FLUDARA

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.

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 10 H 13 FN 5 O 7 P (MW 365.2) and the structure is provided in Figure 1.

Figure 1: Chemical Structure of Fludarabine Phosphate 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.

Injection is a sterile solution intended for intravenous administration.

Injection is a nucleotide metabolic inhibitor 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.

Benefit in treatment-naïve or non-refractory CLL patients is not established. 1.1 Indication Fludarabine Phosphate Injection is indicated for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen.

The safety and effectiveness of Fludarabine Phosphate Injection in previously untreated or non-refractory patients with CLL have not been established.

The treatment should be used with caution in older patients; in terms of their greater vulnerability to toxicity.

Treatment should be used with caution in patients with kidney disorders; Vladrapin should not be given to patients suffering from acute kidney failure (the rate of urean removal below 30 ml/minute).

Treatment may cause a decline in bone marrow function; neurotoxicity; or autoimmune diseases such as degenerative anaemia.

The treatment may cause cancer syndrome; and the high incidence of urea in blood, preferably prophylaxis for the patient to have sufficient amounts of fluids and albinool.

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. 12.3 Pharmacokinetics 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/m 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).

Fladabin is a relative of Pyren

Mflore, discouraging a number of important enzymes in the manufacture of DNA and RNA, which discourages cell activity.

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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.

Very common adverse reactions include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, fatigue, weakness, infection, pneumonia, cough, nausea, vomiting and diarrhea.

Other commonly reported events include malaise, mucositis, and anorexia.

Serious opportunistic infections have occurred in

CLL patients treated with fludarabine phosphate.

The most frequently reported adverse reactions and those reactions which are more clearly related to the drug are arranged below according to body system.

Most common adverse reactions (incidence > 30%) include myelosuppression (neutropenia, thrombocytopenia and anemia), fever, infection, nausea and vomiting, fatigue, anorexia, cough and weakness.fda.gov/medwatch. 6.1 Hematopoietic Systems 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/mm 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.

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. 6.2.

Infections Serious and sometimes fatal infections, including opportunistic infections and reactivations of latent viral infections such as VZV (herpes zoster), Epstein-Barr virus and JC virus (progressive multifocal leukoencephalopathy) have been reported in patients treated with 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. 6.3 Metabolic 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. 6.4 Nervous System 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. 6.5 Pulmonary System 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. 6.6 Gastrointestinal System 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. 6.7 Cardiovascular 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. 6.8 Genitourinary System Hemorrhagic cystitis has been reported in patients treated with fludarabine phosphate. 6.9 Skin 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. 6.10 Neoplasms 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. 6.11 Hepatobiliary.

Disorders Elevations of hepatic enzyme levels have been reported. 6.12 Adverse Reactions from Clinical Trials Data in Table 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 ADVERSE REACTIONS MDAH (N=101) SWOG (N=32) ANY ADVERSE REACTION 88% 91% BODY AS A WHOLE 72 84 FEVER 60 69 CHILLS 11 19 FATIGUE 10 38 INFECTION 33 44 PAIN 20 22 MALAISE 8 6 DIAPHORESIS 1 13 ALOPECIA 0 3 ANAPHYLAXIS 1 0 HEMORRHAGE 1 0 HYPERGLYCEMIA 1 6 DEHYDRATION 1 0 NEUROLOGICAL 21 69 WEAKNESS 9 65 PARESTHESIA 4 12 HEADACHE 3 0 VISUAL DISTURBANCE 3 15 HEARING LOSS 2 6 SLEEP DISORDER 1 3 DEPRESSION 1 0 CEREBELLAR SYNDROME 1 0 IMPAIRED MENTATION 1 0 PULMONARY 35 69 COUGH 10 44 PNEUMONIA 16 22 DYSPNEA 9 22 SINUSITIS 5 0 PHARYNGITIS 0 9 UPPER RESPIRATORY INFECTION 2 16 ALLERGIC PNEUMONITIS 0 6 EPISTAXIS 1 0 HEMOPTYSIS 1 6 BRONCHITIS 1 0 HYPOXIA 1 0 GASTROINTESTINAL 46 63 NAUSEA/VOMITING 36 31 DIARRHEA 15 13 ANOREXIA 7 34 STOMATITIS 9 0 GI BLEEDING 3 13 ESOPHAGITIS 3 0 MUCOSITIS 2 0 LIVER FAILURE 1 0 ABNORMAL LIVER FUNCTION TEST 1 3 CHOLELITHIASIS 0 3 CONSTIPATION 1 3 DYSPHAGIA 1 0 CUTANEOUS 17 18 RASH 15 15 PRURITUS 1 3 SEBORRHEA 1 0 GENITOURINARY 12 22 DYSURIA 4 3 URINARY INFECTION 2 15 HEMATURIA 2 3 RENAL FAILURE 1 0 ABNORMAL RENAL FUNCTION TEST 1 0 PROTEINURIA 1 0 HESITANCY 0 3 CARDIOVASCULAR 12 38 EDEMA 8 19 ANGINA 0 6 CONGESTIVE HEART FAILURE 0 3 ARRHYTHMIA 0 3 SUPRAVENTRICULAR TACHYCARDIA 0 3 MYOCARDIAL INFARCTION 0 3 DEEP VENOUS THROMBOSIS 1 3 PHLEBITIS 1 3 TRANSIENT ISCHEMIC ATTACK 1 0 ANEURYSM 1 0 CEREBROVASCULAR ACCIDENT 0 3 MUSCULOSKELETAL 7 16 MYALGIA 4 16 OSTEOPOROSIS 2 0 ARTHRALGIA 1 0 TUMOR LYSIS SYNDROME 1 0 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.

High doses of fludarabine phosphate 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.

The recommended adult dose is 25 mg/m 2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days.

Each 5 day course of treatment should commence every 28 days.

Reduce dose in patients with creatinine clearance to 70 mL/min/l.73 m 2.

Do not use in patients with severe renal impairment. 2.1 Recommended Dose The recommended adult dose of fludarabine phosphate injection is 25 mg/m 2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days.

Each 5-day course of treatment should commence every 28 days.

Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity.

Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

A number of clinical settings may predispose to increased toxicity from Fludarabine Phosphate Injection.

These include advanced age, renal impairment, and bone marrow impairment.

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

The optimal duration of treatment has not been clearly established.

It is recommended that three additional cycles of Fludarabine Phosphate Injection be administered following the achievement of a maximal response and then the drug should be discontinued. 2.2 Renal Impairment Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance to 79 mL/min, as estimated by the Cockroft-Gault equations.

These adjustments are based on a pharmacokinetic study in patients with renal impairment.

Injection should not be administered to patients with creatinine clearance less than 30 mL/min. Starting Dose Adjustment for Renal Impairment Creatinine Clearance Starting Dose ≥ 80 mL/min 25 mg/m 2 (full dose) 50 to 79 mL/min 20 mg/m 2 30 to 49 mL/min 15 mg/m 2 < 30 mL/min Do not administer Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly. 2.3 Use of Infusion Solutions 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.

Injection should not be mixed with other drugs.

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. 16.2 Storage Store refrigerated between 2° and 8°C (36° and 46°F). 16.3 Handling and Disposal Procedures for proper handling and disposal should be considered.

Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs.

Several guidelines on this subject have been published. 1-4 Caution should be exercised in the handling and preparation of Fludarabine 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.

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

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.

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 to 21) with refractory acute leukemia (45 patients) or solid tumors (17 patients).

Limited pharmacokinetic data for fludarabine phosphate are available in children (ages 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/m 2 /day followed by a continuous infusion of 30.5 mg/m 2 /day for 5 days.

In 12 pediatric patients with solid tumors, dose-limiting myelosuppression was observed with a loading dose of 8 mg/m 2 /day followed by a continuous infusion of 23.5 mg/m 2 /day for 5 days.

The maximum tolerated dose was a loading dose of 7 mg/m 2 /day followed by a continuous infusion of 20 mg/m 2 /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.