara-A clearance was reduced by 56%. Dosage adjustment based on creatinine clearance is recommended as follows:

Reduce dose by 20% in patients with mild to moderate renal impairment (creatinine clearance 30 to 70 mL/min/1.73 m2). [See Warnings and Precautions (5.7)]

Reduce dose by 50% in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2). [See Warnings and Precautions (5.7)]

No animal carcinogenicity studies with fludarabine phosphate have been conducted.

Fludarabine phosphate is a clastogen.

Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberration assay) in the presence of metabolic activation and induced sister chromatid exchanges both in the presence and absence of metabolic activation. In addition, fludarabine phosphate was clastogenic in vivo (mouse micronucleus assay) but was not mutagenic to germ cells (dominant lethal test in male mice). Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells either in the presence or absence of metabolic activation.

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 mice and rats with a trend toward decreased testicular weights in dogs and degeneration and necrosis of spermatogenic epithelium of the testes in mice, rats and dogs.

Study 1, a single-arm, open-label study of fludarabine phosphate film-coated tablets was conducted in 78 adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In this multicenter study patients were treated with oral fludarabine phosphate at a dose of 40 mg/m2 daily for 5 days every 28 days. The patient population median age was 64.5 years and consisted of 72% males and 28% females. Ninety-nine percent of the patients were Caucasian. The Rai stage for patients entering the study was: Stage 0 (3.9%), Stage I (20.5%), Stage II (32.1%), Stage III (11.5%), and Stage IV (32.1%). The mean number of treatment cycles was 5.1 with a mean daily dose of fludarabine phosphate of 38 mg/m2. The overall objective response, according to standardized response criteria developed by the National Cancer Institute CLL Working Group (NCI criteria), was 51 %, including 18% complete responses and 33% partial responses. The overall response rate, according to standardized criteria developed by the International Workshop on CLL (IWCLL criteria), was 46%, including 21% complete responses and 26% partial responses. Data on duration of response was not collected.

{ "type": "p", "children": [], "text": "Study 1, a single-arm, open-label study of fludarabine phosphate film-coated tablets was conducted in 78 adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In this multicenter study patients were treated with oral fludarabine phosphate at a dose of 40 mg/m2 daily for 5 days every 28 days. The patient population median age was 64.5 years and consisted of 72% males and 28% females. Ninety-nine percent of the patients were Caucasian. The Rai stage for patients entering the study was: Stage 0 (3.9%), Stage I (20.5%), Stage II (32.1%), Stage III (11.5%), and Stage IV (32.1%). The mean number of treatment cycles was 5.1 with a mean daily dose of fludarabine phosphate of 38 mg/m2. The overall objective response, according to standardized response criteria developed by the National Cancer Institute CLL Working Group (NCI criteria), was 51 %, including 18% complete responses and 33% partial responses. The overall response rate, according to standardized criteria developed by the International Workshop on CLL (IWCLL criteria), was 46%, including 21% complete responses and 26% partial responses. Data on duration of response was not collected." }

In Study 2, a supportive single-arm, open-label study, fludarabine phosphate tablets were administered to 81 previously untreated patients with B-CLL. In this multicenter study each patient was treated with oral fludarabine phosphate at a dose of 40 mg/m2 daily for 5 days every 28 days. The patient population median age was 64.0 years and consisted of 63% males and 37% females. Ninety-nine percent of the patients were Caucasian. The Rai stage for patients entering the study was: Stage 0 (3.7%), Stage I (37.0%), Stage II (37.0%), Stage III (9.9%), and Stage IV (12.3%). The mean number of treatment cycles was 5.9 with a mean daily dose per patient of 71 mg to 74 mg. The overall responses rate, according to NCI criteria, was 80%, including 12% complete responses and 68% partial responses. The overall response rate, according to IWCLL criteria, was 72%, including 37% complete responses and 35% partial responses. The median duration of response was 22.9 months.

{ "type": "p", "children": [], "text": "In Study 2, a supportive single-arm, open-label study, fludarabine phosphate tablets were administered to 81 previously untreated patients with B-CLL. In this multicenter study each patient was treated with oral fludarabine phosphate at a dose of 40 mg/m2 daily for 5 days every 28 days. The patient population median age was 64.0 years and consisted of 63% males and 37% females. Ninety-nine percent of the patients were Caucasian. The Rai stage for patients entering the study was: Stage 0 (3.7%), Stage I (37.0%), Stage II (37.0%), Stage III (9.9%), and Stage IV (12.3%). The mean number of treatment cycles was 5.9 with a mean daily dose per patient of 71 mg to 74 mg. The overall responses rate, according to NCI criteria, was 80%, including 12% complete responses and 68% partial responses. The overall response rate, according to IWCLL criteria, was 72%, including 37% complete responses and 35% partial responses. The median duration of response was 22.9 months." }

Study 3 was a supportive randomized controlled open label study in patients with previously untreated B-CLL that included fludarabine phosphate monotherapy and fludarabine phosphate combination therapy arms. In this study 107 evaluable patients received fludarabine phosphate 40mg/m2 orally daily for 5 days every 28 days. The overall response rate according to modified NCI criteria was 74% and the CR plus nodular PR rate was 41%.

{ "type": "p", "children": [], "text": "Study 3 was a supportive randomized controlled open label study in patients with previously untreated B-CLL that included fludarabine phosphate monotherapy and fludarabine phosphate combination therapy arms. In this study 107 evaluable patients received fludarabine phosphate 40mg/m2 orally daily for 5 days every 28 days. The overall response rate according to modified NCI criteria was 74% and the CR plus nodular PR rate was 41%." }

{ "type": "", "children": [], "text": "" }

HOW SUPPLIED

{ "type": "p", "children": [], "text": "\nHOW SUPPLIED\n" }

Fludarabine phosphate is supplied in 10 milligram tablets that are film-coated, capsule shaped, salmon pink in color, and marked on one side with ‘LN’ in a regular hexagon. Each film-coated tablet contains 10 mg fludarabine phosphate. The tablets are supplied in blisters, each blister strip containing 5 tablets. Packages of 15 and 20 tablets are available in child-resistant containers.

{ "type": "p", "children": [], "text": "Fludarabine phosphate is supplied in 10 milligram tablets that are film-coated, capsule shaped, salmon pink in color, and marked on one side with ‘LN’ in a regular hexagon. Each film-coated tablet contains 10 mg fludarabine phosphate. The tablets are supplied in blisters, each blister strip containing 5 tablets. Packages of 15 and 20 tablets are available in child-resistant containers." }

NDC 45414-311-15: 15 - 10 milligram film-coated tablets per container. Each film-coated tablet is packaged in an individual blister package; 5 tablets per blister strip; 3 blister strips packaged in a plastic bottle with a child-resistant container closure; each bottle is packaged in an individual chip-board carton.

{ "type": "p", "children": [], "text": "\nNDC 45414-311-15: 15 - 10 milligram film-coated tablets per container. Each film-coated tablet is packaged in an individual blister package; 5 tablets per blister strip; 3 blister strips packaged in a plastic bottle with a child-resistant container closure; each bottle is packaged in an individual chip-board carton." }

NDC 45414-311-20: 20 - 10 milligram film-coated tablets per container. Each film-coated tablet is packaged in an individual blister package; 5 tablets per blister strip; 4 blister strips packaged in a plastic bottle with a child-resistant container closure; each bottle is packaged in an individual chip-board carton.

{ "type": "p", "children": [], "text": "\nNDC 45414-311-20: 20 - 10 milligram film-coated tablets per container. Each film-coated tablet is packaged in an individual blister package; 5 tablets per blister strip; 4 blister strips packaged in a plastic bottle with a child-resistant container closure; each bottle is packaged in an individual chip-board carton." }

STORAGE

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Store under normal lighting conditions at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP controlled room temperature].

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HANDLING AND DISPOSAL

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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 of fludarabine phosphate. Do not crush tablets. Avoid exposure by direct contact of the skin or mucous membranes or by inhalation. If contact occurs, wash thoroughly with soap and water or wash the eyes immediately with gently flowing water for at least 15 minutes. Consult healthcare provider in case of a skin reaction or if the drug gets in the eyes.

{ "type": "p", "children": [], "text": "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 of fludarabine phosphate. Do not crush tablets. Avoid exposure by direct contact of the skin or mucous membranes or by inhalation. If contact occurs, wash thoroughly with soap and water or wash the eyes immediately with gently flowing water for at least 15 minutes. Consult healthcare provider in case of a skin reaction or if the drug gets in the eyes." }

Inform patients that fludarabine phosphate decreases blood cell counts such as white blood cells, platelets, and red blood cells. Thus, it is important that periodic assessment of their blood count be performed to detect the development of neutropenia, thrombocytopenia and anemia. [See Warnings and Precautions (5.2)]

Instruct patients to notify their physician promptly if fever or other signs of infection such as chills, cough, or burning pain on urination occurs while on therapy. [See Warnings and Precautions (5.4)]

Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy.

Fludarabine phosphate may cause fetal harm when administered to a pregnant woman. [See Warnings and Precautions (5.9)]

Instruct patients that caution should be exercised in the handling of fludarabine phosphate. Do not crush tablets. Avoid exposure by direct contact of the skin or mucous membranes or by inhalation. If contact occurs, wash thoroughly with soap and water or wash the eyes immediately with gently flowing water for at least 15 minutes. Consult healthcare provider in case of a skin reaction or if the drug gets in the eyes. Ask your healthcare provider or pharmacist for directions about how to safely dispose of fludarabine phosphate.

Manufactured for: Antisoma Research Limited, Cambridge, MA 02139

Manufactured by: Bayer Schering Pharma AG, Berlin, Germany

Patient Package Insert

[TRADENAME] (phonetic spelling) (oral fludarabine phosphate film-coated tablets)

Read this Patient Information leaflet before you start taking [TRADENAME] and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What Is [TRADENAME]?

[TRADENAME] is a prescription anticancer medicine that slows or stops the growth of cancer cells in adults with chronic lymphocytic leukemia (CLL). [TRADENAME] also stops or slows the growth of some healthy cells. This can cause side effects that you should know about and report to your healthcare provider.

[TRADENAME] has not been studied in children.

What is the most important information I should know about [TRADENAME]?

On rare occasions people taking [TRADENAME] can have life-threatening symptoms. If you:

Tell your healthcare provider right away.

What should I tell my healthcare provider before taking [TRADENAME]?

Before taking [TRADENAME], tell your healthcare provider about all of your medical conditions, including if you:

Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Using [TRADENAME] with certain other medicines may affect each other. Using [TRADENAME] with other medicines may cause serious side effects.

Know the medicines you take. Keep a list of them with you to show your healthcare provider.

How should I take [TRADENAME]?

What should I avoid while taking [TRADENAME]?

What are the possible side effects of [TRADENAME]?

See “What is the most important information I should know about [TRADENAME]?”

[TRADENAME] may cause serious side effects, including:

Low blood cell counts.

[TRADENAME] lessens the number of blood cells that fight infection, help your blood to clot, and carry oxygen throughout your body. This can result in

Avoid activities that can raise your chances of these conditions. Your healthcare provider will check your blood counts so that you will know when you are most at risk for infection, bleeding, and tiredness.

Call your healthcare provider right away if you have a temperature of 100.5 F. or above or do not feel well. Do not take a fever medicine until you check with your healthcare provider.

[TRADENAME] may cause other side effects, including:

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of [TRADENAME]. For more information, ask your healthcare provider or pharmacist.

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

How should I store and throw away [TRADENAME]?

Keep [TRADENAME] and all medicines out of the reach of children.

General information about [TRADENAME]

Medicines are sometimes prescribed for conditions that are not mentioned in patient information. Do not use [TRADENAME] for a condition for which it was not prescribed. Do not give [TRADENAME] to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about [TRADENAME]. For more information about [TRADENAME], talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about [TRADENAME] that is written for health professionals. For more information go to www.fludarabine.com or call 1-8XX-XXX-XXXX.

What are the ingredients in [TRADENAME]?

Active ingredients: fludarabine phosphate

Inactive ingredients: microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, croscarmellose sodium and magnesium stearate. The film-coat contains hypromellose, talc, titanium dioxide (E171) and ferric oxide pigment (red/E172, yellow/E172).

Rx only

PPI Issued August 11, 2008

Antisoma Research Ltd