Arixtra Information
Arixtra (Fondaparinux) Warning: Spinal/epidural Hematomas
Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH), heparinoids, or fondaparinux sodium and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
● use of indwelling epidural catheters
● concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants
● a history of traumatic or repeated epidural or spinal puncture
● a history of spinal deformity or spinal surgery
Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary.
Consider the benefit and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
Arixtra (Fondaparinux) Dosage And Administration
Do not mix other medications or solutions with Arixtra (Fondaparinux) . Administer Arixtra (Fondaparinux) only subcutaneously.
In patients undergoing hip fracture, hip replacement, or knee replacement surgery, the recommended dose of Arixtra (Fondaparinux) 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 (Fondaparinux) 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.
Arixtra (Fondaparinux) Injection is provided in a single-dose, prefilled syringe affixed with an automatic needle protection system. Arixtra (Fondaparinux) is administered by subcutaneous injection. It must not be administered by intramuscular injection. Arixtra (Fondaparinux) 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 (Fondaparinux) 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.
To administer Arixtra (Fondaparinux) :
Arixtra (Fondaparinux) Dosage Forms And Strengths
Single-dose, prefilled syringes containing either 2.5 mg, 5 mg, 7.5 mg, or 10 mg of fondaparinux.
Arixtra (Fondaparinux) Contraindications
Arixtra (Fondaparinux) is contraindicated in the following conditions:
Arixtra (Fondaparinux) Warnings And Precautions
Use Arixtra (Fondaparinux) with extreme caution in conditions with increased risk of hemorrhage, such as congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, uncontrolled arterial hypertension, diabetic retinopathy, or shortly after brain, spinal, or ophthalmological surgery. Isolated cases of elevated aPTT temporally associated with bleeding events have been reported following administration of Arixtra (Fondaparinux) (with or without concomitant administration of other anticoagulants)
Do not administer agents that enhance the risk of hemorrhage with Arixtra (Fondaparinux) unless essential for the management of the underlying condition, such as vitamin K antagonists for the treatment of VTE. If co-administration is essential, closely monitor patients for signs and symptoms of bleeding.
Do not administer the initial dose of Arixtra (Fondaparinux) earlier than 6 to 8 hours after surgery. Administration earlier than 6 hours after surgery increases risk of major bleeding
Arixtra (Fondaparinux) increases the risk of bleeding in patients with impaired renal function due to reduced clearance
The incidence of major bleeding by renal function status reported in clinical trials of patients receiving Arixtra (Fondaparinux) for VTE surgical prophylaxis is provided in Table 1. In these patient populations, the following is recommended:
CrCl = creatinine clearance.
a
Assess renal function periodically in patients receiving Arixtra (Fondaparinux) . Discontinue the drug immediately in patients who develop severe renal impairment while on therapy. After discontinuation of Arixtra (Fondaparinux) , 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 (Fondaparinux) may persist even longer in patients with renal impairment
Arixtra (Fondaparinux) 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:
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 (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).
Thrombocytopenia can occur with the administration of Arixtra (Fondaparinux) . Thrombocytopenia of any degree should be monitored closely. Discontinue Arixtra (Fondaparinux) if the platelet count falls below 100,000/mm. Moderate thrombocytopenia (platelet counts between 100,000/mm and 50,000/mm) occurred at a rate of 3.0% in patients given Arixtra (Fondaparinux) 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/mm) occurred at a rate of 0.2% in patients given Arixtra (Fondaparinux) 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 (Fondaparinux) treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the Arixtra (Fondaparinux) 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 (Fondaparinux) in postmarketing experience.
Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of the activity of Arixtra (Fondaparinux) and international standards of heparin or LMWH are not calibrators to measure anti-Factor Xa activity of Arixtra (Fondaparinux) . If unexpected changes in coagulation parameters or major bleeding occur during therapy with Arixtra (Fondaparinux) , discontinue Arixtra (Fondaparinux) . In postmarketing experience, isolated occurrences of aPTT elevations have been reported following administration of Arixtra (Fondaparinux) .
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 (Fondaparinux) .
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.
Arixtra (Fondaparinux) Adverse Reactions
The most serious adverse reactions reported with Arixtra (Fondaparinux) are bleeding complications and thrombocytopenia .
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 (Fondaparinux) in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment. These trials consisted of the following:
Arixtra (Fondaparinux) Drug Interactions
In clinical studies performed with Arixtra (Fondaparinux) , 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 (Fondaparinux) 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 (Fondaparinux) unless these agents are essential. If co-administration is necessary, monitor patients closely for hemorrhage.
In an 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) , fondaparinux sodium is not expected to significantly interact with other drugs 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.
Arixtra (Fondaparinux) Use In Specific Populations
In clinical trials the efficacy of Arixtra (Fondaparinux) 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 (Fondaparinux) in elderly patients, paying particular attention to dosing directions and concomitant medications (especially anti-platelet medication).
Fondaparinux sodium is substantially excreted by the kidney, and the risk of adverse reactions to Arixtra (Fondaparinux) 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 (Fondaparinux) administration.
In the peri-operative hip fracture, hip replacement, or knee replacement surgery clinical trials with patients receiving Arixtra (Fondaparinux) 2.5 mg, serious adverse events increased with age for patients receiving Arixtra (Fondaparinux) . The incidence of major bleeding in clinical trials of Arixtra (Fondaparinux) by age is provided in Table 6.
a
Arixtra (Fondaparinux) Overdosage
There is no known antidote for Arixtra (Fondaparinux) . Overdose of Arixtra (Fondaparinux) 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 (Fondaparinux) can increase by 20% during hemodialysis.
Arixtra (Fondaparinux) Description
Arixtra (Fondaparinux) (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 CHNNaOS and its molecular weight is 1728. The structural formula is provided below:
Arixtra (Fondaparinux) is supplied as a sterile, preservative-free injectable solution for subcutaneous use.
Each single-dose, prefilled syringe of Arixtra (Fondaparinux) , affixed with an automatic needle protection system, contains 2.5 mg of fondaparinux sodium in 0.5 mL, 5.0 mg of fondaparinux sodium in 0.4 mL, 7.5 mg of fondaparinux sodium in 0.6 mL, or 10.0 mg of fondaparinux sodium in 0.8 mL of an isotonic solution of sodium chloride and water for injection. The final drug product is a clear and colorless to slightly yellow liquid with a pH between 5.0 and 8.0.
Arixtra (Fondaparinux) Clinical Pharmacology
The antithrombotic activity of fondaparinux sodium is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. By selectively binding to ATIII, fondaparinux sodium potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development.
Fondaparinux sodium does not inactivate thrombin (activated Factor II) and has no known effect on platelet function. At the recommended dose, fondaparinux sodium does not affect fibrinolytic activity or bleeding time.
Anti-Xa Activity:
Absorption:
max
Elimination:
max
Gender:
Race:
Arixtra (Fondaparinux) Clinical Studies
In a randomized, double-blind, clinical trial in patients undergoing hip fracture surgery, Arixtra (Fondaparinux) 2.5 mg SC once daily was compared to enoxaparin sodium 40 mg SC once daily, which is not approved for use in patients undergoing hip fracture surgery. A total of 1,711 patients were randomized and 1,673 were treated. Patients ranged in age from 17 to 101 years (mean age 77 years) with 25% men and 75% women. Patients were 99% Caucasian, 1% other races. Patients with multiple traumas affecting more than one organ system, serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm were excluded from the trial. Arixtra (Fondaparinux) was initiated after surgery in 88% of patients (mean 6 hours) and enoxaparin sodium was initiated after surgery in 74% of patients (mean 18 hours). For both drugs, treatment was continued for 7 ± 2 days. The primary efficacy endpoint, venous thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported up to Day 11. The efficacy data are provided in Table 7 and demonstrate that under the conditions of the trial Arixtra (Fondaparinux) was associated with a VTE rate of 8.3% compared with a VTE rate of 19.1% for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 39%, 70%;
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In a noncomparative, unblinded manner, 737 patients undergoing hip fracture surgery were initially treated during the peri-operative period with Arixtra (Fondaparinux) 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 (Fondaparinux) 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 (Fondaparinux) 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],
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In 2 randomized, double-blind, clinical trials in patients undergoing hip replacement surgery, Arixtra (Fondaparinux) 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,
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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 (Fondaparinux) 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,
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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 (Fondaparinux) 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/mm 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 (Fondaparinux) was associated with a VTE rate of 4.6% compared with a VTE rate of 6.1% for dalteparin sodium ( = NS).
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In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT without PE, Arixtra (Fondaparinux) 5 mg (body weight 100 kg) SC once daily (Arixtra (Fondaparinux) 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/mmwere 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.
a
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%).
In a randomized, open-label, clinical trial in patients with a confirmed diagnosis of acute symptomatic PE, with or without DVT, Arixtra (Fondaparinux) 5 mg (body weight 100 kg) SC once daily (Arixtra (Fondaparinux) 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 (Fondaparinux) 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/mm 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.
a
During the initial treatment period, 12 (1.1%) of patients treated with fondaparinux sodium and 19 (1.7%) of patients treated with heparin had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-heparin] for VTE rates: -1.6%; 0.4%).
Arixtra (Fondaparinux) How Supplied/storage And Handling
Arixtra (Fondaparinux) Injection is available in the following strengths and package sizes:
2.5 mg Arixtra (Fondaparinux) 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.
5 mg Arixtra (Fondaparinux) in 0.4 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with white plunger rod.
7.5 mg Arixtra (Fondaparinux) in 0.6 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with white plunger rod.
10 mg Arixtra (Fondaparinux) in 0.8 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with white plunger rod.
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F).
Arixtra (Fondaparinux) Patient Counseling Information
See FDA-Approved Patient Labeling (17.2)
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 tingling, numbness (especially in the lower limbs) and muscular weakness. 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 (Fondaparinux) therapy whenever possible; if co-administration is essential, the patient’s clinical and laboratory status should be closely monitored.
If patients must self-administer Arixtra (Fondaparinux) (e.g., if Arixtra (Fondaparinux) is used at home), they should be advised of the following:
Keep out of the reach of children.
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