ADVERSE REACTIONS
Clinical Trials Experience
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.
Bleeding
In 6010 patients undergoing PCI treated in the REPLACE-2 trial, Angiomax patients exhibited statistically significantly lower rates of bleeding, transfusions, and thrombocytopenia as noted in Table 2.
Table 2. Major Hematologic Outcomes REPLACE-2 Study (Safety Population)
1 GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI group
2 Defined as the occurence of any of the following: intracranial bleeding, retroperitoneal bleeding, a transfusion of ≥2 units of blood/blood products, a fall in hemoglobin >4 g/dL, whether of not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in hemoglobin >3 g/dL
3 Defined as observed bleeding that does not meet the criteria for major hemorrhage
4 TIMI major bleeding is defined as intracranial, or a fall in adjusted Hgb >5 g/dL or Hct of >15%: TIMI minor bleeding is defined as a fall in adjusted Hgb of 3 to <5 g/dL or a fall in adjusted Hct of 9 to <15%, with a bleeding site such as hematuria, hematemesis, hematomas, retroperitoneal bleeding or a decrease in Hgb of >4 g/dL with no bleeding site
5 If <100,000 and >25% reduction from baseline, or <50,000
|
|
Angiomax with "provisional" GPI1
n=2914
|
HEPARIN + GPI
(n=2987)
|
p-value
|
Protocol defined major hemorrhage2 (%)
|
2.3%
|
4.0%
|
<0.001
|
Protocol defined minor hemorrhage3 (%)
|
13.6%
|
25.8%
|
<0.001
|
TIMI defined bleeding4
|
|
|
|
- Major
|
0.6%
|
0.9%
|
0.259
|
- Minor
|
1.3%
|
2.9
|
<0.001
|
Non-access site bleeding
|
|
|
|
- Retroperitoneal bleeding
|
0.2%
|
0.5%
|
0.069
|
- Intracranial bleeding
|
<0.1%
|
0.1%
|
1.0
|
Access site bleeding
|
|
|
|
- Sheath site bleeding
|
0.9%
|
2.4%
|
<0.001
|
Thrombocytopenia5
|
|
|
|
<100,000
|
0.7%
|
1.7%
|
<0.001
|
<50,000
|
0.3%
|
0.6%
|
0.039
|
Transfusions
|
|
|
|
- RBC
|
1.3%
|
1.9%
|
0.08
|
- Platelets
|
0.3%
|
0.6%
|
0.095
|
In 4312 patients undergoing PTCA for treatment of unstable angina in 2 randomized, double-blind studies comparing Angiomax to heparin, Angiomax patients exhibited lower rates of major bleeding and lower requirements for blood transfusions. The incidence of major bleeding is presented in Table 3. The incidence of major bleeding was lower in the Angiomax group than in the heparin group.
Table 3. Major Bleeding and Transfusions in BAT Trial (all patients)1
1 No monitoring of ACT (or PTT) was done after a target ACT was achieved.
2 Major hemorrhage was defined as the occurence of any of the following, intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin ≥3 g/dL or leading to a transfusion of ≥2 units of blood. This table includes data from the entire hospitalization period.
|
|
Angiomax
N=2161
|
Heparin
N=2151
|
No. (%) Patients with Major hemorrhage2
|
79 (3.7)
|
199 (9.3)
|
- with ≥3 g/dL fall in Hgb
|
41 (1.9)
|
124 (5.8)
|
- with ≥5 g/dL fall in Hgb
|
14 (0.6)
|
47 (2.2)
|
- retroperitoneal bleeding
|
5 (0.2)
|
15 (0.7)
|
- intracranial bleeding
|
1 (<0.1)
|
2 (0.1)
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- Required transfusions
|
43 (2.0)
|
123 (5.7)
|
In the AT-BAT study, of the 51 patients with HIT/HITTS, 1 patient who did not undergo PCI had major bleeding during CABG on the day following angiography. Nine patients had minor bleeding (mostly due to access site bleeding), and 2 patients developed thrombocytopenia.
Other Adverse Reactions
Adverse reactions, other than bleeding, observed in clinical trials were similar between the Angiomax treated patients and the control groups.
Adverse reactions (related adverse events) seen in clinical studies in patients undergoing PCI and PTCA are shown in Tables 4 and 5.
Table 4. Most frequent (≥0.2%) treatment-related adverse events (reactions) (through 30 days) in the REPLACE-2 Safety population
Note: A patient could have more than one event in any category. Abbreviation: AE = adverse event.
|
|
Angiomax with
"provisional"
GPI1
(N = 2914)
|
Heparin+GPI
(N = 2987)
|
|
n
|
(%)
|
n
|
(%)
|
Patients with at least one treatment-related AE
|
78
|
(2.7)
|
115
|
(3.9)
|
|
|
|
|
|
Thrombocytopenia
|
9
|
(0.3)
|
30
|
(1.0)
|
Nausea
|
15
|
(0.5)
|
7
|
(0.2)
|
Hypotension
|
7
|
(0.2)
|
11
|
(0.4)
|
Angina pectoris
|
5
|
(0.2)
|
12
|
(0.4)
|
Headache
|
6
|
(0.2)
|
5
|
(0.2)
|
Injection site pain
|
3
|
(0.1)
|
8
|
(0.3)
|
Nausea and vomiting
|
2
|
(0.1)
|
6
|
(0.2)
|
Vomiting
|
3
|
(0.1)
|
5
|
(0.2)
|
Table 5. Adverse Events Other Than Bleeding Occurring In ≥5% Of Patients In Either Treatment Group In BAT Trial
|
Treatment Group
|
EVENT
|
ANGIOMAX
N=2161
|
HEPARIN
N=2151
|
|
Number of Patients (%)
|
CARDIOVASCULAR
|
|
|
Hypotension
|
262 (12)
|
371 (17)
|
Hypertension
|
135 (6)
|
115 (5)
|
Bradycardia
|
118 (5)
|
164 (8)
|
GASTROINTESTINAL
|
|
|
Nausea
|
318 (15)
|
347 (16)
|
Vomiting
|
138 (6)
|
169 (8)
|
Dyspepsia
|
100 (5)
|
111 (5)
|
GENITOURINARY
|
|
|
Urinary retention
|
89 (4)
|
98 (5)
|
MISCELLANEOUS
|
|
|
Back pain
|
916 (42)
|
944 (44)
|
Pain
|
330 (15)
|
358 (17)
|
Headache
|
264 (12)
|
225 (10)
|
Injection site pain
|
174 (8)
|
274 (13)
|
Insomnia
|
142 (7)
|
139 (6)
|
Pelvic pain
|
130 (6)
|
169 (8)
|
Anxiety
|
127 (6)
|
140 (7)
|
Abdominal pain
|
103 (5)
|
104 (5)
|
Fever
|
103 (5)
|
108 (5)
|
Nervousness
|
102 (5)
|
87 (4)
|
Serious, non-bleeding adverse events were experienced in 2% of 2161 Angiomax-treated patients and 2% of 2151 heparin-treated patients. The following individual serious non-bleeding adverse events were rare (>0.1% to <1%) and similar in incidence between Angiomax- and heparin-treated patients. These events are listed by body system: Body as a Whole: fever, infection, sepsis; Cardiovascular: hypotension, syncope, vascular anomaly, ventricular fibrillation; Nervous: cerebral ischemia, confusion, facial paralysis; Respiratory: lung edema; Urogenital: kidney failure, oliguria. In the BAT trial, there was no causality assessment for adverse events.
Immunogenicity/Re-Exposure
In in vitro studies, Angiomax exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS.
Among 494 subjects who received Angiomax in clinical trials and were tested for antibodies, 2 subjects had treatment-emergent positive bivalirudin antibody tests. Neither subject demonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was not performed. Nine additional patients who had initial positive tests were negative on repeat testing.
Postmarketing Experience
Because postmarketing adverse 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.
The following adverse reactions have been identified during postapproval use of Angiomax: fatal bleeding; hypersensitivity and allergic reactions including reports of anaphylaxis; lack of anticoagulant effect; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes.
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REPORTS OF SUSPECTED ANGIOMAX SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Angiomax. The information is not vetted and should not be considered as verified clinical evidence.
Possible Angiomax side effects / adverse reactions in 55 year old male
Reported by a physician from United States on 2011-10-18
Patient: 55 year old male weighing 95.0 kg (209.0 pounds)
Reactions: Medical Device Complication, Surgical Procedure Repeated, Incorrect Drug Administration Duration, Coronary Artery Thrombosis, NO Therapeutic Response, Coagulation Time Abnormal, Myocardial Infarction
Adverse event resulted in: death
Suspect drug(s):
Angiomax
Other drugs received by patient: Plavix; Integrilin
Possible Angiomax side effects / adverse reactions in 74 year old male
Reported by a individual with unspecified qualification from Spain on 2011-10-20
Patient: 74 year old male
Reactions: Anaemia, Coagulopathy
Suspect drug(s):
Aspirin
Dosage: 100 mg
Indication: Acute Coronary Syndrome
Start date: 2011-05-11
End date: 2011-05-11
Angiomax
Dosage: 250 mg, intravenous
Start date: 2011-05-11
End date: 2011-05-11
Arixtra
Dosage: 2.5 mg, qd, subcutaneous
Start date: 2011-05-11
End date: 2011-05-11
Plavix
Dosage: 300 mg, qd, oral
Administration route: Oral
Indication: Acute Coronary Syndrome
Start date: 2011-05-11
End date: 2011-05-11
Other drugs received by patient: Pantoprazole
Possible Angiomax side effects / adverse reactions in 80 year old male
Reported by a physician from United Kingdom on 2011-11-02
Patient: 80 year old male
Reactions: Death
Adverse event resulted in: death
Suspect drug(s):
Angiomax
Other drugs received by patient: Aspirin; Clopidogrel
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