Fludara 10 mg

Second-line treatment in patients with CLL who have failed other conventional therapies.

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

The safety and effectiveness of FLUDARA in children has not been established.

Since there are limited data for the use of FLUDARA in elderly persons (>75 years), caution should be exercised with the administration of FLUDARA in these patients. The total body clearance of the principal plasma metabolite 2F-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Patients with reduced kidney function demonstrated an increased total body exposure (area under the curve [AUC] of 2F-ara-A). Limited clinical data are available in patients with impairment of renal function (creatinine clearance below 70 mL/min). Since renal impairment is frequently present in patients over the age of 70 years, creatinine clearance should be measured.

If creatinine clearance is between 30 and 70 mL/min, the dose should be reduced by up to 50% and close hematologic monitoring should be used to assess toxicity. FLUDARA treatment is contraindicated if creatinine clearance is <30 mL/min. (See Warnings and Precautions and Dosage and Administration.)

Each film-coated tablet contains: fludarabine phosphate 10 mg. Nonmedicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, ferric oxide (red, yellow), hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, talc and titanium dioxide. Units of 3 and 4 blister packs in child-resistant containers. Each blister pack contains 5 tablets. Packages of 20 blister packs in nonchild-resistant containers are available for institutional use only.

Each 6 mL vial of sterile lyophilized solid cake or powder contains: fludarabine phosphate sodium equivalent to fludarabine phosphate 50 mg. Reconstitution with 2 mL of Sterile Water for Injection USP results in a solution containing 25 mg/mL of fludarabine phosphate intended for intravenous administration. Nonmedicinal ingredients: mannitol and sodium hydroxide. pH: 7.2-8.2. Single vial cartons in a shelf pack of 5.

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

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

Disease progression and transformation (eg, Richter’s Syndrome) have been commonly reported in CLL patients (see Warnings and Precautions, Skin).

The safety and effectiveness of FLUDARA in children have not been established.

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

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

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

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

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

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

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

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

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

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

Vaccination with live vaccines should be avoided during and after treatment with FLUDARA.

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

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

FLUDARA may reduce the ability to drive or use machines, since fatigue, weakness, and visual disturbances have been observed.

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

Tumor lysis syndrome associated with FLUDARA treatment has been reported in CLL patients with large tumor burdens. Since FLUDARA 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.

The worsening or flare-up of pre-existing skin cancer lesions as well as new onset of skin cancer has been reported to occur in patients during or after intravenous FLUDARA therapy.

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

Breastfeeding should not be initiated during FLUDARA treatment. Nursing women should discontinue breastfeeding.

There is evidence from preclinical data after intravenous administration to rats that FLUDARA and/or metabolites transfer from maternal blood to milk.

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

Store FLUDARA tablets between 15 and 30°C. Do not freeze. Keep out of reach and sight of children. Leave contents in protective packaging until use.

Store FLUDARA under refrigeration between 2 and 8°C. FLUDARA contains no antimicrobial preservative and thus care must be taken to ensure the sterility of prepared solutions. It is recommended to discard unused solutions 8 hours after reconstitution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the active metabolite, 2F-ara-A, within minutes after intravenous infusion. Consequently, clinical pharmacology studies have focused on 2F-ara-A pharmacokinetics. After single doses of 25 mg 2F-ara-AMP/m² to cancer patients infused over 30 minutes, 2F-ara-A reached mean maximum concentrations in the plasma of 3.5-3.7 µM at the end of infusion. Corresponding 2F-ara-A levels after the fifth dose showed a moderate accumulation with mean maximum levels of 4.4-4.8 µM at the end of infusion. During a 5-day treatment cycle, 2F-ara-A plasma trough levels increased by a factor of about 2. Accumulation of 2F-ara-A over several treatment cycles does not occur. Post maximum levels decayed in three disposition phases with an initial half-life of approximately 5 minutes, an intermediate half-life of 1-2 hours and a terminal half-life of approximately 20 hours.

An interstudy comparison of 2F-ara-A pharmacokinetics resulted in a mean total plasma clearance (CL) of 79 mL/min/m² (2.2 mL/min/kg) and a mean volume of distribution (V_ss) of 83 L/m² (2.4 L/kg). The data showed a high interindividual variability. After IV and peroral administration of fludarabine phosphate, plasma levels of 2F-ara-A and areas under the plasma level time curves increased linearly with the dose, whereas half-lives, plasma clearance and volumes of distribution remained constant independent of the dose, indicating a dose-linear behaviour.

After oral fludarabine phosphate doses, maximum 2F-ara-A plasma levels reached approximately 20-30% of corresponding IV levels at the end of infusion and occurred 1-2 hours after dosing. The mean systemic 2F-ara-A availability was in the range of 50-65% following single and repeated doses and was similar after ingestion of a solution or an immediate release tablet formulation. After oral doses of 2F-ara-AMP with concomitant food intake, a slight increase (<10%) of systemic availability (AUC), a slight decrease in maximum plasma levels (C_max) of 2F-ara-A and a delayed time to occurrence of C_max were observed; terminal half-lives were unaffected.

The mean steady-state volume of distribution (Vd_ss) of 2F-ara-A in one study was 96 L/m², suggesting a significant degree of tissue binding. Another study, in which Vd_ss for patients was determined to be 44 L/m², supports the suggestion of tissue binding.

Based upon compartmental analysis of pharmacokinetic data, the rate-limiting step for excretion of 2F-ara-A from the body appears to be release from tissue-binding sites. Total body clearance of 2F-ara-A has been shown to be inversely correlated with serum creatinine, suggesting renal elimination of the compound.

FLUDARA (fludarabine phosphate) is a fluorinated analog of adenine that is relatively resistant to deamination by adenosine deaminase.

Fludarabine phosphate (2F-ara-AMP) is a water-soluble prodrug, which is rapidly dephosphorylated to 2-fluoro-ara-A (2F-ara-A) and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate 2-fluoro-ara-ATP (2F-ara-ATP). The antitumor activity of this metabolite is the result of inhibition of DNA synthesis via inhibition of ribonucleotide reductase, DNA polymerase α, δ and ε, DNA primase and DNA ligase. Furthermore, partial inhibition of RNA polymerase II and consequent reduction in protein synthesis occur. While some aspects of the mechanism of action of 2F-ara-ATP are as yet unclear, it is believed that effects on DNA, RNA and protein synthesis all contribute to the inhibition of cell growth, with inhibition of DNA synthesis being the dominant factor. In addition, in vitro studies have shown that exposure of CLL lymphocytes to 2F-ara-A triggers extensive DNA fragmentation and apoptosis.

Two open-label studies of fludarabine phosphate have been conducted in patients with CLL refractory to at least one prior standard alkylating agent-containing regimen. Overall objective response rates were 32% in one study and 48% in the other with median time to response at 21 and 7 weeks respectively.

A pharmacokinetic study in patients with and without renal impairment revealed that, in patients with normal renal function, 40 to 60% of the administered IV dose was excreted in the urine. Mass balance studies in laboratory animals with ³H-2F-ara-AMP showed a complete recovery of radio-labelled substances in the urine. Another metabolite, 2F-ara-hypoxanthine, which represents the major metabolite in the dog, was observed in humans only to a minor extent. Patients with impaired renal function exhibited a reduced total body clearance, indicating the need for a reduced dose. Total body clearance of 2F-ara-A has been shown to be inversely correlated with serum creatinine, suggesting renal elimination of the compound. This was confirmed in a study of the pharmacokinetics of 2F-ara-A following administration of 2F-ara-AMP to cancer patients with normal renal function or varying degrees of renal impairment. The total body clearance of the principal metabolite 2F-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Renal clearance represented on average 40% of the total body clearance. In vitro investigations with human plasma proteins revealed no pronounced tendency of 2F-ara-A protein binding.

Maximum 2F-ara-ATP levels in leukemic lymphocytes of CLL patients were observed at a median of 4 hours and exhibited considerable variation with a median peak concentration of approximately 20 µM. 2F-ara-ATP levels in leukemic cells were always considerably higher than maximum 2F-ara-A levels in the plasma, indicating an accumulation at the target sites. In vitro incubation of leukemic lymphocytes showed a linear relationship between extracellular 2F-ara-A exposure (product of 2F-ara-A concentration and duration of incubation) and intracellular 2F-ara-A enrichment. Two independent investigations respectively reported median half-life values of 15 and 23 hours for the elimination of 2F-ara-ATP from target cells.

No clear correlation was found between 2F-ara-A pharmacokinetics and treatment efficacy in cancer patients; however, the occurrence of neutropenia and hematocrit changes indicated that the cytotoxicity of fludarabine phosphate depresses hematopoiesis in a dose-dependent manner.