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Argatroban Injection, USP Adverse Reactions

6 ADVERSE REACTIONS

The following adverse reaction is also discussed in other sections of the labeling:

6.1 Clinical Trials Experience

Adverse Events in Patients with HIT (With or Without Thrombosis)

Because clinical trials are conducted under widely varying conditions, adverse event 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 following safety information is based on all 568 patients treated with argatroban in Study 1 and Study 2. The safety profile of the patients from these studies is compared with that of 193 historical controls in which the adverse events were collected retrospectively. Adverse events are separated into hemorrhagic and non-hemorrhagic events.

Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥2 g/dL, that led to a transfusion of ≥2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. Minor bleeding was overt bleeding that did not meet the criteria for major bleeding.

Table 4 gives an overview of the most frequently observed hemorrhagic events, presented separately by major and minor bleeding, sorted by decreasing occurrence among argatroban-treated patients with HIT (with or without thrombosis).

Table 4 Major and Minor Hemorrhagic Adverse Events in Patients With HIT*
*with or without thrombosis
a)   Patients may have experienced more than 1 adverse event.
b)   One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation.
c)   The historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel.
DIC = disseminated intravascular coagulation.
BKA = below-the-knee amputation.

Major Hemorrhagic Eventsa

 

Argatroban-Treated
Patients (Study 1 and
Study 2)
(n = 568)

%

Historical Controlc
(n = 193)

%

Overall bleeding

5.3

6.7

Gastrointestinal

2.3

1.6

Genitourinary and hematuria

0.9

0.5

Decrease in hemoglobin and hematocrit

0.7

0

Multisystem hemorrhage and DIC

0.5

1

Limb and BKA stump

0.5

0

Intracranial hemorrhage

0b

0.5

Minor Hemorrhagic Eventsa

 

Argatroban-Treated
Patients (Study 1 and
Study 2)
(n = 568)

%

Historical Controlc
(n = 193)

%

Gastrointestinal

14.4

18.1

Genitourinary and hematuria

11.6

0.8

Decrease in hemoglobin and hematocrit

10.4

0

Groin

5.4

3.1

Hemoptysis

2.9

0.8

Brachial

2.4

0.8

Table 5 gives an overview of the most frequently observed non-hemorrhagic events sorted by decreasing frequency of occurrence (≥2%) among argatroban-treated HIT/HITTS patients.

Table 5 Non-hemorrhagic Adverse Events in Patientsa With HITb
a)   Patients may have experienced more than 1 adverse event.
b)   with or without thrombosis
c)   The historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel.

 

Argatroban-Treated
Patients
(Study 1 and Study 2)
(n = 568)

%

Historical
Controlc (n = 193)

%

Dyspnea

8.1

8.8

Hypotension

7.2

2.6

Fever

6.9

2.1

Diarrhea

6.2

1.6

Sepsis

6

12.4

Cardiac arrest

5.8

3.1

Nausea

4.8

0.5

Ventricular tachycardia

4.8

3.1

Pain

4.6

3.1

Urinary tract infection

4.6

5.2

Vomiting

4.2

0

Infection

3.7

3.6

Pneumonia

3.3

9.3

Atrial fibrillation

3

11.4

Coughing

2.8

1.6

Abnormal renal function

2.8

4.7

Abdominal pain

2.6

1.6

Cerebrovascular disorder

2.3

4.1

Adverse Events in Patients with or at Risk for HIT Undergoing PCI

The following safety information is based on 91 patients initially treated with argatroban and 21 patients subsequently re-exposed to argatroban for a total of 112 PCIs with argatroban anticoagulation. Adverse events are separated into hemorrhagic (Table 6) and non-hemorrhagic (Table 7) events.

Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥5 g/dL, that led to a transfusion of  ≥2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint.

The rate of major bleeding events in patients treated with argatroban in the PCI trials was 1.8%.

Table 6 Major and Minor Hemorrhagic Adverse Events in Patients With HIT Undergoing PCI
a)   Patients may have experienced more than 1 adverse event.
b)   91 patients who underwent 112 interventions.
CABG = coronary artery bypass graft.

Major Hemorrhagic Eventsa

Argatroban-Treated Patients
(n = 12)b

Retroperitoneal

0.9

Gastrointestinal

0.9

Intracranial

0

Minor Hemorrhagic Eventsa

Argatroban-Treated Patients
(n = 12)b
%

Groin (bleeding or hematoma)

3.6

Gastrointestinal (includes hematemesis)

2.6

Genitourinary (includes hematuria)

1.8

Decrease in hemoglobin and/or hematocrit

1.8

CABG (coronary arteries)

1.8

Access site

0.9

Hemoptysis

0.9

Other

0.9

Table 7 gives an overview of the most frequently observed non-hemorrhagic events (>2%), sorted by decreasing frequency of occurrence among argatroban-treated PCI patients.

Table 7 Non-hemorrhagic Adverse Eventsa in Patients With HIT Undergoing PCI
a)   Patients may have experienced more than 1 adverse event.
b)   91 patients who underwent 112 interventions.

 

Argatroban
Proceduresa (n = 112)b
%

Chest pain

15.2

Hypotension

10.7

Back pain

8

Nausea

7.1

Vomiting

6.3

Headache

5.4

Bradycardia

4.5

Abdominal pain

3.6

Fever

3.6

Myocardial infarction

3.6

There were 22 serious adverse events in 17 PCI patients (19.6% in 112 interventions). Table 8 lists the serious adverse events occurring in argatroban-treated patients with or at risk for HIT undergoing PCI.

Table 8 Serious Adverse Events in Patients With HIT Undergoing PCIa
a)   Individual events may also have been reported elsewhere (see Table 6 and 7).
b)   91 patients underwent 112 procedures. Some patients may have experienced more than 1 event.

Coded Term

Argatroban Proceduresb
(n = 112)

Myocardial infarction

4 (3.5%)

Angina pectoris

2 (1.8%)

Coronary thrombosis

2 (1.8%)

Myocardial ischemia

2 (1.8%)

Occlusion coronary

2 (1.8%)

Chest pain

1 (0.9%)

Fever

1 (0.9%)

Retroperitoneal hemorrhage

1 (0.9%)

Aortic stenosis

1 (0.9%)

Arterial thrombosis

1 (0.9%)

Gastrointestinal hemorrhage

1 (0.9%)

Gastrointestinal disorder (GERD)

1 (0.9%)

Cerebrovascular disorder

1 (0.9%)

Lung edema

1 (0.9%)

Vascular disorder

1 (0.9%)

Intracranial Bleeding in Other Populations

Increased risks for intracranial bleeding have been observed in investigational studies of argatroban for other uses. In a study of patients with acute myocardial infarction receiving both argatroban and thrombolytic therapy (streptokinase or tissue plasminogen activator), the overall frequency of intracranial bleeding was 1% (8 out of 810 patients). Intracranial bleeding was not observed in 317 subjects or patients who did not receive concomitant thrombolysis [see Drug Interactions (7.4)].

The safety and effectiveness of argatroban for cardiac indications other than PCI in patients with HIT have not been established. Intracranial bleeding was also observed in a prospective, placebo-controlled study of argatroban in patients who had onset of acute stroke within 12 hours of study entry. Symptomatic intracranial hemorrhage was reported in 5 of 117 patients (4.3%) who received argatroban at 1 to 3 mcg/kg/min and in none of the 54 patients who received placebo. Asymptomatic intracranial hemorrhage occurred in 5 (4.3%) and 2 (3.7%) of the patients, respectively.

Allergic Reactions

One hundred fifty-six allergic reactions or suspected allergic reactions were observed in 1,127 individuals who were treated with argatroban in clinical pharmacology studies or for various clinical indications. About 95% (148/156) of these reactions occurred in patients who concomitantly received thrombolytic therapy (e.g., streptokinase) or contrast media.

Allergic reactions or suspected allergic reactions in populations other than patients with HIT (with or without thrombosis) include (in descending order of frequency):

Airway reactions (coughing, dyspnea): 10% or more
Skin reactions (rash, bullous eruption): 1 to <10%
General reactions (vasodilation): 1 to 10%

Limited data are available on the potential formation of drug-related antibodies. Plasma from 12 healthy volunteers treated with argatroban over 6 days showed no evidence of neutralizing antibodies. No loss of anticoagulant activity was noted with repeated administration of argatroban to more than 40 patients.

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