ADVERSE REACTIONS
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 from clinical trials does, however, provide a basis for identifying possible adverse events and for approximating rates.
The data described below reflect exposure in 8,877 patients randomized to ARIXTRA Injection in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment. Patients received ARIXTRA primarily in 2 large peri-operative dose-response trials (n = 989), 4 active-controlled peri-operative trials with enoxaparin sodium (n = 3,616), and an extended prophylaxis trial (n = 327), an active-controlled trial with dalteparin sodium (n = 1,425), a dose-response trial in DVT treatment (n = 111), 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) (see CLINICAL STUDIES).
Hemorrhage
During administration of ARIXTRA, the most common adverse reactions were bleeding complications (see WARNINGS).
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 Injection are provided in Tables 8 and 9 below.
Table 8. Major Bleeding Episodes1 in Randomized, Controlled, Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies |
Indications
|
Peri-Operative Prophylaxis
(Day 1 to Day 7 ± 1 post-surgery)
|
Extended Prophylaxis
(Day 8 to Day 28 ± 2 post-surgery)
|
|
Fondaparinux Sodium
2.5 mg SC
once daily
|
Enoxaparin Sodium 2, 3
|
Fondaparinux Sodium
2.5 mg SC
once daily
|
Placebo
SC once daily
|
|
Hip Fracture
|
18/831 (2.2%)
|
19/842 (2.3%)
|
8/327 (2.4 %)4
|
2/329 (0.6 %)
|
|
Hip Replacement
|
67/2,268 (3.0%)
|
55/2,597 (2.1%)
|
—
|
—
|
|
Knee Replacement
|
11/517 (2.1%)5
|
1/517 (0.2%)
|
—
|
—
|
|
1Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at critical site (e.g. intracranial, retroperitoneal, intra-ocular, pericardial, spinal, or into adrenal gland), (3) associated with re-operation at operative site, or (4) 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].
2Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.
3Not approved for use in patients undergoing hip fracture surgery.
4During noncomparative, unblinded, peri-operative prophylaxis, major bleeding was reported in 22/737 (3.0%) patients. Fifteen (15) of these 22 patients continued to receive ARIXTRA in extended prophylaxis. After randomization, 4/327 (1.2%) patients experienced major bleeding for the first time.
5p value versus enoxaparin sodium: <0.01, 95% confidence interval: (1.1%, 3.3%) in group receiving ARIXTRA versus (0.0%, 1.1%) in enoxaparin sodium group.
|
Table 9. 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
2.5 mg SC
once daily
|
Enoxaparin Sodium 1, 2
|
Fondaparinux Sodium
2.5 mg SC
once daily
|
Placebo
SC once daily
|
|
N = 3,616
|
N = 3,956
|
N = 327
|
N = 329
|
|
Major bleeding3
|
96 (2.7%)
|
75 (1.9%)
|
8 (2.4%)4
|
2 (0.6%)
|
|
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 ≥25
|
84 (2.3%)
|
63 (1.6%)
|
6 (1.8%)
|
0 (0.0%)
|
|
Minor bleeding6
|
109 (3.0%)
|
116 (2.9%)
|
5 (1.5%)
|
2 (0.6%)
|
|
1Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.
2Not approved for use in patients undergoing hip fracture surgery.
3Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at critical site (e.g. intracranial, retroperitoneal, intra-ocular, pericardial, spinal, or into adrenal gland), (3) associated with re-operation at operative site, or (4) with a bleeding index (BI) ≥2.
4During non-comparative, unblinded, peri-operative prophylaxis, 2 fatal bleeds were reported (one in a 50 kg patient, one in a severe renal failure patient).
5BI ≥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].
6Minor 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), 4-6 hours was 2.3% (28/1196), 6-8 hours was 1.9% (38/1965). In all studies, the majority (≥75%) of the major bleeding events occurred during the first 4 days after surgery.
Abdominal Surgery
The rates of major bleeding reported during the abdominal surgery clinical trial with ARIXTRA 2.5 mg are provided in Table 10 below.
Table 10. Major Bleeding Episodes1 in Randomized, Controlled, Abdominal Surgery Study |
Fondaparinux Sodium
2.5 mg SC
once daily
|
Dalteparin Sodium
5,000 IU SC once daily
|
|
N = 1,433
|
N = 1,425
|
|
Major bleeding
|
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
Non-surgical site
|
38 (2.7%)
9 (0.6%)
|
26 (1.8%)
6 (0.4%)
|
|
Minor bleeding2
|
31 (2.2%)
|
23 (1.6%)
|
|
1Major 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, intra-ocular, pericardial, spinal, or into adrenal gland), or leading to an intervention, and/or with a bleeding index (BI) ≥2. (BI ≥2 calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) − (post-bleeding)] hemoglobin (g/dL) values].)
2Minor bleeding was defined as clinically overt bleeding that was not major.
|
A separate analysis of major bleeding according to the time of the first injection of ARIXTRA after surgical closure was performed. In this analysis the incidences of major bleeding were as follows: <6 hours was 3.4% (9/263) and 6-8 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 11 below.
Table 11. Bleeding1 in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies |
Fondaparinux Sodium Treatment Regimen
|
Enoxaparin Sodium 1 mg/kg SC q 12h
|
Heparin
aPTT adjusted IV
|
|
N = 2,294
|
N = 1,101
|
N = 1,092
|
|
Major bleeding2
|
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%)
|
|
Clinically overt bleeding with a 2 g/dL fall in hemoglobin and/or leading to transfusion of PRBC or whole blood ≥2 units
|
22 (1.0%)
|
13 (1.2%)
|
10 (0.9%)
|
|
Minor bleeding3
|
70 (3.1%)
|
33 (3.0%)
|
57 (5.2%)
|
|
1Bleeding 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.
2Major 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.
3Minor bleeding was defined as clinically overt bleeding that was not major.
|
Thrombocytopenia
See WARNINGS: Thrombocytopenia.
Local Reactions
Mild 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 [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in 1.7% and 2.6% of patients, respectively, during treatment with ARIXTRA 2.5 mg Injection 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. Such elevations are fully reversible and are rarely associated with increases in bilirubin. In the extended prophylaxis clinical trial no significant differences in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels between ARIXTRA 2.5 mg Injection and placebo treated patients were observed.
In the DVT and PE treatment clinical trials asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in 0.7% and 1.3% of patients, respectively, during treatment with the ARIXTRA injection treatment regimen. In comparison, these increases have been 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 Events
Other adverse events that occurred during treatment with ARIXTRA, or enoxaparin sodium in clinical trials with patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery and that occurred at a rate of at least 2% in either treatment group, are provided in Table 12 below. Other adverse events that occurred during treatment with ARIXTRA or dalteparin sodium in clinical trials with patients undergoing abdominal surgery and that occurred at a rate of at least 2% in either treatment group are provided in Table 13 below. Other adverse events that occurred during treatment with ARIXTRA, enoxaparin sodium, or heparin in the DVT and PE treatment clinical trials and that occurred at a rate of at least 2% in any treatment group are provided in Table 14 below.
Table 12. Adverse Events Occurring in≥2% of Patients Treated With ARIXTRA, Enoxaparin Sodium, or Placebo Regardless of Relationship to Study Drug Across Randomized, Controlled, Hip Fracture Surgery, Hip Replacement Surgery, or Knee Replacement Surgery Studies |
Adverse Events
|
Peri-Operative Prophylaxis
(Day 1 to Day 7 ± 1 post-surgery)
|
Extended Prophylaxis
(Day 8 to Day 28 ± 2 post-surgery)
|
|
Fondaparinux Sodium
2.5 mg SC
once daily
|
Enoxaparin Sodium 1, 2
|
Fondaparinux Sodium
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%)
|
|
Fever
|
491 (13.6%)
|
610 (15.4%)
|
1 (0.3%)
|
4 (1.2%)
|
|
Nausea
|
409 (11.3%)
|
484 (12.2%)
|
1 (0.3%)
|
4 (1.2%)
|
|
Edema
|
313 (8.7%)
|
348 (8.8%)
|
3 (0.9%)
|
2 (0.6%)
|
|
Constipation
|
309 (8.5%)
|
416 (10.5%)
|
6 (1.8%)
|
7 (2.1%)
|
|
Rash
|
273 (7.5%)
|
329 (8.3%)
|
2 (0.6%)
|
4 (1.2%)
|
|
Vomiting
|
212 (5.9%)
|
236 (6.0%)
|
2 (0.6%)
|
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%)
|
|
Urinary tract infection
|
136 (3.8%)
|
135 (3.4%)
|
13 (4.0%)
|
13 (4.0%)
|
|
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 eruption3
|
112 (3.1%)
|
102 (2.6%)
|
0 (0.0%)
|
1 (0.3%)
|
|
Urinary retention
|
106 (2.9%)
|
117 (3.0%)
|
0 (0.0%)
|
1 (0.3%)
|
|
Hematoma
|
103 (2.8%)
|
109 (2.8%)
|
7 (2.1%)
|
1 (0.3%)
|
|
Diarrhea
|
90 (2.5%)
|
102 (2.6%)
|
6 (1.8%)
|
8 (2.4%)
|
|
Dyspepsia
|
87 (2.4%)
|
102 (2.6%)
|
1 (0.3%)
|
2 (0.6%)
|
|
Post-operative hemorrhage
|
85 (2.4%)
|
69 (1.7%)
|
2 (0.6%)
|
2 (0.6%)
|
|
Headache
|
72 (2.0%)
|
97 (2.5%)
|
0 (0.0%)
|
2 (0.6%)
|
|
Pain
|
62 (1.7%)
|
101 (2.6%)
|
0 (0.0%)
|
0 (0.0%)
|
|
Surgical site reaction
|
29 (0.8%)
|
41 (1.0%)
|
5 (1.5%)
|
8 (2.4%)
|
|
1Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.
2Not approved for use in patients undergoing hip fracture surgery.
3Localized blister coded as bullous eruption.
|
Table 13: Adverse Events Occurring in ≥2% of Patients Treated With ARIXTRA or Dalteparin Sodium Undergoing Abdominal Surgery Regardless of Relationship to Study Drug |
Adverse Events
|
Fondaparinux Sodium
2.5 mg SC
once daily
|
Dalteparin Sodium
5000 IU SC
once daily
|
|
N = 1,433
|
N = 1,425
|
|
Post-operative wound infection
|
70 (4.9%)
|
69 (4.8%)
|
|
Post-operative hemorrhage
|
61 (4.3%)
|
42 (2.9%)
|
|
Fever
|
53 (3.7%)
|
54 (3.8%)
|
|
Surgical site reaction
|
46 (3.2%)
|
40 (2.8%)
|
|
Anemia
|
35 (2.4%)
|
26 (1.8%)
|
|
Hypertension
|
35 (2.4%)
|
41 (2.9%)
|
|
Pneumonia
|
33 (2.3%)
|
23 (1.6%)
|
|
Vomiting
|
31 (2.2%)
|
26 (1.8%)
|
Table 14. Adverse Events Occurring in ≥2% of Patients Treated With ARIXTRA, Enoxaparin Sodium, or Heparin Regardless of Relationship to Study Drug Across VTE Treatment Studies |
Adverse Events
|
Fondaparinux Sodium
|
Enoxaparin Sodium
|
Heparin
|
|
N = 2,294
|
N = 1,101
|
N = 1,092
|
|
Constipation
|
106 (4.6%)
|
32 (2.9%)
|
93 (8.5%)
|
|
Headache
|
104 (4.5%)
|
37 (3.4%)
|
65 (6.0%)
|
|
Insomnia
|
86 (3.7%)
|
19 (1.7%)
|
75 (6.9%)
|
|
Fever
|
81 (3.5%)
|
32 (2.9%)
|
47 (4.3%)
|
|
Nausea
|
76 (3.3%)
|
29 (2.6%)
|
53 (4.9%)
|
|
Urinary tract infection
|
53 (2.3%)
|
20 (1.8%)
|
24 (2.2%)
|
|
Coughing
|
48 (2.1%)
|
7 (0.6%)
|
26 (2.4%)
|
|
Diarrhea
|
43 (1.9%)
|
22 (2.0%)
|
27 (2.5%)
|
|
Abdominal pain
|
33 (1.4%)
|
14 (1.3%)
|
28 (2.6%)
|
|
Chest pain
|
33 (1.4%)
|
8 (0.7%)
|
26 (2.4%)
|
|
Leg pain
|
31 (1.4%)
|
10 (0.9%)
|
22 (2.0%)
|
|
Back pain
|
30 (1.3%)
|
11 (1.0%)
|
34 (3.1%)
|
|
Epistaxis
|
30 (1.3%)
|
12 (1.1%)
|
41 (3.8%)
|
|
Prothrombin decreased
|
30 (1.3%)
|
3 (0.3%)
|
34 (3.1%)
|
|
Anemia
|
28 (1.2%)
|
3 (0.3%)
|
23 (2.1%)
|
|
Vomiting
|
26 (1.1%)
|
14 (1.3%)
|
27 (2.5%)
|
|
Hypokalemia
|
25 (1.1%)
|
2 (0.2%)
|
23 (2.1%)
|
|
Bruise
|
24 (1.0%)
|
24 (2.2%)
|
14 (1.3%)
|
|
Anxiety
|
18 (0.8%)
|
8 (0.7%)
|
22 (2.0%)
|
|
Hepatic function abnormal
|
10 (0.4%)
|
14 (1.3%)
|
24 (2.2%)
|
|
Hepatic enzymes increased
|
7 (0.3%)
|
52 (4.7%)
|
30 (2.7%)
|
|
SGPT increased
|
7 (0.3%)
|
47 (4.3%)
|
8 (0.7%)
|
|
SGOT increased
|
4 (0.2%)
|
31 (2.8%)
|
3 (0.3%)
|
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.
Rare cases of elevated aPTT and heparin-induced thrombocytopenia have been reported. A causal relationship of these events to fondaparinux has not been established.
|
REPORTS OF SIDE EFFECTS / ADVERSE REACTIONS RELATED TO ARIXTRA
Below is a sample of reports where side effects / adverse reactions may be related to Arixtra. The information is not vetted and should not be cosidered as verified clinical evidence.
Possible Arixtra side effects / adverse reactions in 53 year old female
Reported by a pharmacist from United States on 2007-01-08
Patient: 53 year old female weighing 98.9 kg (217.5 pounds)
Reactions: Activated Partial Thromboplastin Time Prolonged, Catheter Related Complication, Urethral Obstruction, Anaemia, Coagulation Time Prolonged, Hypovolaemia, Renal Failure Acute
Adverse event resulted in: life threatening event
Suspect drug(s):
Arixtra
Other drugs received by patient: Geodon; Synthroid; Lipitor; Prinivil; Remeron; Wellbutrin XL; Avandia; Protonix; Lexapro; Ultram; Ferrous Sulfate TAB; Colace; Klonopin; Reglan; Glucophage; Aranesp; Regular Insulin; Oxycodone HCL; Phenergan; Benadryl; Acetaminophen
Possible Arixtra side effects / adverse reactions in 90 year old male
Reported by a physician from France on 2007-01-10
Patient: 90 year old male weighing 70.0 kg (154.0 pounds)
Reactions: Hypotension, Anaemia, Haematuria, Shock Haemorrhagic, Intentional Drug Misuse, Pallor, Malaise, Pigmentation Disorder, Urinary Retention
Adverse event resulted in: life threatening event, hospitalization
Suspect drug(s):
Arixtra
Possible Arixtra side effects / adverse reactions in 76 year old male
Reported by a consumer/non-health professional from United States on 2007-01-10
Patient: 76 year old male
Reactions: Contusion, Haemorrhage, Implantable Defibrillator Malfunction, Ill-Defined Disorder, Renal Impairment, Hyperaesthesia, Skin Discolouration, RED Blood Cell Count Decreased, Abdominal Distension, Blood Pressure Decreased, Pharmaceutical Product Complaint, Asthenia, White Blood Cell Count Increased
Adverse event resulted in: hospitalization
Suspect drug(s):
Arixtra
Other drugs received by patient: Aspirin; Plavix; Mexiletine Hydrochloride; Zoloft; Vasotec; Metoprolol Succinate; Zocor; Nitroglyn 2% Ointment
|
