FLUDARABINE PHOSPHATE

Fludarabine Phosphate for Injection, USP contains fludarabine phosphate USP, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Each vial of sterile lyophilized solid cake contains 50 mg of the active ingredient fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The pH range for the final product is 7.2 to 8.2. 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. The chemical name for fludarabine phosphate is 9 H -Purin-6-amine, 2-fluoro-9-(5- 0 -phosphono-β-D-arabino-furanosyl) (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: 9f8c17ab-figure-01

Fludarabine Phosphate for 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 for Injection in previously untreated or non-refractory patients with CLL have not been established.

Usual Dose The recommended adult dose of Fludarabine Phosphate for 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 for 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 for Injection be administered following the achievement of a maximal response and then the drug should be discontinued. Renal Impairment 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 for 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. Preparation of Solutions Fludarabine Phosphate for Injection should be prepared for parenteral use by aseptically adding Sterile Water for Injection, USP. When reconstituted with 2 mL of Sterile Water for Injection, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg of fludarabine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2 to 8.2. In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection, USP, or 0.9% Sodium Chloride, USP. Reconstituted Fludarabine Phosphate for Injection contains no antimicrobial preservative and thus should be used within 8 hours of reconstitution. Care must be taken to assure the sterility of prepared solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Fludarabine Phosphate for Injection should not be mixed with other drugs. 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 for 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.

Fludarabine Phosphate for Injection is contraindicated in those patients who are hypersensitive to this drug or its components.

Very common adverse events include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, fatigue, weakness, infection, pneumonia, cough, nausea, vomiting, and diarrhea. Other commonly reported events include malaise, mucositis and anorexia. Serious opportunistic infections (such as latent viral reactivation, herpes zoster virus, Epstein-Barr virus, and progressive multifocal leukoencephalopathy) have occurred in CLL patients treated with Fludarabine Phosphate for Injection. Adverse events and those reactions which are more clearly related to the drug are arranged below according to body system. Hematopoietic Systems Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with Fludarabine Phosphate for Injection. During Fludarabine Phosphate for Injection treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm 3 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 for Injection. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in post marketing surveillance. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients. Life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur in patients receiving Fludarabine Phosphate for Injection (see WARNINGS section). The majority of patients rechallenged with Fludarabine Phosphate for Injection developed a recurrence in the hemolytic process. In postmarketing experience, cases of myelodysplastic syndrome and acute myeloid leukemia, mainly associated with prior, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors, or irradiation have been reported. Infections Serious and sometimes fatal infections, including opportunistic infections and reactivations of latent viral infections such as VZV (herpes zoster), Epstein-Barr virus and JC virus (progressive multifocal leukoencephalopathy) have been reported in patients treated with Fludarabine Phosphate for Injection. Rare cases of Epstein Barr virus (EBV) associated lymphoproliferative disorders have been reported in patients treated with Fludarabine Phosphate for Injection. In postmarketing experience, cases of progressive multifocal leukoencephalopathy have been reported. Most cases had a fatal outcome. Many of these cases were confounded by prior and/or concurrent chemotherapy. The time to onset has ranged from a few weeks to approximately one year after initiating treatment. Of the 133 adult CLL patients in the two trials, there were 29 fatalities during study, approximately 50% of which were due to infection. Metabolic Tumor lysis syndrome has been reported in CLL patients treated with 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 (see WARNINGS section) Objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with Fludarabine Phosphate for Injection at the recommended dose. Peripheral neuropathy has been observed in patients treated with Fludarabine Phosphate for Injection and one case of wrist-drop was reported. There have been additional reports of cerebral hemorrhage though the frequency is not known. Pulmonary System Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16% and 22% of those treated with Fludarabine Phosphate for Injection in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to Fludarabine Phosphate for Injection characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed. In post-marketing experience, cases of severe pulmonary toxicity have been observed with Fludarabine Phosphate for Injection use which resulted in ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, pneumonitis and respiratory failure. After an infectious origin has been excluded, some patients experienced symptom improvement with corticosteroids. Gastrointestinal System Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding and hemorrhage have been reported in patients treated with Fludarabine Phosphate for Injection. Elevations of pancreatic enzyme levels have also been reported. Cardiovascular Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with Fludarabine Phosphate for Injection. There have been additional reports of heart failure and arrhythmia though the frequency is rare. No other severe cardiovascular events were considered to be drug related. Genitourinary System Rare cases of hemorrhagic cystitis have been reported in patients treated with Fludarabine Phosphate for Injection. Skin Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with Fludarabine Phosphate for Injection. Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and pemphigus have been reported, with fatal outcomes in some cases. Neoplasms Worsening or flare-up of pre-existing skin cancer lesions, as well as new onset of skin cancer, has been reported in patients during or after treatment with Fludarabine Phosphate for Injection. Hepatobiliary Disorders Elevations of hepatic enzyme levels have been reported. Data in the following table are derived from the 133 patients with CLL who received Fludarabine Phosphate for Injection in the MDAH and SWOG studies. PERCENT OF CLL PATIENTS REPORTING NONHEMATOLOGIC ADVERSE EVENTS ADVERSE EVENTS MDAH (N=101) SWOG (N=32) ANY ADVERSE EVENT 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 for Injection in studies of other leukemias, lymphomas, and other solid tumors. The spectrum of adverse effects reported in these studies was consistent with the data presented above. To report SUSPECTED ADVERSE EVENTS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

The use of Fludarabine Phosphate for Injection in combination with pentostatin is not recommended due to the risk of fatal pulmonary toxicity (see WARNINGS section).