Angiomax: Indications, Dosage, Precautions, Adverse Effects
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Angiomax - Product Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Angina, Percutaneous Coronary Intervention
Class: Thrombin inhibitors
Form: Liquid solution, Intravenous (IV)
Ingredients: bivalirudin, mannitol, sodium hydroxide, trifluoroacetate

Summary product information

Route of
Administration
Dosage Form /
Strength
Nonmedicinal Ingredients

Intravenous injection 250 mg/vial Mannitol, sodium hydroxide & trifluoroacetate

Indications and clinical use

ANGIOMAX (bivalirudin) is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention and in the treatment of patients with moderate to high risk acute coronary syndromes due to unstable angina or non-ST-segment elevation in whom early percutaneous coronary intervention is planned [see also DOSAGE AND ADMINISTRATION – USE SUBSEQUENT TO UNFRACTIONATED HEPARIN (UFH) OR LOW MOLECULAR WEIGHT HEPARIN (LMWH)].

ANGIOMAX is also indicated for the treatment of patients with acute coronary syndromes due to ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI).

ANGIOMAX is intended for use with acetylsalicylic acid (ASA) and has been studied only in patients receiving concomitant ASA. Clopidogrel can also be administered.

ANGIOMAX is also indicated in patients with or at risk of heparin induced thrombocytopenia or heparin induced thrombocytopenia thrombosis syndrome (HIT/TS) undergoing PCI or cardiac surgery. ANGIOMAX may be administered with or without ASA in patients undergoing cardiac surgery.

The safety and effectiveness of ANGIOMAX have not been established in patients with acute coronary syndromes who are not undergoing PCI.

Pediatrics (< 18 years of age)

No studies in patients under 18 years of age have been conducted with ANGIOMAX.

Contraindications

ANGIOMAX (bivalirudin) is contraindicated in patients with:

  • Hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph.
  • Uncontrollable active bleeding
  • Major blood clotting disorders
  • Acute gastric or duodenal ulcer
  • Cerebral hemorrhage
  • Severe cerebro-spinal trauma
  • Bacterial endocarditis
  • Severe uncontrolled hypertension
  • Diabetic or hemorrhagic retinopathy
  • Proximal use of spinal/epidural anesthesia

Warnings and precautions

General

ANGIOMAX (bivalirudin) should not be administered intramuscularly.

There is no known antidote to ANGIOMAX. ANGIOMAX is hemodialysable (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Acute Stent Thrombosis

Acute stent thrombosis (<24 hours) has been observed in patients with STEMI undergoing primary PCI and has been managed by Target Vessel Revascularisation (TVR) (see ADVERSE REACTIONS, HORIZONS; and CLINICAL TRIALS, HORIZONS). Patients should remain for at least 24 hours in a facility capable of managing ischemic complications and should be carefully monitored following primary PCI for signs and symptoms consistent with myocardial ischemia.

Brachytherapy

To date, no formal clinical trials have been conducted with ANGIOMAX as the principal anticoagulant when performing catheter-based brachytherapy (beta or gamma) to reduce the risk of in-stent restenosis. Therefore, ANGIOMAX is not recommended for use in brachytherapy procedures.

An increased risk of thrombus formation has been associated with the use of ANGIOMAX in gamma brachytherapy, including fatal outcomes.

Cardiac Surgery

When ANGIOMAX is used in cardiac surgery, techniques that allow blood or blood-based solutions to lie stagnant should be avoided. Local bivalirudin levels may decrease due to metabolism by proteases from blood exposed to wound or foreign surfaces, potentially leading to local clot formation. During surgery, blood should not be allowed to stand in grafts, and grafts should preferably be stored and tested for flow and leakage with saline, instead of blood. Care should be taken to avoid stasis in the internal mammary artery after harvest. Circulation throughout the cardiopulmonary bypass (CPB) circuit must be ensured with particular attention paid to bypass lines that are blood-filled and then clamped off, or lines that are intermittently used for perfusion.

Hematologic

Hemorrhage

Bleeding may occur in conjunction with use of any anticoagulant drug. As with other anticoagulants, ANGIOMAX should be used with extreme caution in patients at increased risk of hemorrhage. Bleeding can occur at any site during therapy with ANGIOMAX. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site (see DRUG INTERACTIONS; and ADVERSE REACTIONS, Bleeding).

Immune

Immunogenicity/Re-exposure

In in vitro studies, ANGIOMAX exhibited no platelet aggregation response against sera from patients with a history of HIT/TS.

Among 494 patients who received ANGIOMAX in clinical trials and were tested for antibodies, two had treatment-emergent positive bivalirudin antibody tests. Neither patient demonstrated clinical evidence of allergic or anaphylactic reactions, and repeat testing was not performed. Nine other patients who had initial positive tests were negative on repeat testing. Of fifteen healthy volunteers who were exposed to ANGIOMAX twice, none developed antibodies.

Special Populations

Pregnant Women

There are no studies available evaluating ANGIOMAX in pregnant women.

Studies in rats and rabbits have demonstrated no evidence of impaired fertility or harm to the fetus attributable to bivalirudin at clinically relevant doses. Because animal reproduction studies are not always predictive of human response, ANGIOMAX should be used during pregnancy only if clearly indicated.

In PCI, ANGIOMAX is intended for use with ASA (see INDICATIONS AND CLINICAL USE). Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, particularly during the third trimester, ANGIOMAX and ASA should be used together during pregnancy only with caution and if benefit is thought to outweigh risk.

Nursing Women

It is not known whether ANGIOMAX is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ANGIOMAX is administered to a nursing woman.

Pediatrics (< 18 years of age)

The safety and efficacy of ANGIOMAX in children have not been established.

Geriatrics (> 65 years of age)

Across studies approximately 45% of patients were ≥ 65 years of age and 18% of patients were ≥ 75 years old. Elderly patients experienced more bleeding events than younger patients.

Adverse reactions

Adverse Drug Reaction Overview

As with any antithrombotic treatment, hemorrhagic manifestations can occur. Risk factors for bleeding identified with the use of ANGIOMAX (bivalirudin) include elderly status, female gender, and the concomitant use of drugs known to cause bleeding, such as heparin, warfarin and thrombolytics. These risks are comparable to those seen in heparin-treated patients. Petechiae or easy bruising may precede frank hemorrhage. The early signs of bleeding may include epistaxis, hematuria, or melena. Bleeding may occur at any site and be difficult to detect, for example, retroperitoneal bleeding. Bleeding may also occur at surgical sites. Major hemorrhage, including retroperitoneal or intracranial bleeding, has been associated with ANGIOMAX use, in some cases leading to a fatal outcome.

ACUITY (UA/NSTEMI)

The type and severity of adverse events observed in the ACS trials were similar between the ANGIOMAX and other treatment groups, and were typical of ACS trials. Few patients discontinued due to an adverse event, and the overall incidence and types of events that led to discontinuation were balanced between treatment groups. Very few of these events were associated with bleeding.

HORIZONS (STEMI undergoing primary PCI)

During the first 30 days of the study, 0.7% of ANGIOMAX patients and 0.6% of heparin patients reported a serious adverse event leading to study discontinuation. The types of events reported in each arm were similar and the one adverse event reported by >0.1% of patients in either treatment arm was cardiogenic shock.

REPLACE-2 (PCI)

Adverse events observed in clinical trials are similar between the ANGIOMAX-treated patients and the control groups. Adverse events seen are those typical of PCI trials. In clinical trials, adverse events leading to discontinuation occurred in 2% of ANGIOMAX patients and 7% of heparin patients.

CHOOSE and EVOLUTION (Cardiac Surgery)

Pleural effusion, atelectasis and atrial fibrillation were the most frequent adverse events observed in the clinical trials in both the bivalirudin group and the control group; these events are common following cardiac surgery.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Bleeding:

ACUITY (UA/NSTEMI)

In 13,819 patients with ACS treated in the ACUITY trial, patients administered ANGIOMAX monotherapy exhibited statistically significantly lower rates of bleeding, and transfusions when compared to those patients who received heparin+GPI (Glycoprotein IIb/IIIa Inhibitor). There was no statistical difference in bleeding rates when ANGIOMAX+GPI was compared to heparin+GPI (Table 1).

Table 1: Bleeding Rates ACUITY Study
ANGIOMAX1 alone

(N=4612)
ANGIOMAX + GPI

(N=4606)
Heparin* + GPI* (UFH or
enoxaparin)
(N=4603)
ACUITY-defined bleeding
- Major2
- Minor3
3.0%
12.9%
5.3%
21.8%
5.7%
21.6%
TIMI-defined bleeding4
- Major
- Minor
0.9%
3.7%
1.6%
6.1%
1.9%
6.4%
Transfusions 1.6% 2.6% 2.7%

1 GPIs were administered to <7% of patients in the ANGIOMAX group for procedural complications.

2 Defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding, intraocular bleeding, a transfusion of any units of blood/blood products, a fall in haemoglobin (Hgb) ≥4 g/dL, whether or not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in Hgb ≥3 g/dL, reoperation for bleeding, access site bleeding requiring surgical or radiological intervention, or a hematoma ≥5 cm at puncture site.

3 Defined as observed bleeding that does not meet the criteria for major bleeding.

4Thrombolysis in Myocardial Infarction (TIMI) major bleeding is defined as: intracranial, or a fall in adjusted Hgb >5 g/dL or hematocrit (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.

* Heparin was either unfractionated heparin (UFH) or enoxaparin.

HORIZONS (STEMI undergoing primary PCI):

The following adverse reaction data are based on a clinical study of ANGIOMAX in patients with STEMI undergoing PCI; 1,800 patients were randomized to receive ANGIOMAX alone, 1,802 were randomized to unfractionated heparin plus GP IIb/IIIa inhibitor. The major bleeding rate (ACUITY-scale) in the ANGIOMAX arm was statistically superior compared to rate in the unfractionated heparin plus GP IIb/IIIa arm (p<0.0001) (Table 2). Major bleeding occurred most frequently at the sheath puncture site. The most frequent event was a haematoma <5 cm at puncture site. Thrombocytopenia was reported in 26 (1.6%) of ANGIOMAX-treated patients and in 67 (3.9%) of patients treated with unfractionated heparin + GP IIb/IIIa inhibitor.

Table 2: Bleeding Rates HORIZONS Study
ANGIOMAX
(N=1800)
UFH + GP IIb/IIIa
(N=1802)
ACUITY-defined bleeding
- Major1 5.1% 8.8%
TIMI-defined bleeding
- Major2
- Minor3
1.8%
2.3%
3.2%
4.3%
GUSTO-defined bleeding4
- Severe/Life-threatening
- Moderate
- Mild
0.5%
3.2%
3.4%
0.6%
5.2%
5.8%

1 Defined as the occurrence of any of the following: intracranial bleeding, intraocular bleeding, retroperitoneal bleeding, access site haemorrhage requiring surgery or a radiologic or interventional procedure, haematoma ≥5 cm in diameter at the puncture site, reduction in haemoglobin concentration of ≥4 g/dL without an overt source of bleeding, reduction in haemoglobin concentration of ≥3 g/dL with overt bleeding, re-operation for bleeding, or any blood product transfusion.

2 Thrombolysis in Myocardial Infarction (TIMI) major bleeding is defined as: Intracranial bleeding or bleeding associated with a decrease in haemoglobin ≥5 g/dL (or ≥15% of haematocrit).

3TIMI minor bleeding is defined as: Observed bleeding: ≥3 g/dL decrease in the haemoglobin concentration (or ≥9% decrease in haematocrit); No bleeding observed: ≥4 g/dL decrease in the haemoglobin concentration (or ≥12% decrease in haematocrit)

4 Global use of strategies to open occluded coronary arteries (GUSTO) bleeding defined as: Severe or life-threatening: Either intracranial haemorrhage or bleeding that causes haemodynamic compromise and requires intervention; Moderate: Bleeding that requires blood transfusion but does not result in haemodynamic compromise.

REPLACE-2 (PCI) and BAT (PTCA)

In 6010 patients undergoing PCI treatment in a double-blind trial, ANGIOMAX patients plus provisional GPI (7.2%; see CLINICAL TRIALS) exhibited statistically significant lower rates of bleeding, transfusions, and thrombocytopenia than patients receiving heparin plus a glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor, as noted in Table 3. Major bleeding was seen in 2.4% of patients treated with ANGIOMAX+GPI compared to 4.1% in the patients treated with heparin+GPI.

Table 3: Major Hematologic Outcomes REPLACE-2 Study (Safety Population)
ANGIOMAX
N=2914
Heparin+GPIIb/IIIa
N=2987
P Value
% Patients with Major Hemorrhage1 2.3% 4.0% <0.001
Non-Access Site Bleeding:
-Retroperitoneal Bleeding
-Intracranial Bleeding
-Required Transfusion (any)

Access Site Bleeding
-Sheath Site Bleeding

0.2%
<0.1%
1.5%


0.9%

0.5%
0.1%
2.5%


2.4%

0.069
1
0.009


<0.001
% Patients with Minor Hemorrhage2 13.6% 25.8% <0.001
TIMI-Definition Bleeding3:
- Major and Minor
Thrombocytopenia4:
< 100,000 mm3
< 50,000 mm3

1.9%

0.7%
0.3%

3.8%

1.7%
0.6%

<0.001

<0.001
0.039

1 Defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding, a transfusion ≥ 2 units of blood/blood products, a fall in hemoglobin >4 g/dL, whether or not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in hemoglobin ≥ 3 g/dL.

2 Defined as observed bleeding that does not meet the criteria for major hemorrhage.

3 Defined as: intracranial, a fall in adjusted Hgb >5 g/dL, spontaneous gross hematuria or hematemesis, bleeding associated with a fall in adjusted Hgb >3 g/dL, a fall in adjusted Hgb >4g/dL with no bleeding.

4 If platelets <100,000 and >25% reduction from baseline, or <50,000.

In two randomised, double-blind studies that evaluated 4312 patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA), ANGIOMAX patients exhibited lower rates of major bleeding and lower requirements for blood transfusions than patients treated with heparin (Table 4). It should be noted that the comparator dose of heparin used in these studies was 175 IU/kg, a dose significantly higher than generally used currently (see CLINICAL TRIALS).

Table 4: Major bleeding and transfusions in BAT trial: All patients1 during hospitalization period
ANGIOMAX
N=2161
Heparin
N=2151
Number (%) of Patients with Major Hemorrhage2
  -with ≥3g/dL fall in Hgb
  -with ≥5g/dL fall in Hgb
  -Retroperitoneal Bleeding
  -Intracranial Bleeding
  -Required Transfusion
79 (3.7)
41 (1.9)
14 (<1)
5 (<1)
1 (<1)
43 (2.0)
199 (9.3)
124 (5.8)
47 (2.2)
15 (<1)
2 (<1)
123 (5.7)

1 No monitoring of ACT (or PTT) was done after a target ACT was achieved.

2 Major hemorrhage was defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin ≥3g/dL or leading to a transfusion of ≥2 units of blood. This table includes data from entire hospital period.

CHOOSE and EVOLUTION (Cardiac Surgery)

In the CHOOSE and EVOLUTION studies the incidence of blood product transfusions was lower in the bivalirudin treatment group (Table 5). The incidence of major bleeding and median total postoperative blood loss volumes were similar.

Table 5: Summary of Bleeding Related Safety Data at Day 7/discharge in the CHOOSE Studies and in Pooled On- and Off-pump Studies in Cardiac Surgery (Safety Population)
Parameter CHOOSE Studies (HIT/TS)1 Pooled Studies (HIT/TS and Non-HIT/TS)1
On-pump Off-pump On-pump Off-pump
Angiomax

N=49
n(%)
Historical
control
N=75
n(%)
Angiomax

N=51
n(%)
Historical
control
N=36
n(%)
Angiomax

N=147
n(%)
Heparin/
protamine
N=121
n(%)
Angiomax

N=152
n(%)
Heparin/
protamine
N=88
n(%)
Incidence of
transfusions
41 (83.7) 69 (92.0) 27 (52.9) 32 (88.9) 98 (66.7) 94 (77.7) 73 (48.0) 61 (69.3)
Patients with major
bleeding events
2 (4.1) 6 (8.0) 2 (3.9) 3 (8.3) 8 (5.4) 6 (5.0) 11 (7.2) 5 (5.7)
Patients with
persistent hemorrhage
requiring repeat
operation
2 (4.1) 4 (5.3) 2 (3.9) 3 (8.3) 8 (5.4) 5 (4.1) 10 (6.6) 5 (5.7)
Median total
postoperative blood
loss (mL) up to 24
hours
N=47 N=62 N=51 N=35 N=143 N=106 N=131 N=75
880.0 797.5 780.0 990.0 815.0 750.0 713.0 750.0

110 historical patients from the CHOOSE studies were administered an anticoagulant other than heparin/protamine and are excluded from this analysis.

Other Adverse Reactions:

ACUITY (UA/NSTEMI)

In 13,819 patients with UA/NSTEMI in the ACUITY study, those treated with ANGIOMAX had similar rates of non-bleeding adverse events compared to the patients who received heparin plus GPI. No individual adverse reaction occurred with a frequency higher than 0.1% in the ANGIOMAX population.

HORIZONS (STEMI undergoing primary PCI)

In the HORIZONS study, 55.1% of all patients receiving ANGIOMAX experienced at least one adverse event and 8.7% experienced an adverse drug reaction. The most frequently reported adverse events were the same in both treatment arms and included hypotension, ventricular tachycardia, chest pain, and bradycardia.

Table 6 summarises the most frequently reported (in >2% of patients in either treatment arm) individual adverse events during the first 30 days of the HORIZONS study, irrespective of relationship to study drug. None of the adverse events were reported by more than 8% of patients in the safety population.

The incidence of stent thrombosis within the first 24 hours was 1.5% in patients receiving ANGIOMAX versus 0.3% in patients receiving unfractionated heparin plus GP IIb/IIIa inhibitor (p=0.0002). Two deaths occurred after acute stent thrombosis, 1 in each arm of the study. The incidence of stent thrombosis between 24 hours and 30 days was 1.2% in patients receiving ANGIOMAX versus 1.9% in patients receiving unfractionated heparin plus GP IIb/IIIa inhibitor (p=0.1481). A total of 17 deaths occurred after subacute stent thrombosis, 3 in the ANGIOMAX arm and 14 in the UFH plus GP IIb/IIIa arm. There was no statistically significant difference in the rates of stent thrombosis between the two arms at 30 days (p=0.3257) and 1 year (p=0.7754).

Table 6: Adverse Events Reported by >2% of Patients in Either Treatment Arm in the HORIZONS study (Safety Population)
Preferred Term Number (%) of patients
ANGIOMAX
(N=1749)
UFH + GP IIb/IIIa
(N=1818)
Total
(N=3567)
Any AE
Hypotension
Ventricularbr tachycardia
Chest pain
Bradycardia
Atrial fibrillation
Haematoma
Ventricular fibrillation
Haemorrhage
Back pain
Headache
Cardiac failure
Nausea
Pyrexia
Haemoglobin decreased
Cardiovascular disorder
Injection site haemorrhage
Reperfusion injury
Anaemia
964 (55.1)
134 (7.7)
109 (6.2)
114 (6.5)
82 (4.7)
67 (3.8)
42 (2.4)
68 (3.9)
38 (2.2)
44 (2.5)
50 (2.9)
56 (3.2)
42 (2.4)
37 (2.1)
39 (2.2)
48 (2.7)
24 (1.4)
40 (2.3)
24 (1.4)
1060 (58.3)
142 (7.8)
122 (6.7)
114 (6.3)
97 (5.3)
87 (4.8)
87 (4.8)
57 (3.1)
75 (4.1)
59 (3.2)
55 (3.0)
48 (2.6)
52 (2.9)
48 (2.6)
50 (2.8)
31 (1.7)
52 (2.9)
28 (1.5)
39 (2.1)
2024 (56.7)
276 (7.7)
228 (6.4)
228 (6.4)
179 (5.0)
154 (4.3)
129 (3.6)
125 (3.5)
113 (3.2)
103 (2.9)
105 (2.9)
104 (2.9)
94 (2.6)
85 (2.4)
89 (2.5)
79 (2.2)
76 (2.1)
68 (1.9)
63 (1.8)
REPLACE-2 (PCI) and BAT (PTCA)

In the REPLACE-2 trial similar non-bleeding adverse events were reported in the two treatment groups as shown below in Table 7:

Table 7: Adverse Events Other than Bleeding Occurring in ≥ 2% of Patients in Either Treatment Group in REPLACE-2
EVENT Treatment Group
ANGIOMAX
(n=2914)
Heparin + GPIIb/IIIa
(n=2987)
Cardiovascular
   Hypotension
   Angina Pectoris
91 (3.1)
155 (5.3)
120 (4.0)
156 (5.2)
Gastrointestinal
   Nausea 86 (3.0)96 (3.2)
Miscellaneous
   Back pain
   Pain
   Chest Pain
   Headache
   Injection site pain
268 (9.2)
98 (3.4)
68 (2.3)
75 (2.6)
80 (2.7)
263 (8.8)
72 (2.4)
69 (2.3)
83 (2.8)
80 (2.7)

All adverse events other than bleeding reported for ≥ 5% of patients in either treatment group in the BAT trial are shown below in Table 8.

Table 8: Adverse Events Other than Bleeding Occurring in ≥ 5% of Patients in Either Treatment Group in BAT Trial
EVENT Treatment Group
ANGIOMAX
(n=2161)
Heparin
(n=2151)
Number of Patients (%)
Cardiovascular
   Hypotension
   Hypertension
   Bradycardia
262 (12)
135 (6)
118 (5)
371(17)
115 (5)
164 (8)
Gastrointestinal
   Nausea
   Vomiting
   Dyspepsia
318 (15)
138(6)
100 (5)
347 (16)
)169 (8)
111 (5)
Genitourinary
   Urinary retention 89 (4) 98 (5)
Miscellaneous
   Back pain
   Pain
   Headache
   Injection site pain
   Insomnia
   Pelvic pain
   Anxiety
   Abdominal pain
   Fever
   Nervousness
916 (42)
330 (15)
264 (12)
174 (8)
142 (7)
130 (6)
127 (6)
103 (5)
103 (5)
102 (5)
944 (44)
358 (17)
225 (10)
274 (13)
139 (6)
169 (8)
140 (7)
104 (5)
108 (5)
87 (4)
CHOOSE and EVOLUTION (Cardiac Surgery)

All adverse events other than bleeding reported for ≥ 5% of patients in either treatment group are shown below in Table 9. Adverse events were not collected for the historical cohort in the CHOOSE studies. Prolongations of activated partial thromboplastin time (aPTT) and prothrombin time (PT) were reported more frequently in the bivalirudin group. This is expected with ANGIOMAX due to absence of a reversal agent, and was reported as an adverse event by a single site. All other differences in adverse event rates that were statistically significant occurred in the heparin/protamine group.

Table 9: Adverse Events Other Than Bleeding Occurring in ≥5% of Patients in Either Treatment Group in
Adverse event Bivalirudin
N = 379
Heparin/protamine1
N = 158
Number of patients with any common adverse event
 Pleural effusion
 Atrial fibrillation
 Atelectasis
 Nausea
 Anaemia NOS
 Hypotension NOS
 Activated partial thromboplastin time
 Pain
 NOS
 Oedema peripheral
 Prothrombin time prolonged
 Pericardial effusion
 Constipation
 Wound secretion
 Oliguria
 Vomiting NOS
 Anxiety
 Hypertension NOS
 Chest pain


256 (67.5)
94 (24.8)
59 (15.6)
49 (12.9)
44 (11.6)
41 (10.8)
34 (9.0)
26 (6.9)
26 (6.9)
26 (6.9)
24 (6.3)
23 (6.1)
21 (5.5)
20 (5.3)
20 (5.3)
18 (4.7)
15 (4.0)
13 (3.4)
12 (3.2)


115 (72.8)
55 (34.8)
28 (17.7)
37 (23.4)
29 (18.4)
15 (9.5)
12 (7.6)
0 (0.0)
23 (14.6)
12 (7.6)
0 (0.0)
12 (7.6)
13 (8.2)
19 (12.0)
12 (7.6)
13 (8.2)
14 (8.9)
8 (5.1)
10 (6.3)

1 Does not include data from the historical cohort of the CHOOSE studies

Less Common Clinical Trial Reactions

Rarely, the following have been reported with ANGIOMAX use, without attribution to cause: thrombocytopenia, urticaria, rash.

Post-Market Adverse Drug Reactions

The following events have been reported: fatal bleeding; hypersensitivity and allergic reactions including very rare reports of anaphylaxis; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes.

Drug interactions

Overview

In clinical trials in patients undergoing PCI, co-administration of ANGIOMAX (bivalirudin) with heparin, warfarin or thrombolytics was associated with increased risk of major bleeding events compared to patients not receiving these concomitant medications.

The safety and effectiveness of ANGIOMAX have not been formally established when used in conjunction with GPIIb/IIIa inhibitors. In two clinical trials, however, it was noted that the apparent bleeding advantage of ANGIOMAX over heparin plus planned GPIIb/IIIa inhibitor (Table 1, 3, 12; see also ADVERSE REACTIONS, Bleeding) was practically nullified when a GPIIb/IIIa inhibitor was added to ANGIOMAX therapy.

No formal drug interaction studies have been carried out with bivalirudin. Clinical studies evaluating pharmacodynamic effects and providing preliminary safety information of various products when used in combination with ANGIOMAX have been carried out, including the adenosine diphosphate antagonist, ticlopidine, and the GPIIb/IIIa inhibitors, abciximab, tirofiban and eptifibatide. Although data are limited, precluding conclusions regarding efficacy and safety in combination with these agents, the results do not suggest interaction between ANGIOMAX and the individual drugs studied in respect of their pharmacodynamic activities. These results are not sufficient to conclude definitively that no interaction exists.

Dosage and administration

Dosing considerations

  • ANGIOMAX should be administered with ASA. Clopidogrel can also be administered.
  • Patients can be started with ANGIOMAX 30 minutes after discontinuation of UFH given intravenously, or 8 hours after discontinuation of LMWH given subcutaneously.

UA/NSTEMI

In patients presenting with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI), the recommended dose of ANGIOMAX is an initial intravenous bolus of 0.1 mg/kg bivalirudin followed by an infusion of 0.25 mg/kg/h prior to angiography and continued through angiography and as long as needed. The dose should be administered before assignment to a procedure (PCI, CABG, or drug therapy management).

Patients who are to be medically managed may continue the infusion of 0.25 mg/kg/h for up to 72 hours. No dosage adjustment is needed for these patients.

If the patient proceeds to PCI, an additional bolus of 0.5 mg/kg should be administered and the infusion increased to 1.75 mg/kg/h for the duration of the procedure. Following PCI, the reduced infusion dose of 0.25 mg/kg/h may be resumed for 4 to 12 hours as clinically necessary.

For patients who proceed to CABG surgery off-pump, the i.v. infusion of ANGIOMAX should be continued until the time of surgery. Just prior to surgery, a 0.5 mg/kg bolus dose should be administered followed by a 1.75 mg/kg/h infusion for the duration of the surgery.

For patients who proceed to CABG surgery on-pump, the i.v. infusion of ANGIOMAX should be continued until 1 hour prior to surgery after which the infusion should be discontinued and the patient treated with unfractionated heparin.

PCI , including Primary PCI

The recommended dosage of ANGIOMAX is an i.v. bolus of 0.75 mg/kg. This should be followed by an infusion of 1.75 mg/kg/hr for the duration of the PCI procedure (see also Table 10). Five (5) minutes after the bolus dose has been administered, an ACT (Activated Clotting Time) should be performed and an additional bolus of 0.3 mg/kg should be given if needed. GPI administration should be considered in the event that any of the conditions listed in “CLINICAL TRIALS Replace-2” is present.

Continuation of the infusion following PCI for up to 4 hours post-procedure is optional, at the discretion of the treating physician. After cessation of the 1.75 mg/kg/hr infusion, a reduced infusion dose of 0.25 mg/kg/hr may be continued for 4-12 hours as clinically necessary.

ANGIOMAX is intended for use with aspirin (300 – 325 mg daily) and has only been studied in patients receiving concomitant aspirin.

In STEMI patients undergoing primary PCI, standard pre-PCI adjunctive therapy should include clopidogrel and may include the early administration of UFH (see CLINICAL TRIALS HORIZONS).

Patients should be carefully monitored following PCI for signs and symptoms consistent with myocardial ischemia.

CARDIAC SURGERY (see also Table 10)

On-pump Cardiac Surgery

The recommended dosage of ANGIOMAX is an i.v. bolus of 1.0 mg/kg immediately followed by a 2.5 mg/kg/hr i.v. infusion. ANGIOMAX infusion may be terminated approximately 15 minutes prior to the anticipated end of cardiopulmonary bypass (CPB). The ACT may be used to check that the patient is anticoagulated following administration of ANGIOMAX. Infusion dose adjustment should not be necessary. For patients in whom hemofiltration is required during bypass, periodic ACT monitoring may be used (see Dosing Pre- and Post-Cardiac Surgery,Medical Management for Cardiac Surgery). If CPB is not terminated within 20 minutes or in patients who need to go back on bypass, a bivalirudin i.v. bolus of 0.5 mg/kg should be administered and a 2.5 mg/kg/hr i.v. infusion restarted and continued until 15 minutes prior to the anticipated end of CPB (see DOSAGE AND ADMINISTRATION, Dosing Pre- and Post- Cardiac Surgery, Medical Management for Cardiac Surgery for dosing of the CPB pump with ANGIOMAX).

Off-pump Cardiac Surgery

The recommended dosage of ANGIOMAX is an i.v. bolus of 0.75 mg/kg immediately followed by a 1.75 mg/kg/hr i.v. infusion for the duration of the procedure. The ACT may be used to check that the patient is anticoagulated following administration of ANGIOMAX. In clinical trials, investigators had the option to administer additional boluses of 0.1-0.5 mg/kg or make adjustments to the infusion rate in 0.25 mg/kg/hr increments if a higher level of anticoagulation was desired. The data suggest that infusion dose adjustments should not be necessary.

For patients who may need to go on-pump, an additional ANGIOMAX i.v. bolus dose of 0.25 mg/kg should be administered to the systemic circulation and the infusion rate should be increased to 2.5 mg/kg/hr. In addition, see Dosing Pre- and Post-Cardiac Surgery, Medical Management for Cardiac Surgery for dosing of the pump.

Dosing Pre- and Post-cardiac Surgery

ANGIOMAX may be used for anticoagulation up to 48 hours prior to surgery or in the postoperative phase up to 14 days after the procedure. An ANGIOMAX i.v. bolus of 0.1 mg/kg followed by an i.v. infusion of 0.2 mg/kg/hr may be administered, with aPTT monitoring to attain the clinically desired range of 1.5-2.5 times the baseline value.

Medical Management Guidelines for Cardiac Surgery:
CPB

Use of ANGIOMAX for anticoagulation during CPB requires little modification to the conventional bypass circuit setup. Before initiation of CPB, a bolus dose of 50 mg ANGIOMAX should be added to the circuit regardless of patient weight or volume of the prime. Either an open system or a closed system may be used for venous drainage. A closed system with venous reservoir bags generally has better flow characteristics with more internal mixing than a hardshell open venous reservoir. After completion of CPB, once it is clear that return to bypass support will not be needed, processing of the remaining circuit volume with a cell saver prior to a readministration to the patient is recommended. Provision to allow recirculation of the circuit following termination from CPB may be provided by administration of 50 mg of ANGIOMAX to the circuit followed by a continuous infusion of 50 mg/hr.

Cardioplegia

Crystalloid or blood-based cardioplegia may be used. If blood-based cardioplegia is used, blood should be obtained directly from the circuit and, after mixing with cardioplegia solution, should be immediately infused into the coronary system. If there are non-circulating portions of line between the pump and the patient, these lines should be flushed prior to cardioplegia administration. The cardioplegia setup can be circulated continuously by use of a connector. The volume of the cardioplegia circuit is typically 250 mL; for this volume, a continuous infusion of ANGIOMAX of 6.25 mg/hr will maintain anticoagulation within the circuit.

Hemofiltration

It is recommended that the ACT be measured frequently during hemofiltration to ensure the adequacy of anticoagulation.

Cell Saver

If a cell saver is used, an anticoagulant is necessary. A citrate-based solution (citrate phosphate dextrose [CPD], acid citrate dextrose [ACD], sodium citrate) is recommended.

DOSAGE ADJUSTMENT FOR PATIENTS WITH RENAL IMPAIRMENT

No reduction in the bolus dose of ANGIOMAX is needed regardless of the patient’s baseline renal function.

No infusion dose adjustment is required for patients with mild or moderate renal impairment undergoing either PCI or cardiac surgery. In PCI patients, reduction of the infusion rate to 1.0 mg/kg/hr should be considered if the creatinine clearance is less than 30 mL/min. If a PCI patient is dependent on hemodialysis, the infusion rate should be reduced to 0.25 mg/kg/hr. Patients with creatinine clearance below 30 mL/min have not been studied in cardiac surgery. See “ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics” for details regarding bivalirudin pharmacokinetics in patients with renal impairment.

In patients with renal impairment, the ACT should be monitored with any dose alterations. ACT should be checked at 5 and 45 minutes. If the ACT is ≤ 250 seconds for renally-impaired patients, administer a second bolus (0.3 mg/kg) and double the infusion rate to maintain the ACT at approximately 350 seconds. If the ACT is 250-300 seconds in renally-impaired patients, re- bolus (0.3 mg/kg) to maintain the ACT approximately 350 seconds. ANGIOMAX is hemodialysable (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

USE SUBSEQUENT TO UNFRACTIONATED HEPARIN (UFH) OR LOW MOLECULAR WEIGHT HEPARIN (LMWH)

Patients can be started with ANGIOMAX 30 minutes after discontinuation of UFH given intravenously, or 8 hours after discontinuation of LMWH given subcutaneously.

ADMINISTRATION

ANGIOMAX is intended for i.v. injection and infusion after dilution (see Reconstitution). The dose to be administered is adjusted according to the patient's weight (see Table 10).

Table 10: ANGIOMAX Weight Based Dosing Table for Patients undergoing PCI or Cardiac Surgery*
Using 5 mg/mL Concentration Using 0.5 mg/mL
Concentration
PCI and Off-Pump Cardiac Surgery On-Pump Cardiac Surgery

Weight  
(kg)
Bolus
(0.75 mg/kg)
(mL)
Infusion
(1.75 mg/kg/hr)
(mL/hr)
Bolus
(1 mg/kg)
(mL)
Infusion
(2.5 mg/kg/hr)
(mL/hr)
Subsequent
Low-Rate Infusion
(0.2 mg/kg/hr)
(mL/hr)
33-37 512718 14
38-4261482016
43-4771692318
48-527.517.5102520
53-57819112822
58-62921123024
63-671023133326
68-7210.524.5143528
73-771126153830
78-821228164032
83-871330174334
88-9213.531.5184536
93-971433194838
98-1021535205040
103-1071637215342
108-11216.538.5225544
113-1171740235846
118-1221842246048
123-1271944256350
128-13219.545.5266552
133-1372047276854
138-1422149287056
143-1472251297358
148-15222.552.5307560
153-1572354317862
158-1622456328064
163-1672558338366
168-17225.559.5348568
173-1772661358870
178-1822763369072
183-1872865379374
188-19228.566.5389576
193-1972968399878
198-20230704010080
203-20731724110382
208-21231.573.54210584
213-21732754310886
218-22233774411088
223-22734794511390

*If patients have undergone treatment with ANGIOMAX for ACS prior to PCI and/or CABG, see above for dosing recommendations.

ANGIOMAX should be administered via an intravenous line. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. The following nine drugs should not be administered in the same intravenous line with ANGIOMAX, since they resulted in haze formation, microparticulate formation, or gross precipitation when mixed with ANGIOMAX: alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase, and vancomycin HCl.

The following six drugs show dose-concentration physical incompatibilities with bivalirudin (i.e. gross precipitation, turbidity changes visible in normal diffuse room light with the unaided eye, increases in measured turbidity, and microprecipitation) during Y-site coadministration at room temperature (23oC): Dobutamine HCl, Famotidine, Haloperidol lactate, Labetalol HCl, Lorazepam, Promethazine HCl. Therefore, the administration of these medicinal products in the same intravenous line as bivalirudin is not recommended.

As with all parenteral drug products, i.v. mixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

RECONSTITUTION

ANGIOMAX is to be reconstituted with Water for Injection, USP as summarized below.

Vial Size Volume of Diluent to be
Added to Vial
Approximate
Available Volume
Nominal Concentration per mL
250 mg5 mL5.5 mL50 mg/mL

To each 250 mg vial add 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 50 mL of 5% Dextrose in Water or 0.9% Sodium Chloride for Injection to yield a final concentration of 5 mg/mL (e.g., 1 vial in 50 mL; 2 vials in 100 mL; 5 vials in 250 mL). The dose to be administered is adjusted according to the patient’s weight, see Table 10.

If the low-rate infusion is to be used after the initial infusion, a lower concentration bag should be prepared. In order to prepare this bag, reconstitute the 250 mg vial with 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 500 mL of 5% Dextrose in Water or 0.9% Sodium Chloride for Injection to yield a final concentration of 0.5 mg/mL. The infusion rate to be administered should be selected from the right-hand column in Table 10.

Do not freeze reconstituted or diluted ANGIOMAX. Reconstituted material may be stored at 2-8oC for up to 24 hours. Diluted ANGIOMAX with a concentration of between 0.5 mg/mL and 5 mg/mL is stable at room temperature for up to 24 hours.

Overdosage

Bleeding has been reported in some cases of overdose with single bolus doses of ANGIOMAX (bivalirudin) up to 7.5 mg/kg. Discontinuation of ANGIOMAX leads to a gradual reduction in anticoagulant effects due to metabolism of the drug. There has been no experience of overdosage in human clinical trials. In case of overdosage, ANGIOMAX should be discontinued and the patient should be closely monitored for signs of bleeding. Supportive therapy should be instituted, as necessary. There is no known antidote to ANGIOMAX. ANGIOMAX is hemodialysable (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and clinical pharmacology

Mechanism of action

ANGIOMAX (bivalirudin) is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic peptide composed of twenty amino acids. ANGIOMAX directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, which allows fibrin to develop a covalently cross-linked framework, thus stabilising formed thrombus. Thrombin also activates Factors V and VIII, promoting further thrombin generation; and activates platelets, stimulating aggregation and granule release. The binding of ANGIOMAX to thrombin is reversible as thrombin slowly cleaves the bivalirudin- Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.

In in vitro studies, bivalirudin inhibited both soluble (free) and clot-bound thrombin, and was not neutralized by products of the platelet release reaction. The clinical relevance of these findings is unknown. It also prolonged the aPTT, thrombin time (TT), and PT of normal human plasma in a concentration-dependent manner.

Pharmacodynamics

In healthy volunteers and patients undergoing routine angioplasty, bivalirudin exhibits linear dose-dependent and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of ANGIOMAX produces a prompt anticoagulant effect. Coagulation times return to the normal range approximately 1-2 hours following cessation of ANGIOMAX administration in patients with normal renal function.

In 291 patients undergoing routine angioplasty, a positive correlation was observed between the dose of ANGIOMAX and the proportion of patients achieving ACT values of 300 or 350 seconds. In the subset of patients receiving ANGIOMAX at a dose of 1.0 mg/kg i.v. bolus plus 2.5 mg/kg/hr i.v. infusion for 4 hours, then followed by 0.2 mg/kg/hr, all patients reached maximal ACT values > 300 seconds.

The correlation of various clotting tests with bivalirudin plasma concentration was studied in patients undergoing cardiac surgery. The data confirmed that, as during PCI, the activated clotting times were prolonged in a concentration-dependent manner during cardiac surgery.

Pharmacokinetics

Absorption

Bivalirudin exhibits linear pharmacokinetics following i.v. administration to patients undergoing PTCA. In these patients, a mean steady state bivalirudin concentration of 12.3 ± 1.7 μg/mL is achieved after administration of an i.v. bolus of 1 mg/kg followed by a 2.5 mg/kg/hr i.v. infusion given for 4 hours.

Distribution

Bivalirudin does not bind to plasma proteins other than thrombin, or to red blood cells.

Excretion

Bivalirudin is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage, with a half-life in patients with normal renal function of about 25 minutes. Bivalirudin is hemodialysable, with approximately 25% cleared by hemodialysis.

Special Populations and Conditions

Renal Insufficiency

The disposition of bivalirudin was also studied in PTCA patients with mild and moderate renal impairment and in patients with severe renal impairment. Drug elimination was related to glomerular filtration rate (GFR), see Table 11.

Table 11: Pharmacokinetics in Patients with Renal Impairment*
Renal Function (GFR, mL/min) Clearance (mL/min/kg) Half-life (minutes)
Normal renal function
(≥90 mL/min)
3.4
25
Mild renal impairment
(60-89 mL/min)
3.4
22
Moderate renal impairment
(30-59 mL/min)
2.734
Severe renal impairment
(10-29 mL/min)
2.857
Dialysis-dependent patients
(off dialysis)
1.03.5 hours

* The ACT should be monitored in renally-impaired patients.

For patients with renal impairment, the ACT should be monitored. In patients with renal impairment, the initial bolus dose should not be adjusted, however a reduction of the infusion dose to be administered may be required (see DOSAGE AND ADMINISTRATION, Dosage Adjustments for Patients with Renal Impairment).

Cardiac Surgery

In a population of patients undergoing cardiac surgery utilizing CPB with normal renal function or mild/moderate renal dysfunction at baseline, the mean plasma bivalirudin concentration 5 minutes after administration of an i.v. bolus dose of 1.0 mg/kg followed by a 2.5 mg/kg/hr i.v. infusion was 13.3 ± 2.4 μg/mL. Bivalirudin levels were maintained at or above this concentration for the duration of infusion. Bivalirudin was eliminated with a clearance of 198 mL/min (2.34 mL/min/kg). Following termination of infusion, plasma bivalirudin concentrations declined biexponentially with an initial half-life of 27 minutes and a terminal half-life of 77 minutes. Temperature had no detectable effect on bivalirudin clearance. The clearance of bivalirudin was reduced by 20-30% in patients with mild or moderate renal impairment. The pharmacokinetics of bivalirudin in off-pump cardiac surgery patients was similar to that in on-pump surgery patients.

Storage and stability

ANGIOMAX dosage units are to be shipped and stored at controlled room temperature (15- 25oC). Do not freeze. Discard any unused portion of reconstituted solution remaining in the vial.

Do not freeze reconstituted or diluted ANGIOMAX. Reconstituted material may be stored at 2-8oC for up to 24 hours. Diluted ANGIOMAX with a concentration of between 0.5 mg/mL and 5 mg/mL is stable at room temperature for up to 24 hours.

Dosage forms, composition and packaging

ANGIOMAX (bivalirudin) is supplied as a sterile, lyophilized product in single-use, glass vials. Each vial of ANGIOMAX injection contains 250 mg of bivalirudin. Reconstitution of ANGIOMAX with 5 mL Water for Injection, USP yields a solution of pH 5.0-6.0 with the following composition: bivalirudin, 50 mg/mL; mannitol, 25 mg/mL; bound trifluoroacetate, 4-6 mg/mL; and sodium hydroxide to adjust pH to 5.0-6.0. Reconstituted material will be a clear to slightly opalescent, colourless to slightly yellow solution. Discard any unused portion of reconstituted solution remaining in the vial.