ADVERSE REACTIONS
ADVERSE EVENTS REPORTED IN CLINICAL TRIALS IN HIT PATIENTS
The following safety information is based on all 198 patients treated with REFLUDAN in the HAT-1 and HAT-2 studies. The safety profile of 113 REFLUDAN patients from these studies who presented with TECs at baseline is compared to 91 such patients in the historical control.
Hemorrhagic Events. Bleeding was the most frequent adverse event observed in patients treated with REFLUDAN. Table 4 gives an overview of all hemorrhagic events which occurred in at least two patients.
Table 4: Hemorrhagic Events *
|
|
|
Patients with TECs |
|
|
HAT-1
HAT-2
(All patients) (n = 198) |
REFLUDAN (n = 113) |
Historical
control (n = 91) |
| Bleeding from puncture sites and wounds |
14.1% |
10.6% |
4.4% |
| Anemia or isolated drop in hemoglobin |
13.1% |
12.4% |
1.1% |
| Other hematoma and unclassified bleeding |
11.1% |
10.6% |
4.4% |
| Hematuria |
6.6% |
4.4% |
0 |
| Gastrointestinal and rectal bleeding |
5.1% |
5.3% |
6.6% |
| Epistaxis |
3.0% |
4.4% |
1.1% |
| Hemothorax |
3.0% |
0 |
1.1% |
| Vaginal bleeding |
1.5% |
1.8% |
0 |
| Intracranial bleeding |
0 |
0 |
2.2% |
| *Patients may have suffered more than one event. |
|
Other hemorrhagic events (hemoperitoneum, hemoptysis, liver bleeding, lung bleeding, mouth bleeding, retroperitoneal bleeding) each occurred in one individual among all 198 patients treated with REFLUDAN. Nonhemorrhagic events. Table 5 gives an overview of the most frequently observed nonhemorrhagic events.
Table 5: Nonhemorrhagic adverse events *
|
|
|
Patients with TECs |
|
|
HAT-1
HAT-2
(All patients) (n = 198) |
REFLUDAN (n = 113) |
Historical
control (n = 91) |
| Fever |
6.1% |
4.4% |
8.8% |
| Abnormal liver function |
6.1% |
5.3% |
0 |
| Pneumonia |
4.0% |
4.4% |
5.5% |
| Sepsis |
4.0% |
3.5% |
5.5% |
| Allergic skin reactions |
3.0% |
3.5% |
1.1% |
| Heart failure |
3.0% |
1.8% |
2.2% |
| Abnormal kidney function |
2.5% |
1.8% |
4.4% |
| Unspecified infections |
2.5% |
1.8% |
1.1% |
| Multiorgan failure |
2.0% |
3.5% |
0 |
| Pericardial effusion |
1.0% |
0 |
1.1% |
| Ventricular fibrillation |
1.0% |
0 |
0 |
| *Patients may have suffered more than one event. |
|
ADVERSE EVENTS REPORTED IN CLINICAL TRIALS IN OTHER POPULATIONS
The following safety information is based on a total of 2302 individuals who were treated with REFLUDAN in clinical pharmacology studies (n = 323) or for clinical indications other than HIT (n = 1979). Intracranial Bleeding. Intracranial bleeding was the most serious adverse reaction found in populations other than HIT patients. It occurred in patients with acute myocardial infarction who were started on both REFLUDAN and thrombolytic therapy with rt-PA or streptokinase. The overall frequency of this potentially life-threatening complication among patients receiving both REFLUDAN and thrombolytic therapy was 0.6% (7 out of 1134 patients). Although no intracranial bleeding was observed in 1168 subjects or patients who did not receive concomitant thrombolysis, there have been post marketing reports of intracranial bleeding with REFLUDAN in the absence of concomitant thrombolytic therapy (see ADVERSE REACTIONS - Adverse Events from Post Marketing Reports and WARNINGS).
Allergic Reactions. (See PRECAUTIONS.)
Allergic reactions or suspected allergic reactions in populations other than HIT patients include (in descending order of frequency *):
-
Airway reactions (cough,
bronchospasm, stridor, dyspnea): common
-
Unspecified allergic reactions: uncommon
-
Skin reactions (pruritus, urticaria,
rash, flushes, chills): uncommon
-
General reactions (anaphylactoid or
anaphylactic reactions): uncommon
-
Edema (facial edema, tongue edema,
larynx edema, angioedema): rare
* The CIOMS (Council for International Organization of Medical Sciences) III standard categories are used for classification of frequencies:
very common 10% or more
common (frequent) 1 to <10%
uncommon (infrequent) 0.1 to <1%
rare 0.01 to <0.1%
very rare 0.01% or less
About 53% (n = 46) of all allergic reactions or suspected allergic reactions occurred in patients who concomitantly received thrombolytic therapy (eg, streptokinase) for acute myocardial infarction and/or contrast media for coronary angiography.
ADVERSE EVENTS FROM POST MARKETING REPORTS
Serious anaphylactic reactions that have resulted in shock or death have been reported. (See PRECAUTIONS.)
Intracranial bleeding has been reported in patients treated with REFLUDAN with or without concomitant thrombolytic therapy. (See WARNINGS.) Although no intracranial bleeding was observed in Clinical Trials in those patients who did not receive concomitant thrombolytic therapy (see Adverse Events Reported in Clinical Trials in HIT Patients and Adverse Events Reported in Clinical Trials in Other Populations below), there have been post marketing reports of intracranial bleeding in patients who received REFLUDAN without concomitant thrombolytic therapy.
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