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Arixtra

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Arixtra

Side Effects
Interactions

SIDE EFFECTS

The most serious adverse reactions reported with ARIXTRA are bleeding complications and thrombocytopenia [see WARNINGS AND PRECAUTIONS].

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)

Hemorrhage

During administration of ARIXTRA, the most common adverse reactions were bleeding complications [see WARNINGS AND PRECAUTIONS].

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

  Peri-Operative Prophylaxis
(Day 1 to Day 7 ± 1 postsurgery)
Extended Prophylaxis
(Day 8 to Day 28 ± 2 postsurgery)
ARIXTRA 2.5 mg SC once daily
N = 3,616
Enoxaparin Sodiuma, b
N = 3,956
ARIXTRA 2.5 mg SC once daily
N = 327
Placebo SC once daily
N = 329
Major bleedingc 96
(2.7%)
75
(1.9%)
8
(2.4%)
2
(0.6%)
  Hip fracture 18/831
(2.2%)
19/842
(2.3%)
8/327
(2.4%)
2/329
(0.6%)
  Hip replacement 67/2,268
(3.0%)
55/2,597
(2.1%)
- -
  Knee replacement 11/517
(2.1%)
1/517
(0.2%)
- -
Fatal bleeding 0
(0.0%)
1
( < 0.1%)
0
(0.0%)
0
(0.0%)
Non-fatal bleeding at critical site 0
(0.0%)
1
( < 0.1%)
0
(0.0%)
0
(0.0%)
Re-operation due to bleeding 12
(0.3%)
10
(0.3%)
2
(0.6%)
2
(0.6%)
BI ≥ 2d 84
(2.3%)
63
(1.6%)
6
(1.8%)
0
(0.0%)
Minor bleedinge 109
(3.0%)
116
(2.9%)
5
(1.5%)
2
(0.6%)
a Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.
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

  ARIXTRA 2.5 mg SC once daily
N = 1,433
Dalteparin Sodium 5,000 IU SC once daily
N = 1,425
Major bleedinga 49
(3.4%)
34
(2.4%)
Fatal bleeding 2
(0.1%)
2
(0.1%)
Non-fatal bleeding at critical site 0
(0.0%)
0
(0.0%)
Other non-fatal major bleeding
  Surgical site 38
(2.7%)
26
(1.8%)
  Non-surgical site 9
(0.6%)
6
(0.4%)
Minor bleedingb 31
(2.2%)
23
(1.6%)
a Major bleeding was defined as bleeding that was (1) fatal, (2) bleeding at the surgical site leading to intervention, (3) non-surgical bleeding at a critical site (e.g. intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), or leading to an intervention, and/or with a bleeding index (BI) ≥ 2.
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

  ARIXTRA
N = 2,294
Enoxaparin Sodium
N = 1,101
Heparin aPTT adjusted IV
N = 1,092
Major bleedingb 28
(1.2%)
13
(1.2%)
12
(1.1%)
Fatal bleeding 3
(0.1%)
0
(0.0%)
1
(0.1%)
Non-fatal bleeding at a critical site 3
(0.1%)
0
(0.0%)
2
(0.2%)
Intracranial bleeding 3
(0.1%)
0
(0.0%)
1
(0.1%)
Retro-peritoneal bleeding 0
(0.0%)
0
(0.0%)
1
(0.1%)
Other clinically overt bleedingc 22
(1.0%)
13
(1.2%)
10
(0.9%)
Minor bleedingd 70
(3.1%)
33
(3.0%)
57
(5.2%)
a 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.
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 &get;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.

Local Reactions

Local irritation (injection site bleeding, rash, and pruritus) may occur following subcutaneous injection of ARIXTRA.

Elevations Of Serum Aminotransferases

In the peri-operative prophylaxis randomized clinical trials of 7 ± 2 days, asymptomatic increases in aspartate (AST) and alanine (ALT) aminotransferase levels greater than 3 times the upper limit of normal were reported in 1.7% and 2.6% of patients, respectively, during treatment with ARIXTRA 2.5 mg once daily versus 3.2% and 3.9% of patients, respectively, during treatment with enoxaparin sodium 30 mg every 12 hours or 40 mg once daily enoxaparin sodium. These elevations are reversible and 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.

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

Adverse Reactions Peri-Operative Prophylaxis
(Day 1 to Day 7 ± 1 post-surgery)
Extended Prophylaxis
(Day 8 to Day 28 ± 2 post-surgery)
ARIXTRA 2.5 mg SC once daily
N = 3,616
Enoxaparin Sodiuma,b
N = 3,956
ARIXTRA 2.5 mg SC once daily
N = 327
Placebo SC once daily
N = 329
Anemia 707
(19.6%)
670
(16.9%)
5
(1.5%)
4
(1.2%)
Insomnia 179
(5.0%)
214
(5.4%)
3
(0.9%)
1
(0.3%)
Wound drainage increased 161
(4.5%)
184
(4.7%)
2
(0.6%)
0
(0.0%)
Hypokalemia 152
(4.2%)
164
(4.1%)
0
(0.0%)
0
(0.0%)
Dizziness 131
(3.6%)
165
(4.2%)
2
(0.6%)
0
(0.0%)
Purpura 128
(3.5%)
137
(3.5%)
0
(0.0%)
0
(0.0%)
Hypotension 126
(3.5%)
125
(3.2%)
1
(0.3%)
0
(0.0%)
Confusion 113
(3.1%)
132
(3.3%)
4
(1.2%)
1
(0.3%)
Bullous eruptionc 112
(3.1%)
102
(2.6%)
0
(0.0%)
1
(0.3%)
Hematoma 103
(2.8%)
109
(2.8%)
7
(2.1%)
1
(0.3%)
Post-operative hemorrhage 85
(2.4%)
69
(1.7%)
2
(0.6%)
2
(0.6%)
a Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.
bNot 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%).

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.

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].

Serious allergic reactions, including angioedema, anaphylactoid/anaphylactic reactions have been reported with the use of ARIXTRA [see CONTRAINDICATIONS].

Read the Arixtra (fondaparinux sodium) Side Effects Center for a complete guide to possible side effects

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]

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.

Read the Arixtra Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 7/29/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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