FDA label 3c748655-a9a1-4cac-a912-5155e839ad5b

WARNING: CNS TOXICITY, HEMOLYTIC ANEMIA, AND PULMONARY TOXICITY Severe neurologic effects, including blindness, coma, and death were observed in dose-ranging studies in patients with acute leukemia when fludarabine phosphate was administered at high doses. This severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m 2 /day for 5 days to 7 days) than the recommended intravenous dose (25 mg/m 2 /day). Similar severe central nervous system toxicity has been rarely (≤0.2%) reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia. [ See Warnings and Precautions (5.1) ] Periodic neurological assessments are recommended. Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported after one or more cycles of treatment with fludarabine phosphate. Patients undergoing treatment with Oforta™ should be evaluated and closely monitored for hemolysis. [ See Warnings and Precautions (5.2) ] High incidence of fatal pulmonary toxicity was observed in a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL). Therefore, the use of Oforta™ in combination with pentostatin is not recommended [See Warnings and Precautions (5.3) ] WARNING: CNS TOXICITY, HEMOLYTIC ANEMIA, AND PULMONARY TOXICITY See full prescribing information for complete boxed warning. Severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m 2 /day for 5 days to 7 days) than the recommended intravenous dose. This toxicity was seen in ≤0.2% of patients treated at the recommended intravenous dose levels (25 mg/m 2 ). ( 5.1 ) Life-threatening and sometimes fatal autoimmune hemolytic anemia has been reported after one or more cycles of treatment. ( 5.2 ) High incidence of fatal pulmonary toxicity was observed in a clinical investigation of the combination of fludarabine phosphate with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL). ( 5.3 )

5 WARNINGS AND PRECAUTIONS Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia. Monitor blood counts before and during treatment. ( 5.2 ) Infections. Monitor for signs or symptoms of infection. ( 5.3 ) Tumor lysis syndrome. Take precautions for patients at high risk. ( 5.4 ) Transfusion-associated graft-versus-host disease. Use only irradiated blood products for transfusions. ( 5.6 ) Oforta™ dose should be adjusted in patients with mild to moderate (creatinine clearance 30 to 70 mL/min/1.73 m 2 ) or severe (creatinine clearance < 30 mL/min/1.73 m 2 ) renal impairment. ( 5.7 ) Fetal harm may occur when administered to a pregnant woman. Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy. ( 5.9 ) 5.1 Neurotoxicity Dose-dependent neurotoxicity has been observed with fludarabine phosphate. Dose levels approximately 4 times greater (96 mg/m 2 /day for 5 days to 7 days) than the recommended intravenous dose (25 mg/m 2 /day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 days to 60 days following the last dose. Thirteen of 36 patients (36.1%) who received fludarabine phosphate intravenously at high doses (≥ 96 mg/m 2 /day for 5 days to 7 days per course) developed severe neurotoxicity, while only one of 443 patients (0.2%) who received the drug intravenously at low doses (≤ 40 mg/m 2 /day for 5 days per course) developed toxicity. In the pivotal clinical study conducted with Oforta™ administered at 40 mg/m 2 , severe impairment of consciousness was reported in one patient. The effect of chronic administration of fludarabine phosphate on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs. 5.2 Bone Marrow Suppression Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate. In a study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3 days to 25 days) for granulocytes and 16 days (range, 2 days to 32 days) for platelets. Most patients had hematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of Oforta™ requires careful hematologic monitoring. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients. One case of pancytopenia was reported in the pivotal clinical study conducted with Oforta™. Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine phosphate in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs' test and who may or may not be in remission from their disease. Steroids may or may not be effective in controlling these hemolytic episodes. 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. Patients undergoing treatment with Oforta™ should be evaluated and closely monitored for hemolysis. 5.3 Pulmonary Toxicity A high incidence of fatal pulmonary toxicity was observed in a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults. Therefore, the use of Oforta™ in combination with pentostatin is not recommended. 5.4 Infections Of 133 adult patients with CLL who received intravenous fludarabine phosphate in two clinical trials, there were 29 fatalities during study. Approximately 50% of the fatalities were due to infection and 25% due to progressive disease. Of 183 adult patients with CLL that received Oforta™ in two clinical trials, there were 13 deaths. Approximately 50% of the deaths were due to progressive disease, while two patient deaths (15%) were attributed to infection. Monitor for signs and symptoms of infection. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome associated with fludarabine phosphate treatment has been reported in patients with CLL with large tumor burdens. Since Oforta™ can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication. 5.6 Use of Transfusions Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of non-irradiated blood in fludarabine phosphate treated patients. Consideration should, therefore, be given to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with Oforta™. 5.7 Renal Impairment Oforta™ must be administered cautiously in patients with renal impairment. Following dosing of the intravenous product, the total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with mild to moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m 2 ) should have their Oforta™ dose reduced by 20% and be monitored closely. Patients with severe impairment of renal function (creatinine clearance < 30 mL/min/1.73 m 2 ) should have their Oforta™ dose reduced by 50% and be monitored closely. 5.8 Monitoring Hematologic and Nonhematologic Toxicity Oforta™ is an antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of hematologic and nonhematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the development of anemia, neutropenia and thrombocytopenia. Hematopoietic Suppression During treatment, the patient's hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression. Infections Patients treated with Oforta™ appear to be at an increased risk of infection. Monitor for signs and symptoms of infection. 5.9 Pregnancy Based on its mechanism of action, Oforta™ can cause fetal harm when administered to a pregnant woman. Fludarabine phosphate administered to rats and rabbits during organogenesis caused an increase in resorptions, skeletal and visceral malformation, and decreased fetal body weights. If Oforta™ 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. Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy. [see Use in Specific Populations (8.1) ] .

6 ADVERSE REACTIONS Most common adverse reactions (incidence > 30%) include myelosuppression (neutropenia, thrombocytopenia and anemia). Fever, weakness, infection, pain, cough and anorexia were also reported as common adverse reactions. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. The data described below reflect exposure to Oforta™ in 159 patients exposed to the drug. Oforta™ was studied primarily in Study 1 in 78 patients with CLL who received prior therapy and in Study 2 in 81 patients with CLL who had not received prior therapy. Based on experience with the intravenous and oral use of fludarabine phosphate, the most common adverse reactions include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, infection, and nausea and vomiting. Other commonly reported events include malaise, fatigue, anorexia, and weakness. Serious opportunistic infections have occurred in patients with CLL treated with fludarabine phosphate. The most frequently reported adverse reactions and those reactions which are more clearly related to the drug, as reported in clinical studies conducted with intravenous and oral fludarabine phosphate, are arranged below according to body system. Hematopoietic Systems Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of patients with CLL treated with fludarabine phosphate. During intravenous fludarabine phosphate 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%. Among 78 patients with B-CLL who were treated with Oforta™, the absolute neutrophil count decreased to less than 500/mm 3 in 37% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 14%, and platelet count decreased from pretreatment values by at least 50% in 17% of patients. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with fludarabine phosphate intravenously. In the pivotal oral fludarabine phosphate study (Study 1), there was one report of a non-fatal case of pancytopenia. Similarly, there was one case of non-fatal pancytopenia reported among the 133 patients with CLL treated with intravenous fludarabine phosphate. Life-threatening and sometimes fatal autoimmune hemolytic anemias have been reported to occur in patients receiving fludarabine phosphate. [ See Warnings and Precautions (5.2) ] The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process. Metabolic Tumor lysis syndrome has been reported in patients with CLL 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 Objective weakness, agitation, confusion, visual disturbances, and coma have occurred in patients with CLL treated with fludarabine phosphate at the recommended dose. Peripheral neuropathy and one case of wrist-drop have been observed with intravenous administration of fludarabine phosphate. In Study 1 for Oforta™, there was one report of severe impairment of consciousness that presented concurrent with hemolytic anemia. This patient had enrolled in the study with pre-existing peripheral neurotoxicity. [ See Warnings and Precautions (5.1) ] Pulmonary System Pneumonia, a frequent manifestation of infection in patients with CLL, was observed in two clinical trials conducted with intravenous fludarabine phosphate (16% and 22%) and in two clinical trials with Oforta™ (8% and 3%). Pulmonary hypersensitivity reactions to fludarabine phosphate characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed. In Study 1 conducted with Oforta™, severe pulmonary toxicity was reported in 5 of 78 patients, often in conjunction with respiratory or pulmonary infections and hence not regarded as isolated drug related pulmonary toxicity. Gastrointestinal System Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding have been reported in patients treated with fludarabine phosphate. Nausea and vomiting occurred in up to 38% of patients following treatment with Oforta™ in the clinical trials. Cardiovascular Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with Oforta™. No other severe cardiovascular events were considered to be drug related. Genitourinary System Hemorrhagic cystitis has been reported in patients treated intravenously with fludarabine phosphate. Skin Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with oral and intravenous fludarabine phosphate. Data in Table 2 are derived from the 159 patients with CLL who received Oforta™ in Study 1 and Study 2. TABLE 2: Incidence (≥5%) of Non-Hematologic Adverse Reactions in Patients with CLL Treated with Oforta™ ADVERSE REACTIONS Study 1 (N=78) % Study 2 (N=81) % ANY ADVERSE REACTION 82 89 BODY AS A WHOLE 59 77 FEVER 26 11 INFECTION 12 17 PAIN 5 19 FLU SYNDROME 8 5 DIAPHORESIS 8 0 NEUROLOGICAL 19 41 WEAKNESS/FATIGUE (ASTHENIA) 13 31 SWEATING INCREASED 0 14 HEADACHE 9 9 PULMONARY 37 53 COUGH 21 0 COUGH INCREASED 0 6 PNEUMONIA 8 3 DYSPNEA 1 5 SINUSITIS 1 5 UPPER RESPIRATORY INFECTION 9 14 RHINITIS 3 11 BRONCHITIS 6 9 METABOLIC AND NUTRITIONAL 3 31 WEIGHT DECREASED 1 6 LACTIC DEHYDROGENASE INCREASED 0 6 PERIPHERAL EDEMA 0 7 GASTROINTESTINAL 41 28 NAUSEA 5 1 DIARRHEA 6 5 ANOREXIA 19 0 ABDOMINAL PAIN 8 10 CUTANEOUS 22 25 RASH 5 4 SKIN DISORDER 0 6 HERPES SIMPLEX 8 7 GENITOURINARY 8 14 URINARY TRACT INFECTION 4 5 CARDIOVASCULAR 14 17 CHEST PAIN 0 5 MUSCULOSKELETAL 10 19 BACK PAIN 4 9 6.2 Post Marketing Experience The following adverse reactions have been identified during post approval use of Oforta™. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possibly to reliably estimate their frequency or establish a causal relationship to drug exposure. Hematopoietic Systems 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. Nervous System 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 median time to onset was approximately one year. Pulmonary System In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine phosphate use which resulted in acute respiratory distress syndrome, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, and respiratory failure. After exclusion of an infectious origin, some patients experienced symptom improvement with corticosteroids.

<table width="90%"> <caption>TABLE 2: Incidence (&#x2265;5%) of Non-Hematologic Adverse Reactions in Patients with CLL Treated with Oforta&#x2122;</caption> <col width="50%" align="left" valign="top"/> <col width="25%" align="center" valign="top"/> <col width="25%" align="center" valign="top"/> <thead> <tr> <th align="center"> <content styleCode="underline">ADVERSE REACTIONS</content> </th> <th> <content styleCode="underline">Study 1</content> (N=78) %</th> <th> <content styleCode="underline">Study 2</content> (N=81) %</th> </tr> </thead> <tbody> <tr> <td>ANY ADVERSE REACTION</td> <td>82</td> <td>89</td> </tr> <tr> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>BODY AS A WHOLE</td> <td>59</td> <td>77</td> </tr> <tr> <td> FEVER</td> <td>26</td> <td>11</td> </tr> <tr> <td> INFECTION</td> <td>12</td> <td>17</td> </tr> <tr> <td> PAIN</td> <td>5</td> <td>19</td> </tr> <tr> <td> FLU SYNDROME</td> <td>8</td> <td>5</td> </tr> <tr> <td> DIAPHORESIS</td> <td>8</td> <td>0</td> </tr> <tr> <td>NEUROLOGICAL</td> <td>19</td> <td>41</td> </tr> <tr> <td> WEAKNESS/FATIGUE (ASTHENIA)</td> <td>13</td> <td>31</td> </tr> <tr> <td> SWEATING INCREASED</td> <td>0</td> <td>14</td> </tr> <tr> <td> HEADACHE</td> <td>9</td> <td>9</td> </tr> <tr> <td>PULMONARY</td> <td>37</td> <td>53</td> </tr> <tr> <td> COUGH</td> <td>21</td> <td>0</td> </tr> <tr> <td> COUGH INCREASED</td> <td>0</td> <td>6</td> </tr> <tr> <td> PNEUMONIA</td> <td>8</td> <td>3</td> </tr> <tr> <td> DYSPNEA</td> <td>1</td> <td>5</td> </tr> <tr> <td> SINUSITIS</td> <td>1</td> <td>5</td> </tr> <tr> <td> UPPER RESPIRATORY INFECTION</td> <td>9</td> <td>14</td> </tr> <tr> <td> RHINITIS</td> <td>3</td> <td>11</td> </tr> <tr> <td> BRONCHITIS</td> <td>6</td> <td>9</td> </tr> <tr> <td>METABOLIC AND NUTRITIONAL</td> <td>3</td> <td>31</td> </tr> <tr> <td> WEIGHT DECREASED</td> <td>1</td> <td>6</td> </tr> <tr> <td> LACTIC DEHYDROGENASE INCREASED</td> <td>0</td> <td>6</td> </tr> <tr> <td> PERIPHERAL EDEMA</td> <td>0</td> <td>7</td> </tr> <tr> <td>GASTROINTESTINAL</td> <td>41</td> <td>28</td> </tr> <tr> <td> NAUSEA</td> <td>5</td> <td>1</td> </tr> <tr> <td> DIARRHEA</td> <td>6</td> <td>5</td> </tr> <tr> <td> ANOREXIA</td> <td>19</td> <td>0</td> </tr> <tr> <td> ABDOMINAL PAIN</td> <td>8</td> <td>10</td> </tr> <tr> <td>CUTANEOUS</td> <td>22</td> <td>25</td> </tr> <tr> <td> RASH</td> <td>5</td> <td>4</td> </tr> <tr> <td> SKIN DISORDER</td> <td>0</td> <td>6</td> </tr> <tr> <td> HERPES SIMPLEX</td> <td>8</td> <td>7</td> </tr> <tr> <td>GENITOURINARY</td> <td>8</td> <td>14</td> </tr> <tr> <td> URINARY TRACT INFECTION</td> <td>4</td> <td>5</td> </tr> <tr> <td>CARDIOVASCULAR</td> <td>14</td> <td>17</td> </tr> <tr> <td> CHEST PAIN</td> <td>0</td> <td>5</td> </tr> <tr> <td>MUSCULOSKELETAL</td> <td>10</td> <td>19</td> </tr> <tr> <td> BACK PAIN</td> <td>4</td> <td>9</td> </tr> </tbody> </table>