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Arixtra (Fondaparinux Sodium Injection) - Warnings and Precautions

 
 



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. [See Warnings and Precautions and Drug Interactions (7).]

 

WARNINGS AND PRECAUTIONS

Hemorrhage

Use ARIXTRA 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 (with or without concomitant administration of other anticoagulants) [See Adverse Reactions].

Do not administer agents that enhance the risk of hemorrhage with ARIXTRA 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 earlier than 6 to 8 hours after surgery. Administration earlier than 6 hours after surgery increases risk of major bleeding [see Dosage and Administration and Adverse Reactions].

Renal Impairment and Bleeding Risk

ARIXTRA increases the risk of bleeding in patients with impaired renal function due to reduced clearance [see Clinical Pharmacology].

The incidence of major bleeding by renal function status reported in clinical trials of patients receiving ARIXTRA for VTE surgical prophylaxis is provided in Table 1. In these patient populations, the following is recommended:

  • Do not use ARIXTRA for VTE prophylaxis and treatment in patients with CrCl <30 mL/min [see Contraindications].
  • Use ARIXTRA with caution in patients with CrCl 30 to 50 mL/min.
Table 1. Incidence of Major Bleeding in Patients Treated With ARIXTRA by Renal Function Status for Surgical Prophylaxis and Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE)
Degree of Renal Impairment
Population Timing of Dose

Normal

%

(n/N)

Mild

%

(n/N)

Moderate

%

(n/N)

Severe

%

(n/N)

CrCl (mL/min) ≥80 ≥50 - <80 ≥30 - <50 <30
Orthopedic surgerya Overall

1.6%

(25/1,565)

2.4%

(31/1,288)

3.8%

(19/504)

4.8%

(4/83)

6-8 hours after surgery

1.8%

(16/905)

2.2%

(15/675)

2.3%

(6/265)

0%

(0/40)

Abdominal surgery

Overall

2.1%

(13/606)

3.6%

(22/613)

6.7%

(12/179)

7.1%

(1/14)

6-8 hours after surgery

2.1%

(10/467)

3.3%

(16/481)

5.8%

(8/137)

7.7%

(1/13)

DVT and PE

Treatment

0.4%

(4/1,132)

1.6%

(12/733)

2.2%

(7/318)

7.3%

(4/55)

CrCl = creatinine clearance.

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].

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].
  • 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).

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 .]

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. Monitor patients undergoing these procedures for signs and symptoms of neurologic impairment. Consider the potential risks and benefits before neuraxial intervention in patients anticoagulated or who may be anticoagulated for thromboprophylaxis.

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].

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).]

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.

USE IN SPECIFIC POPULATIONS

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.

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.

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].

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 .]

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 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
Age

<65 years

% (n/N)

65 to 74 years

% (n/N)

≥75 years

% (n/N)

Orthopedic surgerya 1.8% (23/1,253) 2.2% (24/1,111) 2.7% (33/1,277)
   Extended prophylaxis 1.9% (1/52) 1.4% (1/71) 2.9% (6/204)
Abdominal surgery 3.0% (19/644) 3.2% (16/507) 5.0% (14/282)
DVT and PE treatment 0.6% (7/1,151) 1.6% (9/560) 2.1% (12/583)

a Includes hip fracture, hip replacement, and knee replacement surgery prophylaxis.

Renal Impairment

Patients with impaired renal function are at increased risk of bleeding due to reduced clearance of ARIXTRA [see Contraindications and Warnings and Precautions]. 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].

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 and Clinical Pharmacology (12.4).]

Page last updated: 2012-01-23

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