{"adverse_reactions":["The following clinically significant adverse reactions are described elsewhere in the labeling: Neurologic Toxicities [see Warnings and Precautions ( 5.1 )] Myelosuppression [see Warnings and Precautions ( 5.2 )] Autoimmune Cytopenias [see Warnings and Precautions ( 5.3 )] Transfusion Associated Graft-Versus-Host Disease [see Warnings and Precautions ( 5.4 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.5 )] The most common adverse reactions (≥ 20%) are myelosuppression (neutropenia, thrombocytopenia, or anemia), fever, infection, nausea and vomiting, weakness, and pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hisun Pharmaceuticals USA, Inc. at 1-855-554-4786 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. B-cell Chronic Lymphocytic Leukemia Combination with Cyclophosphamide and Rituximab The safety of Fludarabine Phosphate Injection for the treatment of adults with B-cell CLL as a component of a combination regimen was derived from the published literature [see Clinical Studies ( 14 )] . The safety of Fludarabine Phosphate Injection for the treatment of adults with B-cell CLL as a component of a combination regimen was consistent with the known safety profile of fludarabine phosphate. Single Agent The safety of fludarabine phosphate was evaluated in two single-arm open-label studies (MDAH and SWOG) in adult patients (n=133) with CLL refractory to at least one prior alkylating-agent containing regimen [see Clinical Studies ( 14 )] . In these two clinical trials, 22% of the patients treated with fludarabine phosphate had fatal adverse reactions, with approximately 50% of these due to infection. Serious and fatal infections, including opportunistic and reactivation of latent viral infections such as Varicella-Zoster Virus (VZV; herpes zoster), Epstein-Barr Virus (EPV), and John Cunningham (JC) virus (progressive multifocal leukoencephalopathy) occurred in patients treated with fludarabine phosphate. Hematologic adverse reactions, including neutropenia (Grade 4: 59%), thrombocytopenia (55%), and anemia (55%) occurred in a majority of the CLL patients treated with fludarabine phosphate. The most common adverse reactions (≥ 20%) occurring in patients treated with fludarabine in the MDAH and SWOG trials (n=133) were myelosuppression (neutropenia, thrombocytopenia, or anemia), fever, infection, nausea and vomiting, weakness, and pain. Table 2 summarizes the non-hematologic adverse reactions in the MDAH and SWOG studies. Table 2: Non-Hematologic Adverse Reactions (≥ 5%) in CLL Patients Treated with Fludarabine in the MDAH and SWOG Studies Adverse Reactions MDAH (N=101) % SWOG (N=32) % General Fever 60 69 Pain 20 22 Fatigue 10 38 Chills 11 19 Malaise 8 6 Diaphoresis 1 13 Infection Infection 33 44 Pneumonia 16 22 Upper respiratory infection 2 16 Urinary infection 2 15 Sinusitis 5 0 Pharyngitis 0 9 Gastrointestinal Nausea/Vomiting 36 31 Anorexia 7 34 Diarrhea 15 13 Stomatitis 9 0 Gastrointestinal bleeding 3 13 Ne urological Weakness 9 65 Paresthesia 4 12 Visual disturbance 3 15 Hearing loss 2 6 P ulmonary Cough 10 44 Dyspnea 9 22 Allergic pneumonitis 0 6 Hemoptysis 1 6 Skin and Subcutaneous Rash 15 15 C ardiovascular Edema 8 19 Angina 0 6 M usculoskeletal Myalgia 4 16 Endocrine Hyperglycemia 1 6 Clinically relevant adverse reactions in < 5% of patients who received fludarabine phosphate included the following: General: Headache, hemorrhage, tumor lysis syndrome (hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, flank pain, renal failure) Blood and Lymphatic: Bone marrow fibrosis, thrombocytopenia/ITP, Evans syndrome, acquired hemophilia Cardiovascular: Congestive heart failure, arrhythmia, supraventricular tachycardia, myocardial infarction, transient ischemic attack, pericardial effusion Gastrointestinal: Esophagitis, mucositis, constipation, dysphagia, pancreatic enzyme increase Genitourinary: Dysuria, hematuria, renal failure, abnormal renal function test, proteinuria, hesitancy, hemorrhagic cystitis Hepatobiliary: Liver failure, ALT/AST elevation, cholelithiasis Immune System : Anaphylaxis Infection: VZR (herpes zoster), EBV (lymphoproliferative disorders), JC virus (progressive multifocal leukoencephalopathy) Musculoskeletal: Osteoporosis, arthralgia Neoplasms: tumor flare, skin cancer Neurological: Sleep disorder, depression, cerebellar syndrome, impaired mentation, agitation, confusion, seizures, optic neuritis, optic neuropathy, blindness and coma, peripheral neuropathy, cerebral hemorrhage Pulmonary: Epistaxis, bronchitis, hypoxia, interstitial pulmonary infiltrate Renal &Urinary : Dehydration Skin and Subcutaneous Tissue: Alopecia, pruritis, seborrhea; erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis, pemphigus (some fatal cases) Vascular: Deep venous thrombosis, phlebitis, aneurysm, cerebrovascular accident The following adverse reactions have been identified during postapproval use of fludarabine phosphate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic : Bone marrow hypoplasia or aplasia resulting in pancytopenia (range: 2 months to 12 months after treatment initiation; some fatal); myelodysplastic syndrome and acute myeloid leukemia Infection : Progressive multifocal leukoencephalopathy (range: 3 weeks to one year after treatment initiation; some fatal) Pulmonary : Acute Respiratory Distress Syndrome (ARDS), respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, pneumonitis, respiratory failure"],"adverse_reactions_table":["
Adverse ReactionsMDAH(N=101)%SWOG(N=32)%
General
Fever6069
Pain2022
Fatigue1038
Chills1119
Malaise86
Diaphoresis113
Infection
Infection3344
Pneumonia1622
Upper respiratory infection216
Urinary infection215
Sinusitis50
Pharyngitis09
Gastrointestinal
Nausea/Vomiting3631
Anorexia734
Diarrhea1513
Stomatitis90
Gastrointestinal bleeding313
Neurological
Weakness965
Paresthesia412
Visual disturbance315
Hearing loss26
Pulmonary
Cough1044
Dyspnea922
Allergic pneumonitis06
Hemoptysis16
Skin and Subcutaneous
Rash1515
Cardiovascular
Edema819
Angina06
Musculoskeletal
Myalgia416
Endocrine
Hyperglycemia16
"],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["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."],"clinical_pharmacology":["Fludarabine phosphate is rapidly converted to active 2-fluoro-ara-ATP [see Clinical Pharmacology ( 12.3 )] , which appears to inhibit DNA synthesis through inhibition of DNA polymerase alpha, ribonucleotide reductase and DNA primase. The degree of absolute granulocyte count nadir is correlated with increased area under the concentration x time curve (AUC); however, the exposure-response relationship and time-course of pharmacodynamic response of fludarabine have not been fully characterized. Fludarabine phosphate is a prodrug. It is rapidly converted to its active metabolite, 2-fluoro-ara-A which is the focus of the pharmacokinetic characterization. 2-fluoro-ara-A plasma trough concentration accumulated 2-fold. D istribution Plasma protein binding ranged between 19% and 29% in vitro. E limination The terminal half-life of 2-fluoro-ara-A was approximately 20 hours. The total body clearance of 2-fluoro-ara-A correlated with the creatinine clearance. Renal clearance represents approximately 40% of the total body clearance. Me tabolism Fludarabine phosphate is dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP."],"clinical_studies":["B-cell Chronic Lymphocytic Leukemia I n Combination with Cyclophosphamide and Rituximab The efficacy of Fludarabine Phosphate Injection for treatment of adults with B-cell CLL as a component of a combination regimen was derived from studies of fludarabine phosphate in the published literature. Fludarabine phosphate as a component of a combination regimen was evaluated in two randomized clinical trials (NCT00090051 and NCT00281918). In both trials, the major efficacy outcome measure was progression-free survival. Single Agent The efficacy of fludarabine phosphate was evaluated in two single-arm open-label studies in adult patients with CLL refractory to at least one prior alkylating-agent containing regimen. The first study (MDAH) included 48 patients treated with a dose of 22 to 40 mg/m 2 for 5 days every 28 days daily (0.9 – 1.6 times the recommended dose). The second study (SWOG) included 31 patients treated with a dose of 15 to 25 mg/m 2 daily for 5 days every 28 days daily (0.6 – 1.0 times the recommended dose). Patients in the SWOG trial had a median age of 63 years and a baseline median performance status of 1. 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. 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/mm 3 to 103,300/mm 3 at the time of response in a subgroup of patients who were thrombocytopenic at baseline."],"contraindications":["None. None. ( 4 )"],"description":["Fludarabine Phosphate Injection, USP contains fludarabine phosphate, a nucleoside metabolic inhibitor. The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-β-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 has the following chemical structure: Each mL contains 25 mg of the active ingredient fludarabine phosphate (equivalent to 19.5 mg Fludarabine), 1.78 mg disodium phosphate dihydrate, water for injection and sodium hydroxide to adjust pH to 7.5. The pH range for the final product is 7.3 to 7.7. Fludarabine Phosphate Injection, USP is a sterile solution intended for intravenous administration. Chemical structure of fludarabine phosphate"],"dosage_and_administration":["The recommended dosage is: In Combination with Cyclophosphamide and Rituximab: The recommended dosage is 25 mg/m 2 administered intravenously over 30 minutes daily for the first three days (Days 1 to 3) of each 28-day cycle for 6 cycles in combination with cyclophosphamide 250 mg/m 2 administered intravenously daily for three days (Days 1 to 3), and rituximab 375 mg/m 2 administered intravenously on Day 1 of the first cycle, followed by rituximab 500 mg/m 2 on Day 1 of subsequent cycles. ( 2.1 ) Single Agent: The recommended dosage is 25 mg/m 2 administered intravenously over approximately 30 minutes daily for five consecutive days (Days 1 to 5) of each 28-day cycle. ( 2.1 ) Renal impairment: Reduce the dosage for patients with creatinine clearance (CLcr) 30 to 79 mL/min. ( 2.2 , 8.6 ) See the Full Prescribing Information for instructions for preparation and administration. ( 2.3 ) 2.1 Recommended Dosage In Combination with Cyclophosphamide and Rituximab The recommended dosage of Fludarabine Phosphate Injection is 25 mg/m 2 administered intravenously over 30 minutes daily for the first three days (Days 1 to 3) of each 28-day cycle for 6 cycles or until unacceptable toxicity or disease progression, in combination with cyclophosphamide 250 mg/m 2 administered intravenously daily for three days (Days 1 to 3), and rituximab 375 mg/m 2 administered intravenously on Day 1 of the first cycle, followed by rituximab 500 mg/m 2 on Day 1 of subsequent cycles. Refer to the cyclophosphamide and rituximab prescribing information for additional dosing information as appropriate. Single Agent The recommended dosage of Fludarabine Phosphate Injection is 25 mg/m 2 administered intravenously over 30 minutes daily for five consecutive days (Days 1 to 5) of each 28-day cycle. 2.2 Recommended Dosage for Patients with Renal Impairment Reduce the Fludarabine Phosphate Injection dosage for patients with renal impairment as shown in Table 1. Closely monitor patients with renal impairment for adverse reactions. Table 1: Dosage Modifications for Renal Impairment Cre atinine Clearance (Estimated by Cockcroft-Gault equation) Recommended Dosage ​50 – 79 mL/min ​20 mg/m 2 30 – 49 mL/min 15 mg/m 2 < 30 mL/min A dosage has not been established. 2.3 Preparation and Administration Fludarabine Phosphate Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Dilute Fludarabine Phosphate Injection in 100 mL to 125 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Infuse diluted Fludarabine Phosphate Injection intravenously over 30 minutes. Fludarabine Phosphate Injection contains no antimicrobial preservative. If not used immediately, discard the unused portion within 8 hours after opening the single-dose vial. Do not mix Fludarabine Phosphate Injection with other drugs.","2.1 Recommended Dosage In Combination with Cyclophosphamide and Rituximab The recommended dosage of Fludarabine Phosphate Injection is 25 mg/m 2 administered intravenously over 30 minutes daily for the first three days (Days 1 to 3) of each 28-day cycle for 6 cycles or until unacceptable toxicity or disease progression, in combination with cyclophosphamide 250 mg/m 2 administered intravenously daily for three days (Days 1 to 3), and rituximab 375 mg/m 2 administered intravenously on Day 1 of the first cycle, followed by rituximab 500 mg/m 2 on Day 1 of subsequent cycles. Refer to the cyclophosphamide and rituximab prescribing information for additional dosing information as appropriate. Single Agent The recommended dosage of Fludarabine Phosphate Injection is 25 mg/m 2 administered intravenously over 30 minutes daily for five consecutive days (Days 1 to 5) of each 28-day cycle.","2.2 Recommended Dosage for Patients with Renal Impairment Reduce the Fludarabine Phosphate Injection dosage for patients with renal impairment as shown in Table 1. Closely monitor patients with renal impairment for adverse reactions. Table 1: Dosage Modifications for Renal Impairment Cre atinine Clearance (Estimated by Cockcroft-Gault equation) Recommended Dosage ​50 – 79 mL/min ​20 mg/m 2 30 – 49 mL/min 15 mg/m 2 < 30 mL/min A dosage has not been established.","2.3 Preparation and Administration Fludarabine Phosphate Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Dilute Fludarabine Phosphate Injection in 100 mL to 125 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Infuse diluted Fludarabine Phosphate Injection intravenously over 30 minutes. Fludarabine Phosphate Injection contains no antimicrobial preservative. If not used immediately, discard the unused portion within 8 hours after opening the single-dose vial. Do not mix Fludarabine Phosphate Injection with other drugs."],"dosage_and_administration_table":["
Creatinine Clearance(Estimated by Cockcroft-Gault equation)Recommended Dosage
​50 – 79 mL/min​20 mg/m 2
30 – 49 mL/min15 mg/m 2
< 30 mL/minA dosage has not been established.
","
Creatinine Clearance(Estimated by Cockcroft-Gault equation)Recommended Dosage
​50 – 79 mL/min​20 mg/m 2
30 – 49 mL/min15 mg/m 2
< 30 mL/minA dosage has not been established.
"],"dosage_forms_and_strengths":["Injection: 50 mg/2 mL (25 mg/mL). Fludarabine Phosphate Injection, USP is supplied as a clear, colorless to almost colorless sterile solution in single-dose vials. Injection: 50 mg/2 mL (25 mg/mL) ( 3 )"],"drug_interactions":["7.1 Pentostatin Avoid use of Fludarabine Phosphate Injection in combination with pentostatin due to the risk of severe and fatal pulmonary toxicity [see Warnings and Precautions ( 5.6 )]","7.1 Pentostatin Avoid use of Fludarabine Phosphate Injection in combination with pentostatin due to the risk of severe and fatal pulmonary toxicity [see Warnings and Precautions ( 5.6 )]"],"effective_time":"20260827","how_supplied":["HOW SUPPLIED/STORAGE AND HANDLING H ow Supplied Fludarabine Phosphate Injection, USP is supplied as a clear, colorless to almost colorless sterile solution in a single- dose vial containing 50 mg/2 mL (25 mg/mL) of fludarabine phosphate. NDC 42658-024-01 one carton containing 1 vial of Fludarabine Phosphate Injection, USP. Storage Store in a refrigerator between 2˚ and 8˚C (36˚ to 46˚F). Ha ndling and Disposal Fludarabine Phosphate Injection, USP is a hazardous drug. Follow applicable special handling and disposal procedures. 1 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."],"id":"59fd0cfe-f1e3-9b20-e063-6294a90a6ad6","indications_and_usage":["Fludarabine Phosphate Injection is indicated: as a component of a combination regimen for the treatment of adults with B-cell chronic lymphocytic leukemia (CLL); for the treatment of adults with B-cell CLL who have not responded to or whose disease has progressed during treatment with at least one alkylating-agent containing regimen. Fludarabine Phosphate Injection is a nucleoside metabolic inhibitor indicated: as a component of a combination regimen for the treatment of adults with B-cell chronic lymphocytic leukemia (CLL); ( 1 ) for the treatment of adults with B-cell CLL who have not responded to, or whose disease has progressed during treatment with at least one alkylating- agent containing regimen. ( 1 )"],"mechanism_of_action":["Fludarabine phosphate is rapidly converted to active 2-fluoro-ara-ATP [see Clinical Pharmacology ( 12.3 )] , which appears to inhibit DNA synthesis through inhibition of DNA polymerase alpha, ribonucleotide reductase and DNA primase."],"nonclinical_toxicology":["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."],"openfda":{},"overdosage":["Severe myelosuppression, including thrombocytopenia, neutropenia, anemia, and pancytopenia has occurred in patients treated with doses that exceed the recommended dosage of Fludarabine Phosphate Injection [see Warnings and Precautions ( 5.3 )] . Severe, irreversible, central nervous system effects including blindness, coma, and death have occurred in patients treated at doses approximately four times greater (96 mg/m 2 /day for 5 to 7 days) than the recommended dose for fludarabine phosphate [see Warnings and Precautions ( 5.4 )] . There is no known specific antidote for fludarabine phosphate overdosage. Treatment consists of drug discontinuation and supportive therapy."],"package_label_principal_display_panel":["NDC 42658-024-01 Vial Label Fludarabine Phosphate Injection 50mg/2mL (25mg/mL) NDC 42658-024-01 lnner carton Fludarabine Phosphate Injection 50mg/2mL (25mg/mL) Vial Label-25mg/mL Carton-25mg/mL"],"pharmacodynamics":["The degree of absolute granulocyte count nadir is correlated with increased area under the concentration x time curve (AUC); however, the exposure-response relationship and time-course of pharmacodynamic response of fludarabine have not been fully characterized."],"pharmacokinetics":["Fludarabine phosphate is a prodrug. It is rapidly converted to its active metabolite, 2-fluoro-ara-A which is the focus of the pharmacokinetic characterization. 2-fluoro-ara-A plasma trough concentration accumulated 2-fold. D istribution Plasma protein binding ranged between 19% and 29% in vitro. E limination The terminal half-life of 2-fluoro-ara-A was approximately 20 hours. The total body clearance of 2-fluoro-ara-A correlated with the creatinine clearance. Renal clearance represents approximately 40% of the total body clearance. Me tabolism Fludarabine phosphate is dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP."],"recent_major_changes":["Boxed Warning (removed) 11/2024 Indications and Usage ( 1 ) 11/2024 Dosage and Administration, Recommended Dosage ( 2.1 ) 11/2024 Warnings and Precautions ( 5 ) 11/2024"],"references":["“OSHA Hazardous Drugs.” OSHA. https://www.osha.gov/hazardous-drugs"],"set_id":"291f6ee2-f5d2-ae6c-e063-6294a90a5951","spl_product_data_elements":["Fludarabine Phosphate Fludarabine Phosphate FLUDARABINE PHOSPHATE FLUDARABINE WATER SODIUM HYDROXIDE SODIUM PHOSPHATE DIBASIC DIHYDRATE"],"spl_unclassified_section":["Ne urologic Toxicities Inform patients that Fludarabine Phosphate Injection can cause severe CNS adverse reactions, including coma, seizures, agitation, and confusion. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider immediately if they experience signs or symptoms of CNS adverse reactions [see Warnings and Precautions ( 5.1 )] . Myelosuppression Inform patients Fludarabine Phosphate Injection can cause a decrease in white blood cells, platelets, and red blood cells, and the need for frequent monitoring of blood counts. Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . Autoimmune Cytopenias Inform patients that Fludarabine Phosphate Injection can cause autoimmune hemolytic anemia, autoimmune thrombocytopenia/ITP, Evans syndrome, and acquired hemophilia. Advise patients to seek immediate medical attention if any signs or symptoms of autoimmune cytopenias occur [see Warnings and Precautions ( 5.3 )] . Tumor Lysis Syndrome Inform patients about the risk of and the signs and symptoms of tumor lysis syndrome. Advise patients to notify their healthcare provider if they experience these symptoms [see Warnings and Precautions ( 5.5 )] . Vaccination Advise patients they should avoid vaccinations with live vaccines during and after treatment [see Warnings and Precautions ( 5.7 )] . Nausea and Vomiting Advise patients that Fludarabine Phosphate Injection may cause nausea and/or vomiting. Inform patients to report nausea and vomiting so that symptomatic treatment may be provided when this occurs [see Adverse Reactions ( 6.1 )] . Rash Advise patients that a rash or itching may occur during treatment with Fludarabine Phosphate Injection. Advise patients to immediately report severe or worsening rash or itching [see Adverse Reactions ( 6.1 )] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise female patients to contact their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose [see Use in Specific Populations ( 8.3 )] . Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Use in Specific Populations ( 8.3 )] . Lactation Advise women not to breastfeed during treatment and for 1 week after the last dose of Fludarabine Phosphate Injection [see Use in Specific Populations ( 8.2 )] . Infertility Advise males of reproductive potential that Fludarabine Phosphate Injection may impair fertility [see Use in Specific Populations ( 8.3 )] Distributed by: Hisun Pharmaceuticals USA, Inc. Bridgewater, NJ 08807 USA Manufactured in China Revised: 08/2025"],"use_in_specific_populations":["8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman. There are no available data on Fludarabine Phosphate Injection use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, administration of fludarabine phosphate to pregnant animals during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal doses below (rabbits) and above (rats) those in patients at the recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data 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). 8.2 Lactation Risk Summary There are no data on the presence of fludarabine phosphate or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with Fludarabine Phosphate Injection, and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiation of Fludarabine Phosphate Injection [see Use in Specific Populations ( 8.1 )] . Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . I n fer tility Males Based on findings in animals and humans, Fludarabine Phosphate Injection may impair male fertility. Fludarabine phosphate may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The reversibility of this effect is unknown [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of Fludarabine Phosphate Injection have not been established in pediatric patients. Safety and effectiveness were assessed, but not established for Fludarabine Phosphate Injection in pediatric patients 1 year to < 17 years with refractory acute leukemia or solid tumors. No new safety signals were observed in pediatric patients across these studies. 8.5 Geriatric Use Among patients with CLL evaluated in two randomized active-controlled trials treated with fludarabine, cyclophosphamide, and rituximab, 36% were 65 years of age or older; of these, 15% were 70 years of age or older. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving fludarabine in combination with cyclophosphamide and rituximab who were 70 years or older compared to younger patients for neutropenia, febrile neutropenia, anemia, thrombocytopenia, pancytopenia, and infections. Clinical studies of fludarabine as a single agent for patients with B-cell CLL did not include a sufficient numbers of younger adults to determine if patients with B-cell CLL who are 65 years of age and older respond differently from younger adults. 8.6 Renal Impairment Reduce the dosage in patients with CLcr 30 to 79 mL/min. A dosage has not been established for patients with severe renal impairment (CLcr < 30 mL/min) [see Dosage and Administration ( 2.2 )] . The total body clearance of 2-fluoro-ara-A is correlated with the creatinine clearance [see Clinical Pharmacology ( 12.3 )] ; however, the effect of varying degrees of renal impairment on the pharmacokinetics of this metabolite has not been fully characterized. • Lactation : Advise not to breastfeed. ( 8.2 ) • Infertility : May impair fertility. ( 8.3 ) See 17 for PATIENT COUNSELING INFORMATION. Revised: 08/2025"],"version":"6","warnings_and_cautions":["N eurological Toxicities : Coma, seizures, agitation and confusion can occur and are dose dependent. Monitor patients for signs and symptoms of neurologic toxicity. Consider delaying or discontinuing Fludarabine Phosphate Injection if neurotoxicity occurs. ( 5.1 , 10 ) M y elosuppression : Severe anemia, thrombocytopenia, neutropenia, or pancytopenia can occur and are dose dependent. Monitor blood counts before and during treatment. Consider dose delays, dose reductions, or permanent discontinuation if recovery has not occurred by the first day of the next scheduled cycle. ( 5.2 , 10 ) A u t o immune Cytopenias : Life-threatening and fatal autoimmune hemolytic anemia, autoimmune thrombocytopenia/ thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia can occur. Closely monitor patients for hemolysis and manage as clinically indicated. ( 5.3 ) Transfusion-Associated Graft-Versus-Host Disease : Use only irradiated blood products for transfusions. ( 5.4 ) Tumor Lysis Syndrome (TLS) : Closely monitor patients at risk for TLS, consider appropriate prophylaxis including hydration, and manage as clinically indicated. ( 5.5 ) P u lmonary Toxicity in Patients with CLL when Fludarabine Phosphate is Used with Pentostatin : Severe and sometimes fatal pulmonary toxicity when used concomitantly with pentostatin. Concomitant use is not recommended. ( 5.6 , 7.1 ) V accination : Avoid live attenuated vaccines during or after treatment with Fludarabine Phosphate Injection. ( 5.7 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.8 , 8.1 ) 5.1 Neurologic Toxicities Severe central nervous system (CNS) adverse reactions, including coma, seizures, agitation and confusion, can occur in patients treated with Fludarabine Phosphate Injection. CNS adverse reactions may occur either early or late after the initiation of Fludarabine Phosphate Injection (range 7 to 225 days). CNS adverse reactions are dose dependent and occur at greater incidence and severity in patients treated at doses higher than the recommended dose of Fludarabine Phosphate Injection [see Overdosage ( 10 )] . Monitor patients for signs and symptoms of neurologic toxicity during and after treatment with Fludarabine Phosphate Injection. Consider delaying or discontinuing Fludarabine Phosphate Injection if neurotoxicity occurs. Do not administer Fludarabine Phosphate Injection at doses higher than the recommended dose. Advise patients that Fludarabine Phosphate Injection may reduce the ability to drive or use mechanical equipment, since fatigue, weakness, visual disturbances, confusion, agitation, or seizures may occur. 5.2 Myelosuppression Fludarabine phosphate can cause severe and fatal myelosuppression, which may include neutropenia, thrombocytopenia, or anemia. Cases of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported. The median time to nadir of counts was approximately 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32 days) for platelets. The duration of the cytopenia in reported cases has ranged from approximately 2 months to approximately 1 year. Monitor complete blood counts at baseline, prior to and during each treatment cycle, and as clinically needed. Consider dosage delays, dose reductions, or permanent discontinuation if recovery has not occurred by the first day of the next scheduled cycle. 5.3 Autoimmune Cytopenias Life-threatening and fatal autoimmune hemolytic anemia, autoimmune thrombocytopenia/idiopathic thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia can occur in patients treated with fludarabine phosphate with or without a previous history of autoimmune hemolytic anemia or a positive Coombs’ test. 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. Closely monitor patients during treatment with Fludarabine Phosphate Injection for autoimmune cytopenias and manage as clinically indicated. 5.4 Transfusion Associated Graft-Versus-Host Disease Transfusion-associated graft-versus-host disease has been observed after transfusion of non-irradiated blood in patients treated with fludarabine phosphate. Fatal outcome as a consequence of this disease has been reported. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received, treatment with Fludarabine Phosphate Injection should receive irradiated blood only. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) can occur in patients treated with Fludarabine Phosphate Injection. TLS has been reported in patients with CLL who have large tumor burdens and can occur as early as the first week of treatment. Closely monitor patients at risk for TLS, consider appropriate prophylaxis including hydration, and manage as clinically indicated. 5.6 Pulmonary Toxicity in Patients with CLL When Fludarabine Phosphate is Used with Pentostatin In clinical trials, patients experienced fatal pulmonary toxicity when treated with fludarabine phosphate and pentostatin for refractory CLL. Avoid concomitant use of Fludarabine Phosphate Injection with pentostatin [see Drug Interactions ( 7.1 )] . 5.7 Vaccination During and after treatment with Fludarabine Phosphate Injection, avoid vaccination with live vaccines. 5.8 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fludarabine phosphate to pregnant animals during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal doses below (rabbits) and above (rats) those in patients at the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] .","5.1 Neurologic Toxicities Severe central nervous system (CNS) adverse reactions, including coma, seizures, agitation and confusion, can occur in patients treated with Fludarabine Phosphate Injection. CNS adverse reactions may occur either early or late after the initiation of Fludarabine Phosphate Injection (range 7 to 225 days). CNS adverse reactions are dose dependent and occur at greater incidence and severity in patients treated at doses higher than the recommended dose of Fludarabine Phosphate Injection [see Overdosage ( 10 )] . Monitor patients for signs and symptoms of neurologic toxicity during and after treatment with Fludarabine Phosphate Injection. Consider delaying or discontinuing Fludarabine Phosphate Injection if neurotoxicity occurs. Do not administer Fludarabine Phosphate Injection at doses higher than the recommended dose. Advise patients that Fludarabine Phosphate Injection may reduce the ability to drive or use mechanical equipment, since fatigue, weakness, visual disturbances, confusion, agitation, or seizures may occur.","5.2 Myelosuppression Fludarabine phosphate can cause severe and fatal myelosuppression, which may include neutropenia, thrombocytopenia, or anemia. Cases of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported. The median time to nadir of counts was approximately 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32 days) for platelets. The duration of the cytopenia in reported cases has ranged from approximately 2 months to approximately 1 year. Monitor complete blood counts at baseline, prior to and during each treatment cycle, and as clinically needed. Consider dosage delays, dose reductions, or permanent discontinuation if recovery has not occurred by the first day of the next scheduled cycle.","5.3 Autoimmune Cytopenias Life-threatening and fatal autoimmune hemolytic anemia, autoimmune thrombocytopenia/idiopathic thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia can occur in patients treated with fludarabine phosphate with or without a previous history of autoimmune hemolytic anemia or a positive Coombs’ test. 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. Closely monitor patients during treatment with Fludarabine Phosphate Injection for autoimmune cytopenias and manage as clinically indicated.","5.4 Transfusion Associated Graft-Versus-Host Disease Transfusion-associated graft-versus-host disease has been observed after transfusion of non-irradiated blood in patients treated with fludarabine phosphate. Fatal outcome as a consequence of this disease has been reported. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received, treatment with Fludarabine Phosphate Injection should receive irradiated blood only.","5.5 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) can occur in patients treated with Fludarabine Phosphate Injection. TLS has been reported in patients with CLL who have large tumor burdens and can occur as early as the first week of treatment. Closely monitor patients at risk for TLS, consider appropriate prophylaxis including hydration, and manage as clinically indicated.","5.6 Pulmonary Toxicity in Patients with CLL When Fludarabine Phosphate is Used with Pentostatin In clinical trials, patients experienced fatal pulmonary toxicity when treated with fludarabine phosphate and pentostatin for refractory CLL. Avoid concomitant use of Fludarabine Phosphate Injection with pentostatin [see Drug Interactions ( 7.1 )] .","5.7 Vaccination During and after treatment with Fludarabine Phosphate Injection, avoid vaccination with live vaccines.","5.8 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fludarabine phosphate to pregnant animals during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal doses below (rabbits) and above (rats) those in patients at the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] ."]}