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英文药名：ARIXTRA(fondaparinux sodium Injection) 中文药名：戊聚糖钠注射器 生产厂家：Glaxo Smith Kline
ARIXTRA is a Factor Xa inhibitor (anticoagulant) indicated for: Prophylaxis of deep vein thrombosis (DVT) in patients undergoing hip fracture surgery (including extended prophylaxis), hip replacement surgery, knee replacement surgery, or abdominal surgery. (1.1) Treatment of DVT or acute pulmonary embolism (PE) when administered in conjunction with warfarin. (1.2, 1.3) DOSAGE AND ADMINISTRATION Prophylaxis of deep vein thrombosis: ARIXTRA 2.5 mg subcutaneously once daily after hemostasis has been established. The initial dose should be given no earlier than 6 to 8 hours after surgery and continued for 5 to 9 days. For patients undergoing hip fracture surgery, extended prophylaxis up to 24 additional days is recommended. (2.1, 2.2) Treatment of deep vein thrombosis and pulmonary embolism: ARIXTRA 5 mg (body weight <50 kg), 7.5 mg (50 to 100 kg), or 10 mg (>100 kg) subcutaneously once daily. Treatment should continue for at least 5 days until INR 2 to 3 achieved with warfarin sodium. (2.3) Do not use as intramuscular injection. For subcutaneous use, do not mix with other injections or infusions. DOSAGE FORMS AND STRENGTHS Single-dose, prefilled syringes containing 2.5 mg, 5 mg, 7.5 mg, or 10 mg of fondaparinux. (3) CONTRAINDICATIONS ARIXTRA is contraindicated in the following conditions: (4) Severe renal impairment (creatinine clearance <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 <50 kg (venous thromboembolism prophylaxis only). History of serious hypersensitivity reaction (e.g., angioedema, anaphylactoid/anaphylactic reactions) to ARIXTRA. WARNINGS AND PRECAUTIONS Use with caution in patients who have conditions or are taking concomitant medications that increase risk of hemorrhage. (5.1) Bleeding risk is increased in renal impairment and in patients with low body weight <50 kg. (5.2, 5.3) Thrombocytopenia can occur with administration of ARIXTRA. (5.4) Periodic routine complete blood counts (including platelet counts), serum creatinine level, and stool occult blood tests are recommended (5.6) The packaging (needle guard) contains dry natural rubber and may cause allergic reactions in latex sensitive individuals (5.7) ADVERSE REACTIONS The most common adverse reactions associated with the use of ARIXTRA are bleeding complications. (6.1) Mild local irritation (injection site bleeding, rash, and pruritus) may occur following subcutaneous injection. (6.2) Anemia, insomnia, increased wound drainage, hypokalemia, dizziness, hypotension, confusion, bullous eruption, hematoma, post-operative hemorrhage, and purpura may occur. (6.4) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS 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. (7) USE IN SPECIFIC POPULATIONS Safety and effectiveness of ARIXTRA in pediatric patients have not been established. Because the risk for bleeding during treatment with ARIXTRA is increased in adults who weigh <50 kg, bleeding may be a particular safety concern for use of ARIXTRA in the pediatric population. (4, 5.3) Because elderly patients are more likely to have reduced renal function, ARIXTRA should be used with caution in these patients. (8.5) The risk of bleeding is increased with reduced renal or hepatic function. (8.6, 8.7) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 7/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Prophylaxis of Deep Vein Thrombosis ARIXTRA® is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): in patients undergoing hip fracture surgery, including extended prophylaxis; in patients undergoing hip replacement surgery; in patients undergoing knee replacement surgery; in patients undergoing abdominal surgery who are at risk for thromboembolic complications. 1.2 Treatment of Acute Deep Vein Thrombosis ARIXTRA is indicated for the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium. 1.3 Treatment of Acute Pulmonary Embolism ARIXTRA is indicated for the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital. 2 DOSAGE AND ADMINISTRATION Do not mix other medications or solutions with ARIXTRA. Administer ARIXTRA only subcutaneously. 2.1 Deep Vein Thrombosis Prophylaxis Following Hip Fracture, Hip Replacement, and Knee Replacement Surgery In patients undergoing hip fracture, hip replacement, or knee replacement surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection once daily after hemostasis has been established. Administer the initial dose no earlier than 6 to 8 hours after surgery. Administration of ARIXTRA earlier than 6 hours after surgery increases the risk of major bleeding. The usual duration of therapy is 5 to 9 days; up to 11 days of therapy was administered in clinical trials. In patients undergoing hip fracture surgery, an extended prophylaxis course of up to 24 additional days is recommended. In patients undergoing hip fracture surgery, a total of 32 days (peri-operative and extended prophylaxis) was administered in clinical trials. [See Warnings and Precautions (5.6), Adverse Reactions (6), and Clinical Studies (14).] 2.2 Deep Vein Thrombosis Prophylaxis Following Abdominal Surgery In patients undergoing abdominal surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection once daily after hemostasis has been established. Administer the initial dose no earlier than 6 to 8 hours after surgery. Administration of ARIXTRA earlier than 6 hours after surgery increases the risk of major bleeding. The usual duration of administration is 5 to 9 days, and up to 10 days of ARIXTRA was administered in clinical trials. 2.3 Deep Vein Thrombosis and Pulmonary Embolism Treatment In patients with acute symptomatic DVT and in patients with acute symptomatic PE, the recommended dose of ARIXTRA is 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) by subcutaneous injection once daily (ARIXTRA treatment regimen). Initiate concomitant treatment with warfarin sodium as soon as possible, usually within 72 hours. Continue treatment with ARIXTRA for at least 5 days and until a therapeutic oral anticoagulant effect is established (INR 2 to 3). The usual duration of administration of ARIXTRA is 5 to 9 days; up to 26 days of ARIXTRA injection was administered in clinical trials. [See Warnings and Precautions (5.6), Adverse Reactions (6), and Clinical Studies (14).] 2.4 Hepatic Impairment No dose adjustment is recommended in patients with mild to moderate hepatic impairment, based upon single-dose pharmacokinetic data. Pharmacokinetic data are not available for patients with severe hepatic impairment. Patients with hepatic impairment may be particularly vulnerable to bleeding during ARIXTRA therapy. Observe these patients closely for signs and symptoms of bleeding. [See Clinical Pharmacology (12.4).] 2.5 Instructions for Use ARIXTRA Injection is provided in a single-dose, prefilled syringe affixed with an automatic needle protection system. ARIXTRA is administered by subcutaneous injection. It must not be administered by intramuscular injection. ARIXTRA is intended for use under a physician's guidance. Patients may self-inject only if their physician determines that it is appropriate and the patients are trained in subcutaneous injection techniques. Prior to administration, visually inspect ARIXTRA to ensure the solution is clear and free of particulate matter. To avoid the loss of drug when using the prefilled syringe, do not expel the air bubble from the syringe before the injection. Administration should be made in the fatty tissue, alternating injection sites (e.g., between the left and right anterolateral or the left and right posterolateral abdominal wall). To administer ARIXTRA: Wipe the surface of the injection site with an alcohol swab. Hold the syringe with either hand and use your other hand to twist the rigid needle guard (covers the needle) counter-clockwise. Pull the rigid needle guard straight off the needle (Figure 1). Discard the needle guard. Do not try to remove the air bubbles from the syringe before giving the injection. Pinch a fold of skin at the injection site between your thumb and forefinger and hold it throughout the injection. Hold the syringe with your thumb on the top pad of the plunger rod and your next 2 fingers on the finger grips on the syringe barrel. Pay attention to avoid sticking yourself with the exposed needle (Figure 2).
a Hip fracture, hip replacement, and knee replacement surgery prophylaxis. Assess renal function periodically in patients receiving ARIXTRA. Discontinue the drug immediately in patients who develop severe renal impairment while on therapy. After discontinuation of ARIXTRA, its anticoagulant effects may persist for 2 to 4 days in patients with normal renal function (i.e., at least 3 to 5 half-lives). The anticoagulant effects of ARIXTRA may persist even longer in patients with renal impairment [see Clinical Pharmacology (12.4)]. 5.3 Body Weight <50 Kg and Bleeding Risk ARIXTRA increases the risk for bleeding in patients who weigh less than 50 kg, compared to patients with higher weights. In patients who weigh less than 50 kg: Do not administer ARIXTRA as prophylactic therapy for patients undergoing hip fracture, hip replacement, or knee replacement surgery and abdominal surgery [see Contraindications (4)]. Use ARIXTRA with caution in the treatment of PE and DVT. During the randomized clinical trials of VTE prophylaxis in the peri-operative period following hip fracture, hip replacement, or knee replacement surgery and abdominal surgery, major bleeding occurred at a higher rate among patients with a body weight <50 kg compared to those with a body weight >50 kg (5.4% versus 2.1% in patients undergoing hip fracture, hip replacement, or knee replacement surgery; 5.3% versus 3.3% in patients undergoing abdominal surgery). 5.4 Thrombocytopenia Thrombocytopenia can occur with the administration of ARIXTRA. Thrombocytopenia of any degree should be monitored closely. Discontinue ARIXTRA if the platelet count falls below 100,000/mm3. Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 3.0% in patients given ARIXTRA 2.5 mg in the peri-operative hip fracture, hip replacement, or knee replacement surgery and abdominal surgery clinical trials. Severe thrombocytopenia (platelet counts less than 50,000/mm3) occurred at a rate of 0.2% in patients given ARIXTRA 2.5 mg in these clinical trials. During extended prophylaxis, no cases of moderate or severe thrombocytopenia were reported. Moderate thrombocytopenia occurred at a rate of 0.5% in patients given the ARIXTRA treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the ARIXTRA treatment regimen in the DVT and PE treatment clinical trials. Isolated occurrences of thrombocytopenia with thrombosis that manifested similar to heparin-induced thrombocytopenia have been reported with the use of ARIXTRA in postmarketing experience. [See Adverse Reactions (6.5).] 5.5 Neuraxial Anesthesia and Post-operative Indwelling Epidural Catheter Use Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur with the use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events may be higher with post-operative use of indwelling epidural catheters or concomitant use of other drugs affecting hemostasis such as NSAIDs [see Boxed Warning]. In the postmarketing experience, epidural or spinal hematoma has been reported in association with the use of ARIXTRA by subcutaneous (SC) injection. Optimal timing between the administration of ARIXTRA and neuraxial procedures is not known. Monitor patients undergoing these procedures for signs and symptoms of neurologic impairment such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), and bowel or bladder dysfunction. Consider the potential risks and benefits before neuraxial intervention in patients anticoagulated or who may be anticoagulated for thromboprophylaxis. 5.6 Monitoring: Laboratory Tests Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of the activity of ARIXTRA and international standards of heparin or LMWH are not calibrators to measure anti-Factor Xa activity of ARIXTRA. If unexpected changes in coagulation parameters or major bleeding occur during therapy with ARIXTRA, discontinue ARIXTRA. In postmarketing experience, isolated occurrences of aPTT elevations have been reported following administration of ARIXTRA [see Adverse Reactions (6.5)]. Periodic routine complete blood counts (including platelet count), serum creatinine level, and stool occult blood tests are recommended during the course of treatment with ARIXTRA. The anti-Factor Xa activity of fondaparinux sodium can be measured by anti-Xa assay using the appropriate calibrator (fondaparinux). The activity of fondaparinux sodium is expressed in milligrams (mg) of the fondaparinux and cannot be compared with activities of heparin or low molecular weight heparins. [See Clinical Pharmacology (12.2, 12.3).] 5.7 Latex The packaging (needle guard) of the prefilled syringe of ARIXTRA contains dry natural latex rubber that may cause allergic reactions in latex sensitive individuals. 6 ADVERSE REACTIONS The most serious adverse reactions reported with ARIXTRA are bleeding complications and thrombocytopenia [see Warnings and Precautions (5)]. 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 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. These trials consisted of the following: 2 peri-operative dose-response trials (n = 989) 4 active-controlled peri-operative VTE prophylaxis trials with enoxaparin sodium (n = 3,616), an extended VTE prophylaxis trial (n = 327), and an active-controlled trial with dalteparin sodium (n = 1,425) a dose-response trial (n = 111) and an active-controlled trial with enoxaparin sodium in DVT treatment (n = 1,091) an active-controlled trial with heparin in PE treatment (n = 1,092) 6.1 Hemorrhage During administration of ARIXTRA, the most common adverse reactions were bleeding complications [see Warnings and Precautions (5.1)]. Hip Fracture, Hip Replacement, and Knee Replacement Surgery: The rates of major bleeding events reported during the hip fracture, hip replacement, or knee replacement surgery clinical trials with ARIXTRA 2.5 mg are provided in Table 2. Table 2. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies
b Not approved for use in patients undergoing hip fracture surgery. c 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) ≥2. d BI ≥2: Overt bleeding associated only with a bleeding index (BI) ≥2 calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) – (post-bleeding)] hemoglobin (g/dL) values]. e Minor bleeding was defined as clinically overt bleeding that was not major. 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: <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 (≥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 3. Table 3. Bleeding in the Abdominal Surgery Study
b Minor bleeding was defined as clinically overt bleeding that was not major. The rates of major bleeding according to the time interval following the first ARIXTRA injection were as follows: <6 hours was 3.4% (9/263) and 6 to 8 hours was 2.9% (32/1112). Treatment of Deep Vein Thrombosis and Pulmonary Embolism: The rates of bleeding events reported during the DVT and PE clinical trials with the ARIXTRA injection treatment regimen are provided in Table 4. Table 4. Bleedinga in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies
b 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 ≥2 g/dL – and/or leading to a transfusion ≥2 units of packed red blood cells or whole blood. c Clinically overt bleeding with a 2 g/dL fall in hemoglobin and/or leading to transfusion of PRBC or whole blood ≥2 units. d Minor bleeding was defined as clinically overt bleeding that was not major. 6.2 Local Reactions Local irritation (injection site bleeding, rash, and pruritus) may occur following subcutaneous injection of ARIXTRA. 6.3 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 rarely 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. 6.4 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 5. Table 5. Adverse Reactions Across Randomized, Controlled, Hip Fracture Surgery, Hip Replacement Surgery, and Knee Replacement Surgery Studies
b Not approved for use in patients undergoing hip fracture surgery. c Localized blister coded as bullous eruption. Adverse reactions in the abdominal surgery study and in the VTE treatment trials generally occurred at lower rates than in the hip and knee surgery trials described above. 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%). 6.5 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 (5.5)]. Isolated occurrences of thrombocytopenia with thrombosis that manifested similar to heparin-induced thrombocytopenia have been reported in the postmarketing experience and isolated 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 (5.4)]. Serious allergic reactions, including angioedema, anaphylactoid/anaphylactic reactions have been reported with the use of ARIXTRA [see Contraindications (4)]. 7 DRUG INTERACTIONS In clinical studies performed with ARIXTRA, the concomitant use of oral anticoagulants (warfarin), 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, 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. [See Warnings and Precautions (5.1).] 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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. Reproduction studies have been performed in pregnant rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area) and pregnant rabbits at subcutaneous doses up to 10 mg/kg/day (about 65 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to fondaparinux sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ARIXTRA should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers Fondaparinux sodium was found to be excreted in the milk of lactating rats. However, it is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARIXTRA is administered to a nursing mother. 8.4 Pediatric Use Safety and effectiveness of ARIXTRA in pediatric patients have not been established. Because risk for bleeding during treatment with ARIXTRA is increased in adults who weigh <50 kg, bleeding may be a particular safety concern for use of ARIXTRA in the pediatric population [see Warnings and Precautions (5.3)]. 8.5 Geriatric Use In clinical trials the efficacy of ARIXTRA in the elderly (65 years or older) was similar to that seen in patients younger than 65 years; however, serious adverse events increased with age. Exercise caution when using ARIXTRA in elderly patients, paying particular attention to dosing directions and concomitant medications (especially anti-platelet medication). [See Warnings and Precautions (5.1).] Fondaparinux sodium is substantially excreted by the kidney, and the risk of adverse reactions to ARIXTRA may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, assess renal function prior to ARIXTRA administration. [See Contraindications (4), Warnings and Precautions (5.2), and Clinical Pharmacology (12.4).] In the peri-operative hip fracture, hip replacement, or knee replacement surgery clinical trials with patients receiving ARIXTRA 2.5 mg, serious adverse events increased with age for patients receiving ARIXTRA. The incidence of major bleeding in clinical trials of ARIXTRA by age is provided in Table 6. Table 6. Incidence of Major Bleeding in Patients Treated With ARIXTRA by Age
8.6 Renal Impairment Patients with impaired renal function are at increased risk of bleeding due to reduced clearance of ARIXTRA [see Contraindications (4) and Warnings and Precautions (5.2)]. Assess renal function periodically in patients receiving ARIXTRA. Discontinue ARIXTRA immediately in patients who develop severe renal impairment while on therapy. After discontinuation of ARIXTRA, its anticoagulant effects may persist for 2 to 4 days in patients with normal renal function (i.e., at least 3 to 5 half-lives). The anticoagulant effects of ARIXTRA may persist even longer in patients with renal impairment [see Clinical Pharmacology (12.4)]. 8.7 Hepatic Impairment Following a single, subcutaneous dose of 7.5 mg of ARIXTRA in patients with moderate hepatic impairment (Child-Pugh Category B) compared to subjects with normal liver function, changes from baseline in aPTT, PT/INR, and antithrombin III were similar in the two groups. However, a higher incidence of hemorrhage was observed in subjects with moderate hepatic impairment than in normal subjects, especially mild hematomas at the blood sampling or injection site. The pharmacokinetics of fondaparinux have not been studied in patients with severe hepatic impairment. [See Dosage and Administration (2.4) and Clinical Pharmacology (12.4).] 10 OVERDOSAGE There is no known antidote for ARIXTRA. Overdose of ARIXTRA may lead to hemorrhagic complications. Discontinue treatment and initiate appropriate therapy if bleeding complications associated with overdosage occur. Data obtained in patients undergoing chronic intermittent hemodialysis suggest that clearance of ARIXTRA can increase by 20% during hemodialysis. 11 DESCRIPTION ARIXTRA (fondaparinux sodium) Injection is a sterile solution containing fondaparinux sodium. It is a synthetic and specific inhibitor of activated Factor X (Xa). Fondaparinux sodium is methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-β-D-glucopyra-nuronosyl-(1→4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-2-O-sulfo-α-L-idopyranuronosyl-(1→4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside, decasodium salt. The molecular formula of fondaparinux sodium is C31H43N3Na10O49S8 and its molecular weight is 1728. The structural formula is provided below:
b P value versus enoxaparin sodium <0.001. c P value versus enoxaparin sodium: NS. 14.2 Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery In a noncomparative, unblinded manner, 737 patients undergoing hip fracture surgery were initially treated during the peri-operative period with ARIXTRA 2.5 mg once daily for 7 ± 1 days. Eighty-one (81) of the 737 patients were not eligible for randomization into the 3-week double-blind period. Three hundred twenty-six (326) patients and 330 patients were randomized to receive ARIXTRA 2.5 mg once daily or placebo, respectively, in or out of the hospital for 21 ± 2 days. Patients ranged in age from 23 to 96 years (mean age 75 years) and were 29% men and 71% women. Patients were 99% Caucasian and 1% other races. Patients with multiple traumas affecting more than one organ system or serum creatinine level more than 2 mg/dL (180 micromol/L) were excluded from the trial. The primary efficacy endpoint, venous thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported for up to 24 days following randomization. The efficacy data are provided in Table 8 and demonstrate that extended prophylaxis with ARIXTRA was associated with a VTE rate of 1.4% compared with a VTE rate of 35.0% for placebo for a relative risk reduction of 95.9% (95% CI = [98.7; 87.1], P <0.0001). Major bleeding rates during the 3-week extended prophylaxis period for ARIXTRA occurred in 2.4% of patients receiving ARIXTRA and 0.6% of placebo-treated patients [see Adverse Reactions (6.1)]. Table 8. Efficacy of ARIXTRA Injection in the Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery
b P value versus placebo <0.001 c P value versus placebo = 0.021. d P value versus placebo = NS. 14.3 Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery In 2 randomized, double-blind, clinical trials in patients undergoing hip replacement surgery, ARIXTRA 2.5 mg SC once daily was compared to either enoxaparin sodium 30 mg SC every 12 hours (Study 1) or to enoxaparin sodium 40 mg SC once a day (Study 2). In Study 1, a total of 2,275 patients were randomized and 2,257 were treated. Patients ranged in age from 18 to 92 years (mean age 65 years) with 48% men and 52% women. Patients were 94% Caucasian, 4% black, <1% Asian, and 2% others. In Study 2, a total of 2,309 patients were randomized and 2,273 were treated. Patients ranged in age from 24 to 97 years (mean age 65 years) with 42% men and 58% women. Patients were 99% Caucasian, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm3 were excluded from both trials. In Study 1, ARIXTRA was initiated 6 ± 2 hours (mean 6.5 hours) after surgery in 92% of patients and enoxaparin sodium was initiated 12 to 24 hours (mean 20.25 hours) after surgery in 97% of patients. In Study 2, ARIXTRA was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in 86% of patients and enoxaparin sodium was initiated 12 hours before surgery in 78% of patients. The first post-operative enoxaparin sodium dose was given within 12 hours after surgery in 60% of patients and 12 to 24 hours after surgery in 35% of patients with a mean of 13 hours. For both studies, both study treatments were continued for 7 ± 2 days. The efficacy data are provided in Table 9. Under the conditions of Study 1, ARIXTRA was associated with a VTE rate of 6.1% compared with a VTE rate of 8.3% for enoxaparin sodium for a relative risk reduction of 26% (95% CI: -11%, 53%; P = NS). Under the conditions of Study 2, fondaparinux sodium was associated with a VTE rate of 4.1% compared with a VTE rate of 9.2% for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 33%, 73%; P <0.001). For the 2 studies combined, the major bleeding episodes occurred in 3.0% of patients receiving ARIXTRA and 2.1% of enoxaparin sodium patients [see Adverse Reactions (6.1)]. Table 9. Efficacy of ARIXTRA in the Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery
b VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11. c P value versus enoxaparin sodium: NS. d P value versus enoxaparin sodium in study 1: <0.05. e P value versus enoxaparin sodium in study 2: <0.001. f P value versus enoxaparin sodium in study 2: <0.01. 14.4 Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery In a randomized, double-blind, clinical trial in patients undergoing knee replacement surgery (i.e., surgery requiring resection of the distal end of the femur or proximal end of the tibia), ARIXTRA 2.5 mg SC once daily was compared to enoxaparin sodium 30 mg SC every 12 hours. A total of 1,049 patients were randomized and 1,034 were treated. Patients ranged in age from 19 to 94 years (mean age 68 years) with 41% men and 59% women. Patients were 88% Caucasian, 8% black, <1% Asian, and 3% others. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm3 were excluded from the trial. ARIXTRA was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in 94% of patients, and enoxaparin sodium was initiated 12 to 24 hours (mean 21 hours) after surgery in 96% of patients. For both drugs, treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 10 and demonstrate that under the conditions of the trial, ARIXTRA was associated with a VTE rate of 12.5% compared with a VTE rate of 27.8% for enoxaparin sodium for a relative risk reduction of 55% (95% CI: 36%, 70%; P <0.001). Major bleeding episodes occurred in 2.1% of patients receiving ARIXTRA and 0.2% of enoxaparin sodium patients [see Adverse Reactions (6.1)]. Table 10. Efficacy of ARIXTRA in the Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery
b VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11. c P value versus enoxaparin sodium <0.001. d P value versus enoxaparin sodium: NS. 14.5 Prophylaxis of Thromboembolic Events Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications Abdominal surgery patients at risk included the following: Those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 60 years with or without additional risk factors; and those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 40 years with additional risk factors. Risk factors included neoplastic disease, obesity, chronic obstructive pulmonary disease, inflammatory bowel disease, history of deep vein thrombosis (DVT) or pulmonary embolism (PE), or congestive heart failure. In a randomized, double-blind, clinical trial in patients undergoing abdominal surgery, ARIXTRA 2.5 mg SC once daily started postoperatively was compared to dalteparin sodium 5,000 IU SC once daily, with one 2,500 IU SC preoperative injection and a 2,500 IU SC first postoperative injection. A total of 2,927 patients were randomized and 2,858 were treated. Patients ranged in age from 17 to 93 years (mean age 65 years) with 55% men and 45% women. Patients were 97% Caucasian, 1% black, 1% Asian, and 1% others. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm3 were excluded from the trial. Sixty-nine percent (69%) of study patients underwent cancer-related abdominal surgery. Study treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 11 and demonstrate that prophylaxis with ARIXTRA was associated with a VTE rate of 4.6% compared with a VTE rate of 6.1% for dalteparin sodium (P = NS). Table 11. Efficacy of ARIXTRA In Prophylaxis of Thromboembolic Events Following Abdominal Surgery
b VTE was a composite of venogram positive DVT, symptomatic DVT, non-fatal PE and/or fatal PE reported up to Day 10. c P value versus dalteparin sodium: NS. 14.6 Treatment of Deep Vein Thrombosis In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT without PE, ARIXTRA 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) SC once daily (ARIXTRA treatment regimen) was compared to enoxaparin sodium 1 mg/kg SC every 12 hours. Almost all patients started study treatment in hospital. Approximately 30% of patients in both groups were discharged home from the hospital while receiving study treatment. A total of 2,205 patients were randomized and 2,192 were treated. Patients ranged in age from 18 to 95 years (mean age 61 years) with 53% men and 47% women. Patients were 97% Caucasian, 2% black, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm3 were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range of 7 ± 2 days, and both treatment groups received vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2 to 3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 12. Table 12. Efficacy of ARIXTRA in the Treatment of Deep Vein Thrombosis (All Randomized)
During the initial treatment period, 18 (1.6%) of patients treated with fondaparinux sodium and 10 (0.9%) of patients treated with enoxaparin sodium had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-enoxaparin sodium] for VTE rates: -0.2%; 1.7%). 14.7 Treatment of Pulmonary Embolism In a randomized, open-label, clinical trial in patients with a confirmed diagnosis of acute symptomatic PE, with or without DVT, ARIXTRA 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) SC once daily (ARIXTRA treatment regimen) was compared to heparin IV bolus (5,000 USP units) followed by a continuous IV infusion adjusted to maintain 1.5 to 2.5 times aPTT control value. Patients with a PE requiring thrombolysis or surgical thrombectomy were excluded from the trial. All patients started study treatment in hospital. Approximately 15% of patients were discharged home from the hospital while receiving ARIXTRA therapy. A total of 2,213 patients were randomized and 2,184 were treated. Patients ranged in age from 18 to 97 years (mean age 62 years) with 44% men and 56% women. Patients were 94% Caucasian, 5% black, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm3 were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range 7 ± 2 days, and both treatment groups received vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2 to 3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 13. Table 13. Efficacy of ARIXTRA in the Treatment of Pulmonary Embolism (All Randomized)
16 HOW SUPPLIED/STORAGE AND HANDLING ARIXTRA Injection is available in the following strengths and package sizes: 2.5 mg ARIXTRA in 0.5 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with white plunger rod.
PHARMACIST: Dispense a Patient Information Leaflet with each prescription. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) 17.1 Patient Advice If the patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDS, platelet inhibitors, or other anticoagulants, they should be informed to watch for signs and symptoms of spinal or epidural hematomas, such as back pain, tingling, numbness (especially in the lower limbs), muscular weakness, and stool or urine incontinence. If any of these symptoms occur, the patients should contact his or her physician immediately. The use of aspirin and other NSAIDS may enhance the risk of hemorrhage. Their use should be discontinued prior to ARIXTRA therapy whenever possible; if co-administration is essential, the patient's clinical and laboratory status should be closely monitored. [See Drug Interactions (7).] If patients must self-administer ARIXTRA (e.g., if ARIXTRA is used at home), they should be advised of the following: ARIXTRA should be given by subcutaneous injection. Patients must be instructed in the proper technique for administration.
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