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adverse reactions
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Spinal or epidural hematomas [see Warnings and Precautions (5.1) ] • Hemorrhage [see Warnings and Precautions (5.2) ] • Renal impairment and bleeding risk [see Warnings and Precautions (5.3) ] • Body weight less than 50 kg and bleeding risk [see Warnings and Precautions (5.4) ] • Thrombocytopenia [see Warnings and Precautions (5.5) ] The most serious adverse reactions associated with the use of fondaparinux sodium are bleeding complications. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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. Clinical Trials Experience in Adults The adverse reaction information below is based on data from 8,877 patients exposed to fondaparinux sodium in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment. Hemorrhage During administration of fondaparinux sodium, the most common adverse reactions were bleeding complications [see Warnings and Precautions (5.2) ]. Hip Fracture, Hip Replacement, and Knee Replacement Surgery The rates of major bleeding events reported during 3 active-controlled peri-operative VTE prophylaxis trials with enoxaparin sodium in hip fracture, hip replacement, or knee replacement surgery (N = 3,616) and in an extended VTE prophylaxis trial (n = 327) with fondaparinux sodium 2.5 mg are provided in Table 5. Table 5. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) Fondaparinux Sodium 2.5 mg subcutaneously once daily N = 3,616 Enoxaparin Sodium Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily. , Not approved for use in patients undergoing hip fracture surgery. N = 3,956 Fondaparinux Sodium 2.5 mg subcutaneously once daily N = 327 Placebo subcutaneously once daily N = 329 Major bleeding Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at critical site (e.g., intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), (3) associated with re-operation at operative site, or (4) with a bleeding index (BI) greater than or equal to 2. 96 (2.7%) 75 (1.9%) 8 (2.4%) 2 (0.6%) Hip fracture 18/831 (2.2%) 19/842 (2.3%) 8/327 (2.4%) 2/329 (0.6%) Hip replacement 67/2,268 (3.0%) 55/2,597 (2.1%) — — Knee replacement 11/517 (2.1%) 1/517 (0.2%) — — Fatal bleeding 0 (0%) 1 (less than 0.1%) 0 (0%) 0 (0%) Non-fatal bleeding at critical site 0 (0%) 1 (less than 0.1%) 0 (0%) 0 (0%) Re-operation due to bleeding 12 (0.3%) 10 (0.3%) 2 (0.6%) 2 (0.6%) BI greater than or equal to 2 BI greater than or equal to 2: Overt bleeding associated only with a bleeding index (BI) greater than or equal to 2 calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) – (post-bleeding)] hemoglobin (g/dL) values]. 84 (2.3%) 63 (1.6%) 6 (1.8%) 0 (0%) Minor bleeding Minor bleeding was defined as clinically overt bleeding that was not major. 109 (3%) 116 (2.9%) 5 (1.5%) 2 (0.6%) A separate analysis of major bleeding across all randomized, controlled, peri-operative, prophylaxis clinical studies of hip fracture, hip replacement, or knee replacement surgery according to the time of the first injection of fondaparinux sodium after surgical closure was performed in patients who received fondaparinux sodium only post-operatively. In this analysis, the incidences of major bleeding were as follows: less than 4 hours was 4.8% (5/104), 4 to 6 hours was 2.3% (28/1,196), 6 to 8 hours was 1.9% (38/1,965). In all studies, the majority (greater than or equal to 75%) of the major bleeding events occurred during the first 4 days after surgery. Abdominal Surgery In a randomized study of patients undergoing abdominal surgery, fondaparinux sodium 2.5 mg once daily (n = 1,433) was compared with dalteparin 5,000 IU once daily (n = 1,425). Bleeding rates are shown in Table 6. Table 6. Bleeding in the Abdominal Surgery Study Fondaparinux Sodium 2.5 mg subcutaneously once daily Dalteparin Sodium 5,000 IU subcutaneously once daily N = 1,433 N = 1,425 Major bleeding Major bleeding was defined as bleeding that was (1) fatal, (2) bleeding at the surgical site leading to intervention, (3) non-surgical bleeding at a critical site (e.g. intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), or leading to an intervention, and/or with a bleeding index (BI) greater than or equal to 2. 49 (3.4%) 34 (2.4%) Fatal bleeding 2 (0.1%) 2 (0.1%) Non-fatal bleeding at critical site 0 (0%) 0 (0%) Other non-fatal major bleeding Surgical site 38 (2.7%) 26 (1.8%) Non-surgical site 9 (0.6%) 6 (0.4%) Minor bleeding Minor bleeding was defined as clinically overt bleeding that was not major. 31 (2.2%) 23 (1.6%) The rates of major bleeding according to the time interval following the first fondaparinux sodium injection were as follows: less than 6 hours was 3.4% (9/263) and 6 hours to 8 hours was 2.9% (32/1,112). Treatment of Deep Vein Thrombosis and Pulmonary Embolism The rates of bleeding events reported during a dose-response trial (n = 111) and an active-controlled trial with enoxaparin sodium in DVT treatment (n = 1,091) and an active-controlled trial with heparin in PE treatment (n = 1,092) with fondaparinux sodium are provided in Table 7. Table 7. Bleeding Bleeding rates are during the study drug treatment period (approximately 7 days). Patients were also treated with vitamin K antagonists initiated within 72 hours after the first study drug administration. in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies Fondaparinux Sodium N = 2,294 Enoxaparin Sodium N = 1,101 Heparin aPTT adjusted IV N = 1,092 Major bleeding Major bleeding was defined as clinically overt: – and/or contributing to death – and/or in a critical organ including intracranial, retroperitoneal, intraocular, spinal, pericardial, or adrenal gland – and/or associated with a fall in hemoglobin level greater than or equal to 2 g/dL – and/or leading to a transfusion greater than or equal to 2 units of packed red blood cells or whole blood. 28 (1.2%) 13 (1.2%) 12 (1.1%) Fatal bleeding 3 (0.1%) 0 (0%) 1 (0.1%) Non-fatal bleeding at a critical site 3 (0.1%) 0 (0%) 2 (0.2%) Intracranial bleeding 3 (0.1%) 0 (0%) 1 (0.1%) Retro-peritoneal bleeding 0 (0%) 0 (0%) 1 (0.1%) Other clinically overt bleeding Clinically overt bleeding with a 2 g/dL fall in hemoglobin and/or leading to transfusion of PRBC or whole blood greater than or equal to 2 units. 22 (1%) 13 (1.2%) 10 (0.9%) Minor bleeding Minor bleeding was defined as clinically overt bleeding that was not major. 70 (3.1%) 33 (3%) 57 (5.2%) Local Reactions Local irritation (injection site bleeding, rash, and pruritus) has occurred following subcutaneous injection of fondaparinux sodium. Elevations of Serum Aminotransferases In the peri-operative prophylaxis randomized clinical trials of 7 ± 2 days, asymptomatic increases in aspartate (AST) and alanine (ALT) aminotransferase levels greater than 3 times the upper limit of normal were reported in 1.7% and 2.6% of patients, respectively, during treatment with fondaparinux sodium 2.5 mg once daily versus 3.2% and 3.9% of patients, respectively, during treatment with enoxaparin sodium 30 mg every 12 hours or 40 mg once daily enoxaparin sodium. These elevations are reversible and may be associated with increases in bilirubin. In the extended prophylaxis clinical trial, no significant differences in AST and ALT levels between fondaparinux sodium 2.5 mg and placebo-treated patients were observed. In the DVT and PE treatment clinical trials, asymptomatic increases in AST and ALT levels greater than 3 times the upper limit of normal of the laboratory reference range were reported in 0.7% and 1.3% of patients, respectively, during treatment with fondaparinux sodium. In comparison, these increases were reported in 4.8% and 12.3% of patients, respectively, in the DVT treatment trial during treatment with enoxaparin sodium 1 mg/kg every 12 hours and in 2.9% and 8.7% of patients, respectively, in the PE treatment trial during treatment with aPTT adjusted heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like fondaparinux sodium should be interpreted with caution. Other Adverse Reactions Other adverse reactions that occurred during treatment with fondaparinux sodium in clinical trials with patients undergoing hip fracture, hip replacement, or knee replacement surgery are provided in Table 8. Table 8. Adverse Reactions Across Randomized, Controlled, Hip Fracture Surgery, Hip Replacement Surgery, and Knee Replacement Surgery Studies Adverse Reactions Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) Fondaparinux Sodium 2.5 mg subcutaneously once daily Enoxaparin Sodium Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily. , Not approved for use in patients undergoing hip fracture surgery. Fondaparinux Sodium 2.5 mg subcutaneously once daily Placebo subcutaneously once daily N = 3,616 N = 3,956 N = 327 N = 329 Anemia 707 (19.6%) 670 (16.9%) 5 (1.5%) 4 (1.2%) Insomnia 179 (5%) 214 (5.4%) 3 (0.9%) 1 (0.3%) Wound drainage increased 161 (4.5%) 184 (4.7%) 2 (0.6%) 0 (0%) Hypokalemia 152 (4.2%) 164 (4.1%) 0 (0%) 0 (0%) Dizziness 131 (3.6%) 165 (4.2%) 2 (0.6%) 0 (0%) Purpura 128 (3.5%) 137 (3.5%) 0 (0%) 0 (0%) Hypotension 126 (3.5%) 125 (3.2%) 1 (0.3%) 0 (0%) Confusion 113 (3.1%) 132 (3.3%) 4 (1.2%) 1 (0.3%) Bullous eruption Localized blister coded as bullous eruption. 112 (3.1%) 102 (2.6%) 0 (0%) 1 (0.3%) Hematoma 103 (2.8%) 109 (2.8%) 7 (2.1%) 1 (0.3%) Post-operative hemorrhage 85 (2.4%) 69 (1.7%) 2 (0.6%) 2 (0.6%) The most common adverse reaction in the abdominal surgery trial was post-operative wound infection (4.9%), and the most common adverse reaction in the VTE treatment trials was epistaxis (1.3%). Clinical Trials Experience in Pediatric Patients Safety data for use of fondaparinux sodium in the treatment of VTE in pediatric patients aged 1 year or older is available from Study FDPX-IJS-7001. In Study FDPX-IJS-7001 (n = 366), the median duration of treatment with fondaparinux sodium injection was 85 days (range 1 day to 3,768 days). The incidence of major bleeding events, defined as per the ISTH criteria, was the primary safety outcome of interest in Study FDPX-IJS-7001. Seven patients (1.9%) had composite major bleeding events: 1 patient (0.3%) had clinically overt bleeding (associated with a decrease in hemoglobin of at least 20 g/L (2 g/dL) in a 24-hour period), 3 patients (0.8%) had bleeding that was retroperitoneal, pulmonary, intracranial, or otherwise involved the central nervous system, and 3 patients (0.8%) had major bleeding that required surgical intervention in an operating suite. Major bleeding events resulted in the interruption of fondaparinux sodium injection treatment for 4 patients and the discontinuation of fondaparinux sodium injection for 3 patients. All major bleeding events were reported in patients between the ages of greater than or equal to 2 years to less than 18 years. Eleven patients (3%) had non-major bleeding events: 8 patients (2.2%) had overt bleeding for which a blood product was administered, and which was not directly attributable to the patient’s underlying medical condition and 4 patients (1.1%) had bleeding that required medical or surgical intervention to restore hemostasis other than in an operating room. All non-major bleeding events warranted either interruption or withdrawal of fondaparinux sodium injection treatment except for 1 patient for whom the action taken with fondaparinux was not reported. All non-major bleeding events were reported in patients between the ages of greater than or equal to 2 years to less than 18 years. Overall, 65 patients (18%) had composite minor bleeding events: 64 patients (18%) had overt or macroscopic evidence of bleeding that did not fulfill the criteria for either major bleeding or clinically relevant, non-major bleeding and two patients (0.5%) had non-major menstrual bleeding which resulted in a medical consultation and/or intervention. Other Adverse Reactions Other adverse reactions that occurred during treatment with fondaparinux sodium injection in pediatric studies included: anemia, thrombocytopenia, allergic reactions, generalized skin associated events, abnormal liver function, hypokalemia, and hypotension. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of fondaparinux sodium. 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. In the postmarketing experience, epidural or spinal hematoma has been reported in association with the use of fondaparinux sodium by subcutaneous (SC) injection [see Warnings and Precautions (5.1) ]. Occurrences of thrombocytopenia with thrombosis that manifested similar to heparin-induced thrombocytopenia have been reported in the postmarketing experience and cases of elevated aPTT temporally associated with bleeding events have been reported following administration of fondaparinux sodium (with or without concomitant administration of other anticoagulants) [see Warnings and Precautions (5.5) ]. Serious allergic reactions, including angioedema, anaphylactoid/anaphylactic reactions have been reported with the use of fondaparinux sodium [see Contraindications (4) ] . Elevations of hepatic transaminases have been reported in pediatric patients with elevations greater than 10x ULN.
adverse reactions table
<table width="100%"><caption>Table 5. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies</caption><col width="21%"/><col width="21%"/><col width="21%"/><col width="18%"/><col width="18%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Peri-Operative Prophylaxis</content> <content styleCode="bold">(Day 1 to Day 7 ± 1 post-surgery)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Extended Prophylaxis</content> <content styleCode="bold">(Day 8 to Day 28 ± 2 post-surgery)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Fondaparinux Sodium </content></paragraph><paragraph><content styleCode="bold">2.5 mg subcutaneously</content></paragraph><paragraph><content styleCode="bold">once daily</content></paragraph><paragraph>N = 3,616</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Enoxaparin Sodium</content><footnote ID="_Ref238124244">Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.</footnote><content styleCode="bold"><sup>, </sup></content><footnote ID="_Ref238124266">Not approved for use in patients undergoing hip fracture surgery.</footnote></paragraph><paragraph>N = 3,956</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Fondaparinux Sodium </content></paragraph><paragraph><content styleCode="bold">2.5 mg subcutaneously</content></paragraph><paragraph><content styleCode="bold">once daily</content></paragraph><paragraph>N = 327</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">subcutaneously once daily</content></paragraph><paragraph>N = 329</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Major bleeding<footnote ID="_Ref238124284">Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at critical site (e.g., intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), (3) associated with re-operation at operative site, or (4) with a bleeding index (BI) greater than or equal to 2.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>96 (2.7%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>75 (1.9%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>8 (2.4%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>2 (0.6%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hip fracture</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>18/831 (2.2%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>19/842 (2.3%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>8/327 (2.4%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>2/329 (0.6%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hip replacement</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>67/2,268 (3.0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>55/2,597 (2.1%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>—</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>—</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Knee replacement</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>11/517 (2.1%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>1/517 (0.2%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>—</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>—</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatal bleeding</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0 (0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (less than 0.1%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0 (0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0 (0%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Non-fatal bleeding at critical site</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0 (0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (less than 0.1%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0 (0%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0 (0%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Re-operation due to bleeding</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12 (0.3%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (0.3%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (0.6%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (0.6%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>BI greater than or equal to 2<footnote ID="_Ref238124302">BI greater than or equal to 2: Overt bleeding associated only with a bleeding index (BI) greater than or equal to 2 calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) – (post-bleeding)] hemoglobin (g/dL) values].</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>84 (2.3%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>63 (1.6%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (1.8%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0 (0%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Minor bleeding<footnote ID="_Ref238124319">Minor bleeding was defined as clinically overt bleeding that was not major.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>109 (3%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>116 (2.9%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5 (1.5%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2 (0.6%)</paragraph></td></tr></tbody></table>