Arixtra Drug Information

Deep Vein Thrombosis Prophylaxis Following Hip Fracture, Hip Replacement, and Knee Replacement Surgery in Adults In adult 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 hours 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 days 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.

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). There is no available prefilled syringe for patients in this weight range, and a patient specific dose should be prepared see section

Instructions for Preparation of Individual Pediatric Doses in Pharmacies. The dose should be exact and rounded to the nearest 0.1 mg ( see Table 1 ). Table 1.

There is no available information for dosing pediatric patients who weigh less than 10 kg. Table 2. Recommended Prefilled Syringe Selection for Initial Dose of ARIXTRA for Treatment of VTE in Pediatric Patients Weighing More Than 20 kg Monitor fondaparinux levels 2 hours to 4 hours after the second or third dose and then weekly for a month followed by every 1 month to 3 months for the duration of treatment using a fondaparinux-based anti-Xa assay with a therapeutic goal range of 0.5 mg/L to 1 mg/L.

Dosing adjustments may be necessary to achieve peak blood concentration within the therapeutic target of 0.5 mg/L to 1 mg/L ( see Table 3 ). Do not exceed the maximum dose of 7.5 mg/day. Table 3.

Recommended There is no adequate data to support the use of ARIXTRA in pediatric patients below 1 year of age. 2.6 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. 2.7 Instructions for Use for Prefilled Syringe 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: 1.

Wipe the surface of the injection site with an alcohol swab. 2. 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 A).

Discard the needle guard. 3. Do not try to remove the air bubbles from the syringe before giving the injection. 4. Pinch a fold of skin at the injection site between your thumb and forefinger and hold it throughout the injection. 5.

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. 6. Insert the full length of the syringe needle perpendicularly into the skin fold held between the thumb and forefinger (Figure B). 7.

Push the plunger rod firmly with your thumb as far as it will go. This will ensure you have injected all the contents of the syringe (Figure C). 8. When you have injected all the contents of the syringe, the plunger should be released.

The plunger will then rise automatically while the needle withdraws from the skin and retracts into the security sleeve. Discard the syringe into the sharps container. 9. These instructions may also be used to prepare pediatric patient-specific doses for patients weighing over 20 kg when dose adjustments are needed and therapeutic levels are not achievable using the prefilled syringe available strengths.

General Aseptic Preparation Practices Strictly observe aseptic technique when preparing patient specific pediatric doses of ARIXTRA. To prevent accidental contamination, prepare ARIXTRA according to aseptic standards, including but not limited to: • Prepare ARIXTRA in an ISO Class 5 laminar airflow (LAF) hood • Ensure that the dose preparation area, including the LAF hood, has appropriate environmental specifications, confirmed by periodic monitoring. • Ensure that personnel are appropriately trained in aseptic manipulations of sterile products. • Ensure that personnel wear appropriate clothing and gloves. • Ensure that gloves and surfaces are disinfected. All steps should be completed in accordance with aseptic techniques: 1.

Determine the total dose and volume per the duration, and the appropriate number of ARIXTRA prefilled syringes. One ARIXTRA prefilled syringe is used in cases where the total required dose is less than 0.5 mL. Where the total dose required is greater than or equal to 0.5 mL, only two ARIXTRA prefilled syringes may be pooled together.

The maximum number of ARIXTRA prefilled syringes that may be pooled together is two. Do not combine ARIXTRA prefilled syringes of different concentrations in one injection to give the prescribed dose. 2. Gather the required supplies including the appropriate ARIXTRA prefilled syringe(s), a sterile, closed/sealed, empty glass vial (recommended 5 mL), and required number of suitable sized graduated tuberculin sterile syringes with 27 gauge x ½” staked needles or sterile needles (if not pre-attached to syringe). 3.

Verify the required supplies are correct and within expiry date. Ensure only the materials required for the preparation are present in the work area. 4. While wearing sterile gloves, clean the LAF hood and wipe it down with sterile 70% alcohol.

Ensure the LAF hood is within specification and continually monitored. 5. Ensure equipment and consumables are cleaned with isopropyl alcohol (IPA). 6. Before transferring into the LAF hood, clean all supplies including ancillary items (such as vial holder jigs, syringe cap holder jigs, sharps containers) with IPA. 7.

Perform all the dose preparation steps within the LAF hood. 8. Pre-sterilize gloves with IPA. Pull the rigid needle guard straight off the needle.

Discard the needle guard. 9. Dispense the full contents of the ARIXTRA prefilled syringe into the vial by fully depressing the plunger. 10. Discard the ARIXTRA prefilled syringe into a sharps container. 11.

Take an empty graduated tuberculin sterile syringe and attach a suitable sterile needle if not already supplied pre-attached. 12. Remove needle cap. 13. Withdraw required dose from vial into the tuberculin syringe. 14.

Replace needle cap over the needle. Clean the external surfaces of the filled tuberculin syringe with IPA. 15. Repeat steps 11 to 14 as required for the appropriate number of tuberculin syringes necessary for the patient. 16.

Label each ARIXTRA tuberculin syringe with patient specific information (e.g., dosing instructions, patient information), storage information (e.g., store refrigerated between 36°F to 46°F (2°C to 8°C), do not freeze, and the beyond use date). The beyond use date should be the earlier of the product expiration date of the ARIXTRA prefilled syringe or 30 days after preparation of the tuberculin syringe. 17. Prepared tuberculin syringes may be dispensed in an empty plastic bag.

Include Patient Information and Instructions for Use for the tuberculin syringe within the plastic bag to be dispensed to patients. They may be stored at refrigerated temperatures between 36°F to 46°F (2°C to 8°C) for up to the beyond use date. Do not freeze.

Do not store the pediatric preparations at room temperature as they are growth promoting at room temperature. Discard unused portion.

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.

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 Major bleeding Major bleeding was defined as clinically overt bleeding that was fatal, bleeding at critical site (e.g., intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), associated with re-operation at operative site, or with a bleeding index (BI) greater than or equal to 2.

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 hemoglobin (g/dL) values]. 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 hours was 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. 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 fatal, bleeding at the surgical site leading to intervention, 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. 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 Local Reactions Local irritation (injection site bleeding, rash, and pruritus) has occurred following subcutaneous injection of ARIXTRA. 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. 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 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. The incidence of major bleeding events, defined as per the ISTH criteria, was the primary safety outcome of interest in Study FDPX-IJS-7001. 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.

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.

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.

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). Serious allergic reactions, including angioedema, anaphylactoid/anaphylactic reactions have been reported with the use of ARIXTRA. 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. 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.

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 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.

• ARIXTRA is contraindicated in the following conditions:
• Severe renal impairment (creatinine clearance less than 30 mL/min).
• 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. ARIXTRA is contraindicated in the following conditions:
• Severe renal impairment (creatinine clearance less than 30 mL/min) in prophylaxis or treatment of venous thromboembolism.
• Active major bleeding.
• Bacterial endocarditis.
• 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.