FDA label 59fd0cfe-f1e3-9b20-e063-6294a90a6ad6

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.

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

<table border="1" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td><paragraph><content styleCode="bold">MDAH</content></paragraph><paragraph><content styleCode="bold">(N=101)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph><content styleCode="bold">SWOG</content></paragraph><paragraph><content styleCode="bold">(N=32)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">General</content></paragraph></td></tr><tr><td><paragraph>Fever</paragraph></td><td><paragraph>60</paragraph></td><td><paragraph>69</paragraph></td></tr><tr><td><paragraph>Pain</paragraph></td><td><paragraph>20</paragraph></td><td><paragraph>22</paragraph></td></tr><tr><td><paragraph>Fatigue</paragraph></td><td><paragraph>10</paragraph></td><td><paragraph>38</paragraph></td></tr><tr><td><paragraph>Chills</paragraph></td><td><paragraph>11</paragraph></td><td><paragraph>19</paragraph></td></tr><tr><td><paragraph>Malaise</paragraph></td><td><paragraph>8</paragraph></td><td><paragraph>6</paragraph></td></tr><tr><td><paragraph>Diaphoresis</paragraph></td><td><paragraph>1</paragraph></td><td><paragraph>13</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">Infection</content></paragraph></td></tr><tr><td><paragraph>Infection</paragraph></td><td><paragraph>33</paragraph></td><td><paragraph>44</paragraph></td></tr><tr><td><paragraph>Pneumonia</paragraph></td><td><paragraph>16</paragraph></td><td><paragraph>22</paragraph></td></tr><tr><td><paragraph>Upper respiratory infection</paragraph></td><td><paragraph>2</paragraph></td><td><paragraph>16</paragraph></td></tr><tr><td><paragraph>Urinary infection</paragraph></td><td><paragraph>2</paragraph></td><td><paragraph>15</paragraph></td></tr><tr><td><paragraph>Sinusitis</paragraph></td><td><paragraph>5</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Pharyngitis</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>9</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td></tr><tr><td><paragraph>Nausea/Vomiting</paragraph></td><td><paragraph>36</paragraph></td><td><paragraph>31</paragraph></td></tr><tr><td><paragraph>Anorexia</paragraph></td><td><paragraph>7</paragraph></td><td><paragraph>34</paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td><paragraph>15</paragraph></td><td><paragraph>13</paragraph></td></tr><tr><td><paragraph>Stomatitis</paragraph></td><td><paragraph>9</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Gastrointestinal bleeding</paragraph></td><td><paragraph>3</paragraph></td><td><paragraph>13</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">Ne</content><content styleCode="bold">urological</content></paragraph></td></tr><tr><td><paragraph>Weakness</paragraph></td><td><paragraph>9</paragraph></td><td><paragraph>65</paragraph></td></tr><tr><td><paragraph>Paresthesia</paragraph></td><td><paragraph>4</paragraph></td><td><paragraph>12</paragraph></td></tr><tr><td><paragraph>Visual disturbance</paragraph></td><td><paragraph>3</paragraph></td><td><paragraph>15</paragraph></td></tr><tr><td><paragraph>Hearing loss</paragraph></td><td><paragraph>2</paragraph></td><td><paragraph>6</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">P</content><content styleCode="bold">ulmonary</content></paragraph></td></tr><tr><td><paragraph>Cough</paragraph></td><td><paragraph>10</paragraph></td><td><paragraph>44</paragraph></td></tr><tr><td><paragraph>Dyspnea</paragraph></td><td><paragraph>9</paragraph></td><td><paragraph>22</paragraph></td></tr><tr><td><paragraph>Allergic pneumonitis</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>6</paragraph></td></tr><tr><td><paragraph>Hemoptysis</paragraph></td><td><paragraph>1</paragraph></td><td><paragraph>6</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">Skin and Subcutaneous</content></paragraph></td></tr><tr><td><paragraph>Rash</paragraph></td><td><paragraph>15</paragraph></td><td><paragraph>15</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">C</content><content styleCode="bold">ardiovascular</content></paragraph></td></tr><tr><td><paragraph>Edema</paragraph></td><td><paragraph>8</paragraph></td><td><paragraph>19</paragraph></td></tr><tr><td><paragraph>Angina</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>6</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">M</content><content styleCode="bold">usculoskeletal</content></paragraph></td></tr><tr><td><paragraph>Myalgia</paragraph></td><td><paragraph>4</paragraph></td><td><paragraph>16</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">Endocrine</content></paragraph></td></tr><tr><td><paragraph>Hyperglycemia</paragraph></td><td><paragraph>1</paragraph></td><td><paragraph>6</paragraph></td></tr></tbody></table>