Adverse Events Reported in HIT/HITTS Patients: 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. The adverse events reported in this section include all events regardless of relationship to treatment. 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 3 gives an overview of the most frequently observed hemorrhagic events, presented separately by major and minor bleeding, sorted by decreasing occurrence among Argatroban-treated HIT/HITTS patients.

Table 3. Major and Minor Hemorrhagic Adverse Events in HIT/HITTS Patients

Table 4 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 4. Non-hemorrhagic Adverse Events in HIT/HITTS Patients*

Adverse Events Reported in HIT/HITTS Patients Undergoing PCI: The following safety information is based on 91 patients initially treated with Argatroban and 21 patients subsequently reexposed to Argatroban for a total of 112 PCIs with Argatroban anticoagulation. The adverse events reported in this section include all events regardless of relationship to treatment. Adverse events are separated into hemorrhagic (Table 5) and non-hemorrhagic (Table 6) 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 and intracranial hemorrhage in the PCI trials was 1.8% and in the placebo arm of the EPILOG trial (placebo plus standard dose, weight-adjusted heparin) was 3.1%.

Table 5. Major and Minor Hemorrhagic Adverse Events in HIT/HITTS Patients Undergoing PCI

Table 6 gives an overview of the most frequently observed non-hemorrhagic events ( > 2%), sorted by decreasing frequency of occurrence among Argatroban-treated PCI patients.

Table 6. Non-hemorrhagic Adverse Events^* in HIT/HITTS Patients Undergoing PCI

There were 22 serious adverse events in 17 PCI patients (19.6% in 112 interventions). The types of events, which are listed regardless of relationship to treatment, are shown in Table 7. Table 7 lists the serious adverse events occurring in Argatroban-treated HIT/HITTS patients undergoing PCI.

Table 7. Serious Adverse Events in HIT/HITTS Patients Undergoing PCI*

Adverse Events Reported in Other Populations: Intracranial Bleeding: The overall frequency of intracranial bleeding among patients with acute myocardial infarction receiving both Argatroban and thrombolytic therapy (streptokinase or tissue plasminogen activator) was 1% (8 out of 810 patients). Intracranial bleeding was not observed in 317 subjects or patients who did not receive concomitant thrombolysis (see PRECAUTIONS: DRUG INTERACTIONS.

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 1.0 to 3.0 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: 156 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) for acute myocardial infarction and/or contrast media for coronary angiography.

Allergic reactions or suspected allergic reactions in populations other than HIT/HITTS patients 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%

* The CIOMS (Council for International Organization of Medical Sciences) III standard categories are used for classification of frequencies.

Heparin: Since heparin is contraindicated in patients with heparin-induced thrombocytopenia, the co-administration of Argatroban and heparin is unlikely for this indication. However, if Argatroban is to be initiated after cessation of heparin therapy, allow sufficient time for heparin's effect on the aPTT to decrease prior to initiation of Argatroban therapy.

Aspirin/Acetaminophen: Pharmacokinetic or pharmacodynamic drug-drug interactions have not been demonstrated between Argatroban and concomitantly administered aspirin (162.5 mg orally given 26 and 2 hours prior to initiation of Argatroban 1 mcg/kg/min over 4 hours) or acetaminophen (1,000 mg orally given 12, 6, and 0 hours prior to, and 6 and 12 hours subsequent to, initiation of Argatroban 1.5 mcg/kg/min over 18 hours).

Oral Anticoagulant Agents: Pharmacokinetic drug-drug interactions between Argatroban and warfarin (7.5 mg single oral dose) have not been demonstrated. However, the concomitant use of Argatroban and warfarin (5 to 7.5 mg initial oral dose, followed by 2.5 to 6 mg/day orally for 6 to 10 days) results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR) (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Thrombolytic Agents: The safety and effectiveness of Argatroban with thrombolytic agents have not been established (see ADVERSE REACTIONS, Intracranial Bleeding).

Glycoprotein IIb/IIIa Antagonists: The safety and effectiveness of Argatroban with glycoprotein IIb/IIIa antagonists have not been established.

Co-Administration: Concomitant use of Argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding (see WARNINGS). Drug-drug interactions have not been observed between Argatroban and digoxin or erythromycin (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).

Bookmark this page: