Arixtra Drug Information

• 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 ARIXTRA 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 ARIXTRA in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment. Hemorrhage During administration of ARIXTRA, 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 ARIXTRA 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) ARIXTRA 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 ARIXTRA 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 ARIXTRA after surgical closure was performed in patients who received ARIXTRA 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, ARIXTRA 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 ARIXTRA 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 ARIXTRA 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 ARIXTRA 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 ARIXTRA 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 ARIXTRA. 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 ARIXTRA 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 ARIXTRA 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 ARIXTRA. 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 ARIXTRA should be interpreted with caution. Other Adverse Reactions Other adverse reactions that occurred during treatment with ARIXTRA 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) ARIXTRA 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. ARIXTRA 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 ARIXTRA 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, including ARIXTRA, 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 ARIXTRA. 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 ARIXTRA 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 ARIXTRA (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 ARIXTRA [see Contraindications (4) ] . Elevations of hepatic transaminases have been reported in pediatric patients with elevations greater than 10x ULN.

In clinical studies performed with ARIXTRA, the concomitant use of oral anticoagulants (warfarin sodium), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam), and digoxin did not significantly affect the pharmacokinetics/pharmacodynamics of fondaparinux sodium. In addition, ARIXTRA neither influenced the pharmacodynamics of warfarin sodium, acetylsalicylic acid, piroxicam, and digoxin, nor the pharmacokinetics of digoxin at steady state. Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of therapy with ARIXTRA unless these agents are essential.

If co-administration is necessary, monitor patients closely for hemorrhage . In an in vitro study in human liver microsomes, inhibition of CYP2A6 hydroxylation of coumarin by fondaparinux (200 micromolar i.e., 350 mg/L) was 17% to 28%. Inhibition of the other isozymes evaluated (CYPs 1A2, 2C9, 2C19, 2D6, 3A4, and 3E1) was 0% to 16%. Since fondaparinux does not markedly inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4) in vitro, fondaparinux sodium is not expected to significantly interact with other drugs in vivo by inhibition of metabolism mediated by these isozymes. Since fondaparinux sodium does not bind significantly to plasma proteins other than ATIII, no drug interactions by protein-binding displacement are expected. Discontinue agents that may enhance the risk of hemorrhage prior to initiation of therapy with ARIXTRA unless essential.

If co-administration is necessary, monitor patients closely for hemorrhage.

Pregnancy Risk Summary Available data from published literature and postmarketing reports have not reported a clear association with fondaparinux sodium and adverse developmental outcomes. Fondaparinux sodium plasma concentrations obtained from four women treated with ARIXTRA during pregnancy and their newborn infants demonstrated low placental transfer of fondaparinux sodium (see Data ). There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with use of anticoagulants (see Clinical Considerations ). In animal reproduction studies, there was no evidence of adverse developmental outcomes when fondaparinux sodium was administered to pregnant rats and rabbits during organogenesis at doses 32 times and 65 times, respectively, the recommended human dose based on body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions.

Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. Fetal/Neonatal Adverse Reactions Fondaparinux sodium has been demonstrated to cross the placenta in humans (see Data ). Use of anticoagulants, including fondaparinux sodium, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding . Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.

Fondaparinux sodium use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Pregnant women receiving fondaparinux sodium should be carefully monitored for evidence of bleeding or unexpected changes in coagulation parameters. Consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches . Data Human Data In a study of five pregnant women treated with fondaparinux sodium during the third trimester of pregnancy at a dose of 2.5 mg/day, four of the women had elevated anti-factor Xa activity noted in the cord blood.

Anti-factor Xa clotting times in these four cases were between 37.5 seconds and 50.9 seconds. The patient who did not have elevated anti-factor Xa activity had received only one dose of fondaparinux sodium 22 hours prior to delivery. The concentration of fondaparinux sodium in umbilical cord plasma was approximately 1/10 th the level of fondaparinux sodium in maternal plasma.

None of the infants experienced adverse effects. Animal Data Embryo-fetal development studies have been conducted with fondaparinux sodium in pregnant rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area) administered from days 6 to 17 of gestation and pregnant rabbits at subcutaneous doses up to 10 mg/kg/day (about 65 times the recommended human dose based on body surface area) administered from days 6 to 18 of gestation. These studies have revealed no evidence of adverse developmental outcomes when fondaparinux sodium was administered to pregnant rats and rabbits during organogenesis.

Additionally, there were no effects on pre- and postnatal development in a study conducted in rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area).

Pediatric Use The safety and effectiveness of ARIXTRA for the treatment of venous thromboembolism have been established in pediatric patients aged 1 year and older weighing at least 10 kg. Use of ARIXTRA for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, pharmacodynamic, safety, and efficacy data in pediatric patients aged 0.3 years and older . The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults. The safety and effectiveness of ARIXTRA have not been established in pediatric patients for the treatment of venous thromboembolism who are younger than 1 year old, weigh less than 10 kg, or with any category of renal or hepatic impairment.

The safety and effectiveness of ARIXTRA have not been established in pediatric patients for the prophylaxis of DVT and treatment of DVT or PE in conjunction with warfarin sodium.

• is contraindicated in the following conditions:
• Severe renal impairment (creatinine clearance [CrCl] less than 30 mL/min) [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6) ] .
• Active major bleeding.
• Bacterial endocarditis.
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of fondaparinux sodium.
• Body weight less than 50 kg (venous thromboembolism [VTE] prophylaxis in adults only) [see Warnings and Precautions (5.4) ] .
• History of serious hypersensitivity reaction (e.g., angioedema, anaphylactoid/anaphylactic reactions) to ARIXTRA. ARIXTRA is contraindicated in the following conditions: ( 4 )
• Severe renal impairment (creatinine clearance less than 30 mL/min) in prophylaxis or treatment of venous thromboembolism.
• Active major bleeding.
• Bacterial endocarditis.
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of fondaparinux sodium.
• Body weight less than 50 kg (venous thromboembolism prophylaxis in adults only).
• History of serious hypersensitivity reaction (e.g., angioedema, anaphylactoid/anaphylactic reactions) to ARIXTRA.

Overdose of ARIXTRA may lead to hemorrhagic complications. Discontinue treatment and initiate appropriate therapy if bleeding complications associated with overdosage occur. There is no known antidote for ARIXTRA. Data obtained in patients undergoing chronic intermittent hemodialysis suggest that clearance of ARIXTRA can increase by 20% during hemodialysis.