Prophylaxis of Deep Vein Thrombosis
Fondaparinux Sodium Solution 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.
Treatment of Acute Deep Vein Thrombosis
Fondaparinux Sodium Solution is indicated for the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium.
Treatment of Acute Pulmonary Embolism
Fondaparinux Sodium Solution is indicated for the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital.
Fondaparinux Sodium Dosage and Administration
Do not mix other medications or solutions with Fondaparinux Sodium Solution. Administer Fondaparinux Sodium Solution only subcutaneously.
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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution 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)].
Deep Vein Thrombosis Prophylaxis Following Abdominal Surgery
In patients undergoing abdominal surgery, the recommended dose of Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution was administered in clinical trials.
Deep Vein Thrombosis and Pulmonary Embolism Treatment
In patients with acute symptomatic DVT and in patients with acute symptomatic PE, the recommended dose of Fondaparinux Sodium Solution 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 (Fondaparinux Sodium Solution treatment regimen). Initiate concomitant treatment with warfarin sodium as soon as possible, usually within 72 hours. Continue treatment with Fondaparinux Sodium Solution for at least 5 days and until a therapeutic oral anticoagulant effect is established (INR 2 to 3). The usual duration of administration of Fondaparinux Sodium Solution is 5 to 9 days; up to 26 days of Fondaparinux Sodium Solution was administered in clinical trials. [See Warnings and Precautions (5.6), Adverse Reactions (6), and Clinical Studies (14)].
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 Fondaparinux Sodium Solution therapy. Observe these patients closely for signs and symptoms of bleeding. [See Clinical Pharmacology (12.4).]
Instructions for Use
Fondaparinux Sodium Solution is provided in a single-dose, prefilled syringe affixed with an automatic needle protection system. Fondaparinux Sodium Solution is administered by subcutaneous injection. It must not be administered by intramuscular injection. Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution:
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 1). 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 (Figure 2). |
|
|
6. Insert the full length of the syringe needle perpendicularly into the skin fold held between the thumb and forefinger (Figure 3).
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 4). |
|
|
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. You will know that the syringe has worked when:
- The needle is pulled back into the security sleeve and the white safety indicator appears above the upper body.
- You may also hear or feel a soft click when the plunger rod is released fully.
|
Dosage Forms and Strengths
Single-dose, prefilled syringes containing either 2.5 mg, 5 mg, 7.5 mg, or 10 mg of fondaparinux.
Contraindications
Fondaparinux Sodium Solution is contraindicated in the following conditions:
- Severe renal impairment (creatinine clearance [CrCl] <30 mL/min). [See Warnings and Precautions (5.2) and Use in Specific Populations (8.6).]
- 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 [VTE] prophylaxis only) [see Warnings and Precautions (5.3)].
Warnings and Precautions
Hemorrhage
Use Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution (with or without concomitant administration of other anticoagulants) [See Adverse Reactions (6.5)].
Do not administer agents that enhance the risk of hemorrhage with Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution earlier than 6 to 8 hours after surgery. Administration earlier than 6 hours after surgery increases risk of major bleeding [see Dosage and Administration (2) and Adverse Reactions (6.1)].
Renal Impairment and Bleeding Risk
Fondaparinux Sodium Solution increases the risk of bleeding in patients with impaired renal function due to reduced clearance [see Clinical Pharmacology (12.4)].
The incidence of major bleeding by renal function status reported in clinical trials of patients receiving Fondaparinux Sodium Solution for VTE surgical prophylaxis is provided in Table 1. In these patient populations, the following is recommended:
- Do not use Fondaparinux Sodium Solution for VTE prophylaxis and treatment in patients with CrCl <30 mL/min [see Contraindications (4)].
- Use Fondaparinux Sodium Solution with caution in patients with CrCl 30 to 50 mL/min.
Table 1. Incidence of Major Bleeding in Patients Treated With Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution. Discontinue the drug immediately in patients who develop severe renal impairment while on therapy. After discontinuation of Fondaparinux Sodium Solution, 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 Fondaparinux Sodium Solution may persist even longer in patients with renal impairment [see Clinical Pharmacology (12.4)].
Body Weight <50 Kg and Bleeding Risk
Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution as prophylactic therapy for patients undergoing hip fracture, hip replacement, or knee replacement surgery and abdominal surgery [see Contraindications (4)].
- Use Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution. Thrombocytopenia of any degree should be monitored closely. Discontinue Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution in postmarketing experience. [See Adverse Reactions (6.5).]
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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution and international standards of heparin or LMWH are not calibrators to measure anti-Factor Xa activity of Fondaparinux Sodium Solution. If unexpected changes in coagulation parameters or major bleeding occur during therapy with Fondaparinux Sodium Solution, discontinue Fondaparinux Sodium Solution. In postmarketing experience, isolated occurrences of aPTT elevations have been reported following administration of Fondaparinux Sodium Solution [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 Fondaparinux Sodium Solution.
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 Fondaparinux Sodium Solution contains dry natural latex rubber that may cause allergic reactions in latex sensitive individuals.
Adverse Reactions
The most serious adverse reactions reported with Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution, 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 Fondaparinux Sodium Solution 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 post-surgery) |
Extended Prophylaxis
(Day 8 to Day 28 ± 2 post-surgery) |
Fondaparinux Sodium Solution
2.5 mg SC
once daily
N = 3,616 |
Enoxaparin Sodiuma, b
N = 3,956 |
Fondaparinux Sodium Solution
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 Fondaparinux Sodium Solution after surgical closure was performed in patients who received Fondaparinux Sodium Solution 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, Fondaparinux Sodium Solution 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
|
Fondaparinux Sodium Solution
2.5 mg SC once daily |
Dalteparin Sodium
5,000 IU SC once daily |
| N = 1,433 |
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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution treatment regimen are provided in Table 4.
Table 4. Bleedinga in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies
|
Fondaparinux Sodium Solution
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 ≥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 Fondaparinux Sodium Solution.
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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution. 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 Fondaparinux Sodium Solution should be interpreted with caution.
Other Adverse Reactions
Other adverse reactions that occurred during treatment with Fondaparinux Sodium Solution 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) |
Fondaparinux Sodium Solution
2.5 mg SC
once daily |
Enoxaparin Sodiuma, b |
Fondaparinux Sodium Solution
2.5 mg SC
once daily |
Placebo
SC once daily |
|
|
N = 3,616 |
N = 3,956 |
N = 327 |
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.
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%).
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Fondaparinux Sodium Solution. 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 Fondaparinux Sodium Solution (with or without concomitant administration of other anticoagulants) [see Warnings and Precautions (5.4)].
Drug Interactions
In clinical studies performed with Fondaparinux Sodium Solution, 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, Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution 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.
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, Fondaparinux Sodium Solution 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 Fondaparinux Sodium Solution is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Fondaparinux Sodium Solut
